Neonatal mucosal immunology.

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Torow, N; Marsland, B J; Hornef, M W; Gollwitzer, E S

2017-01-01

Although largely deprived from exogenous stimuli in utero, the mucosal barriers of the neonate after birth are bombarded by environmental, nutritional, and microbial exposures. The microbiome is established concurrently with the developing immune system. The nature and timing of discrete interactions between these two factors underpins the long-term immune characteristics of these organs, and can set an individual on a trajectory towards or away from disease. Microbial exposures in the gastrointestinal and respiratory tracts are some of the key determinants of the overall immune tone at these mucosal barriers and represent a leading target for future intervention strategies. In this review, we discuss immune maturation in the gut and lung and how microbes have a central role in this process.

Gut Microbiota-brain Axis

Institute of Scientific and Technical Information of China (English)

Hong-Xing Wang; Yu-Ping Wang

2016-01-01

Objective:To systematically review the updated information about the gut microbiota-brain axis.Data Sources:All articles about gut microbiota-brain axis published up to July 18,2016,were identified through a literature search on PubMed,ScienceDirect,and Web of Science,with the keywords of"gut microbiota","gut-brain axis",and "neuroscience".Study Selection:All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed,with no limitation of study design.Results:It is well-recognized that gut microbiota affects the brain's physiological,behavioral,and cognitive functions although its precise mechanism has not yet been fully understood.Gut microbiota-brain axis may include gut microbiota and their metabolic products,enteric nervous system,sympathetic and parasympathetic branches within the autonomic nervous system,neural-immune system,neuroendocrine system,and central nervous system.Moreover,there may be five communication routes between gut microbiota and brain,including the gut-brain's neural network,neuroendocrine-hypothalamic-pituitary-adrenal axis,gut immune system,some neurotransmitters and neural regulators synthesized by gut bacteria,and barrier paths including intestinal mucosal barrier and blood-brain barrier.The microbiome is used to define the composition and functional characteristics of gut microbiota,and metagenomics is an appropriate technique to characterize gut microbiota.Conclusions:Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain,which may provide a new way to protect the brain in the near future.

Mucosal innate immune cells regulate both gut homeostasis and intestinal inflammation.

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Kurashima, Yosuke; Goto, Yoshiyuki; Kiyono, Hiroshi

2013-12-01

Continuous exposure of intestinal mucosal surfaces to diverse microorganisms and their metabolites reflects the biological necessity for a multifaceted, integrated epithelial and immune cell-mediated regulatory system. The development and function of the host cells responsible for the barrier function of the intestinal surface (e.g., M cells, Paneth cells, goblet cells, and columnar epithelial cells) are strictly regulated through both positive and negative stimulation by the luminal microbiota. Stimulation by damage-associated molecular patterns and commensal bacteria-derived microbe-associated molecular patterns provokes the assembly of inflammasomes, which are involved in maintaining the integrity of the intestinal epithelium. Mucosal immune cells located beneath the epithelium play critical roles in regulating both the mucosal barrier and the relative composition of the luminal microbiota. Innate lymphoid cells and mast cells, in particular, orchestrate the mucosal regulatory system to create a mutually beneficial environment for both the host and the microbiota. Disruption of mucosal homeostasis causes intestinal inflammation such as that seen in inflammatory bowel disease. Here, we review the recent research on the biological interplay among the luminal microbiota, epithelial cells, and mucosal innate immune cells in both healthy and pathological conditions. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Influence of functional food components on gut health.

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Wan, Murphy L Y; Ling, K H; El-Nezami, Hani; Wang, M F

2018-01-30

Intestinal epithelial cells (IECs) lining the gastrointestinal tract establish a barrier between external environments and the internal milieu. An intact intestinal barrier maintains gut health and overall good health of the body by preventing from tissue injury, pathogen infection and disease development. When the intestinal barrier function is compromised, bacterial translocation can occur. Our gut microbiota also plays a fundamentally important role in health, for example, by maintaining intestinal barrier integrity, metabolism and modulating the immune system, etc. Any disruption of gut microbiota composition (also termed dysbiosis) can lead to various pathological conditions. In short, intestinal barrier and gut microbiota are two crucial factors affecting gut health. The gastrointestinal tract is a complex environment exposed to many dietary components and commensal bacteria. Dietary components are increasingly recognized to play various beneficial roles beyond basic nutrition, resulting in the development of the functional food concepts. Various dietary modifiers, including the consumption of live bacteria (probiotics) and ingestible food constituents such as prebiotics, as well as polyphenols or synbiotics (combinations of probiotics and prebiotics) are the most well characterized dietary bioactive compounds and have been demonstrated to beneficially impact the gut health and the overall well-being of the host. In this review we depict the roles of intestinal epithelium and gut microbiota in mucosal defence responses and the influence of certain functional food components on the modulation of gut health, with a particular focus on probiotics, prebiotics and polyphenols.

Manipulation of the gut microbiota in C57BL/6 mice changes glucose tolerancewithout affecting weight development and gut mucosal immunity

DEFF Research Database (Denmark)

Bech-Nielsen, Gunilla Veslemöy; Hansen, Camilla Hartmann Friis; Hufeldt, Majbritt Ravn

2012-01-01

Inflammatory diseases such as type 2 diabetes (T2D) in humans and mice are under the influence of the composition of the gut microbiota (GM). It was previously demonstrated that treating Lepob mice with antibiotics improved glucose tolerance. However, wild type C57BL/6J mice may also exhibit plasma...... glucose tolerance without significantly affecting the weight or the number of gut mucosal regulatory T cells, tolerogenic dendritic cells or T helper cells type 1. 16S rRNA gene based denaturing gradient gel electrophoresis profiles clearly clustered according to treatment and showed that antibiotic...

The "Gut Feeling": Breaking Down the Role of Gut Microbiome in Multiple Sclerosis.

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Freedman, Samantha N; Shahi, Shailesh K; Mangalam, Ashutosh K

2018-01-01

Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system with unknown etiology. Recently, the gut microbiota has emerged as a potential factor in the development of MS, with a number of studies having shown that patients with MS exhibit gut dysbiosis. The gut microbiota helps the host remain healthy by regulating various functions, including food metabolism, energy homeostasis, maintenance of the intestinal barrier, inhibition of colonization by pathogenic organisms, and shaping of both mucosal and systemic immune responses. Alteration of the gut microbiota, and subsequent changes in its metabolic network that perturb this homeostasis, may lead to intestinal and systemic disorders such as MS. Here we discuss the findings of recent MS microbiome studies and potential mechanisms through which gut microbiota can predispose to, or protect against, MS. These findings highlight the need of an improved understanding of the interactions between the microbiota and host for developing therapies based on gut commensals with which to treat MS.

Extracorporeal membrane oxygenation causes loss of intestinal epithelial barrier in the newborn piglet.

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Kurundkar, Ashish R; Killingsworth, Cheryl R; McIlwain, R Britt; Timpa, Joseph G; Hartman, Yolanda E; He, Dongning; Karnatak, Rajendra K; Neel, Mary L; Clancy, John P; Anantharamaiah, G M; Maheshwari, Akhil

2010-08-01

Extracorporeal membrane oxygenation (ECMO) is an important life-support system used in neonates and young children with intractable cardiorespiratory failure. In this study, we used our porcine neonatal model of venoarterial ECMO to investigate whether ECMO causes gut barrier dysfunction. We subjected 3-wk-old previously healthy piglets to venoarterial ECMO for up to 8 h and evaluated gut mucosal permeability, bacterial translocation, plasma levels of bacterial products, and ultrastructural changes in gut epithelium. We also measured plasma lipopolysaccharide (LPS) levels in a small cohort of human neonates receiving ECMO. In our porcine model, ECMO caused a rapid increase in gut mucosal permeability within the first 2 h of treatment, leading to a 6- to 10-fold rise in circulating bacterial products. These changes in barrier function were associated with cytoskeletal condensation in epithelial cells, which was explained by phosphorylation of a myosin II regulatory light chain. In support of these findings, we also detected elevated plasma LPS levels in human neonates receiving ECMO, indicating a similar loss of gut barrier function in these infants. On the basis of these data, we conclude that ECMO is an independent cause of gut barrier dysfunction and bacterial translocation may be an important contributor to ECMO-related inflammation.

Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation

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Tailford, Louise E.; Owen, C. David; Walshaw, John; Crost, Emmanuelle H.; Hardy-Goddard, Jemma; Le Gall, Gwenaelle; de Vos, Willem M.; Taylor, Garry L.; Juge, Nathalie

2015-07-01

The gastrointestinal mucus layer is colonized by a dense community of microbes catabolizing dietary and host carbohydrates during their expansion in the gut. Alterations in mucosal carbohydrate availability impact on the composition of microbial species. Ruminococcus gnavus is a commensal anaerobe present in the gastrointestinal tract of >90% of humans and overrepresented in inflammatory bowel diseases (IBD). Using a combination of genomics, enzymology and crystallography, we show that the mucin-degrader R. gnavus ATCC 29149 strain produces an intramolecular trans-sialidase (IT-sialidase) that cleaves off terminal α2-3-linked sialic acid from glycoproteins, releasing 2,7-anhydro-Neu5Ac instead of sialic acid. Evidence of IT-sialidases in human metagenomes indicates that this enzyme occurs in healthy subjects but is more prevalent in IBD metagenomes. Our results uncover a previously unrecognized enzymatic activity in the gut microbiota, which may contribute to the adaptation of intestinal bacteria to the mucosal environment in health and disease.

The gut microbiome and mucosal defenses in cats with coronaviruses: a pilot study

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Sara Meazzi

2017-05-01

Full Text Available Feline Infectious Peritonitis (FIP develops from a mutation of enteric feline coronaviruses (FCoVs and an imbalance of the host immune response. The wide polymorphism of FCoVs is associated with the viral replication rate (Licitra et al. 2013.  Changes in the composition of the gut microbiota may induce quali-quantitative modifications in FCoVs and/or different immune profiles (Weese et al., 2015. Few information is available on feline gut microbiome and the association between microbiota and the predisposition to pathological conditions (Ramadan et al., 2014. The aim of this study is to provide preliminary data about the composition of gut microbiota in healthy cats compared with FCoV infected cats (with and without  FIP, in order to evaluate whether changes of gut microbiota may induce changes in FCoV, in its genetic polymorphism and in the mucosal immunity. Screening analyses have been performed on 22 cats: - Routine hematology and biochemistry on EDTA and serum (included electrophoresis and alpha-1-acid glycoprotein measurement for cats suspected with FIP - Nested RT-PCR-3’UTR on frozen faeces - Effusion evaluation - FIV/FeLV serology Due to strict inclusion criteria (cats younger than 2.5 years old, indoor and not assuming antibiotics in the previous two months and based on the results obtained from the complete set of analysis, only 15 cats, specifically 5 cats for each of the following 3 groups: FIP- affected, healthy negative and positive for FCoV, have been recruited to perform the following analyses:  - microbiota analysis through NGS of 16S rRNA gene (V4 region amplicons followed by bioinformatic analysis  -  evaluation of secretory IgA (ELISA kit - phylogenetic analysis of FCoVs S gene sequences Innovative results will be provided on the feline gut microbiota composition. These will be correlated with the presence and genetic polymorphisms of FCoV and mucosal defenses to establish significant correlations between the analysed

Gut Homeostasis, Microbial Dysbiosis, and Opioids.

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Wang, Fuyuan; Roy, Sabita

2017-01-01

Gut homeostasis plays an important role in maintaining animal and human health. The disruption of gut homeostasis has been shown to be associated with multiple diseases. The mutually beneficial relationship between the gut microbiota and the host has been demonstrated to maintain homeostasis of the mucosal immunity and preserve the integrity of the gut epithelial barrier. Currently, rapid progress in the understanding of the host-microbial interaction has redefined toxicological pathology of opioids and their pharmacokinetics. However, it is unclear how opioids modulate the gut microbiome and metabolome. Our study, showing opioid modulation of gut homeostasis in mice, suggests that medical interventions to ameliorate the consequences of drug use/abuse will provide potential therapeutic and diagnostic strategies for opioid-modulated intestinal infections. The study of morphine's modulation of the gut microbiome and metabolome will shed light on the toxicological pathology of opioids and its role in the susceptibility to infectious diseases.

Role of viability of probiotic strains in their persistence in the gut and in mucosal immune stimulation.

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Galdeano, C Maldonado; Perdigón, G

2004-01-01

To determine how probiotic bacteria contact with intestinal epithelial and immune cells and the conditions to induce a good mucosal immune stimulation. Lactobacillus casei was studied by transmission electron microscopy (TEM) to determine its interaction with the gut. We compared the influence of viable and nonviable lactic acid bacteria on the intestinal mucosal immune system (IMIS) and their persistence in the gut of mice. TEM showed whole Lact. casei adhered to the villi; the bacterial antigen was found in the cytoplasm of the enterocytes. Viable bacteria stimulated the IMIS to a greater extent than nonviable bacteria with the exception of Lact. delbrueckii subsp. bulgaricus. For all the strains assayed at 72 h no antigenic particles were found in the intestine. Antigenic particles but not the whole bacteria can enter to epithelial cells and contact with the immune cells. Bacterial viability is a condition for a better stimulation of the IMIS. We demonstrated that only antigenic particle interact with the immune cells and their fast clearance from the gut agrees with those described for the particulate antigens. The regular consumption of probiotics should not adversely affect the host.

Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity.

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Gil-Cardoso, Katherine; Ginés, Iris; Pinent, Montserrat; Ardévol, Anna; Blay, Mayte; Terra, Ximena

2016-12-01

Diet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.

A diet containing whey protein, glutamine, and TGFbeta modulates gut protein metabolism during chemotherapy-induced mucositis in rats.

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Boukhettala, Nabile; Ibrahim, Ayman; Claeyssens, Sophie; Faure, Magali; Le Pessot, Florence; Vuichoud, Jacques; Lavoinne, Alain; Breuillé, Denis; Déchelotte, Pierre; Coëffier, Moïse

2010-08-01

Mucositis, a common side effect of chemotherapy, is characterized by compromised digestive function, barrier integrity and immune competence. Our aim was to evaluate the impact of a specifically designed diet Clinutren Protect (CP), which contains whey proteins, TGFbeta-rich casein, and free glutamine, on mucositis in rats. Mucositis was induced by three consecutive injections (day 0, day 1, day 2) of methotrexate (2.5 mg/kg). Rats had free access to CP or placebo diets from days -7 to 9. In the placebo diet, whey proteins and TGFbeta-rich casein were replaced by TGFbeta-free casein and glutamine by alanine. Intestinal parameters were assessed at day 3 and 9. Values, expressed as mean +/- SEM, were compared using two-way ANOVA. At day 3, villus height was markedly decreased in the placebo (296 +/- 11 microm) and CP groups (360 +/- 10 microm) compared with controls (464 +/- 27 microm), but more markedly in the placebo as compared to CP group. The intestinal damage score was also reduced in the CP compared with the placebo group. Glutathione content increased in the CP compared with the placebo group (2.2 +/- 0.2 vs. 1.7 +/- 0.2 micromol/g tissue). Gut protein metabolism was more affected in the placebo than in the CP group. The fractional synthesis rate was decreased in the placebo group (93.8 +/- 4.9%/day) compared with controls (121.5 +/- 12.1, P < 0.05), but not in the CP group (106.0 +/- 13.1). In addition, at day 9, rats exhibited improved body weight and food intake recovery in the CP compared to the placebo group. Clinutren Protect feeding reduces intestinal injury in the acute phase of methotrexate-induced mucositis in rats and improves recovery.

Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis.

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Ciccia, Francesco; Guggino, Giuliana; Rizzo, Aroldo; Alessandro, Riccardo; Luchetti, Michele Maria; Milling, Simon; Saieva, Laura; Cypers, Heleen; Stampone, Tommaso; Di Benedetto, Paola; Gabrielli, Armando; Fasano, Alessio; Elewaut, Dirk; Triolo, Giovanni

2017-06-01

Dysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS. Ileal biopsies were obtained from 50 HLA-B27 + patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed. Adherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats. Bacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour. Published by the BMJ Publishing Group Limited. For permission to use

Physiology and immunology of mucosal barriers in catfish (Ictalurus spp.)

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The mucosal barriers of catfish (Ictalurus spp.) constitute the first line of defense against pathogen invasion while simultaneously carrying out a diverse array of other critical physiological processes, including nutrient adsorption, osmoregulation, waste excretion, and environmental sensing. Catf...

Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction

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Lakhan Shaheen E

2011-11-01

Full Text Available Abstract Obesity is a chronic disease characterized by persistent low-grade inflammation with alterations in gut motility. Motor abnormalities suggest that obesity has effects on the enteric nervous system (ENS, which controls virtually all gut functions. Recent studies have revealed that the gut microbiota can affect obesity and increase inflammatory tone by modulating mucosal barrier function. Furthermore, the observation that inflammatory conditions influence the excitability of enteric neurons may add to the gut dysfunction in obesity. In this article, we discuss recent advances in understanding the role of gut microbiota and inflammation in the pathogenesis of obesity and obesity-related gastrointestinal dysfunction. The potential contribution of sirtuins in protecting or regulating the circuitry of the ENS under inflamed states is also considered.

The intriguing role of Rifaximin in gut barrier chronic inflammation and in the treatment of Crohn's disease.

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Lopetuso, Loris R; Napoli, Marco; Rizzatti, Gianenrico; Gasbarrini, Antonio

2018-06-04

The gastrointestinal tract acts as a functional unit organized as a semipermeable multilayer system, in which commensal gut microbiota represents the anatomical barrier. Recently,, several studies have highlighted the involvement of gut microbiota in IBD pathogenesis, in sustaining gut barrier chronic inflammation, and in conditioning disease course and therapeutical response. This evidence provides a rationale for treating patients with gut microbiota modifiers. Among these, Rifaximin represents a non-traditional antibiotic able to act as a "eubiotic" on intestinal barrier. Area covered: The purpose of this narrative review is to explore the impact of Rifaximin on gut barrier and gut microbiota in IBD, in particular in Crohn's disease, and to analyze its potential therapeutic applications. Expert opinion: The possibility of a beneficial activity of Rifaximin in chronic intestinal inflammation and Crohn's disease has been debated and evaluated with different studies having obtained promising but still preliminary data. Larger trials are therefore needed. This gut-specific antibiotic could represent an alternative to systemic antibiotics thanks to its favorable safety profile and promising efficacy data. Rifaximin could exert, when appropriate, a synergic effect with immunomodulators in IBD, acting on both the microbial and immunological sides of gut barrier impairment.

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

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Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric...

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure.

Science.gov (United States)

Kim, Seungbum; Goel, Ruby; Kumar, Ashok; Qi, Yanfei; Lobaton, Gil; Hosaka, Koji; Mohammed, Mohammed; Handberg, Eileen M; Richards, Elaine M; Pepine, Carl J; Raizada, Mohan K

2018-03-30

Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut-epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R 2 = 0.5301, P <0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R 2 = 0.4608, P <0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders

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Kelly, John R.; Kennedy, Paul J.; Cryan, John F.; Dinan, Timothy G.; Clarke, Gerard; Hyland, Niall P.

2015-01-01

The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a “leaky gut” may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. PMID:26528128

Application of Prodrugs to Inflammatory Diseases of the Gut

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Jeffrey L. Ebersole

2008-02-01

Full Text Available Oral delivery is the most common and preferred route of drug administrationalthough the digestive tract exhibits several obstacles to drug delivery including motilityand intraluminal pH profiles. The gut milieu represents the largest mucosal surfaceexposed to microorganisms with 1010-12 colony forming bacteria/g of colonic content.Approximately, one third of fecal dry matter is made of bacteria/ bacterial components.Indeed, the normal gut microbiota is responsible for healthy digestion of dietary fibers(polysaccharides and fermentation of short chain fatty acids such as acetate and butyratethat provide carbon sources (fuel for these bacteria. Inflammatory bowel disease (IBDresults in breakage of the mucosal barrier, an altered microbiota and dysregulated gutimmunity. Prodrugs that are chemically constructed to target colonic release or aredegraded specifically by colonic bacteria, can be useful in the treatment of IBD. Thisreview describes the progress in digestive tract prodrug design and delivery in light of gutmetabolic activities.

Effects of synbiotics on intestinal mucosal barrier in rat model

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Zhigang Xue

2017-06-01

Conclusions: Probiotics can improve the concentration of colonic probiotics, while synbiotics can improve probiotics concentration and mucosa thickness in colon, decrease L/M ratio and bacterial translocation. Synbiotics shows more protective effects on intestinal mucosal barrier in rats after cecectomy and gastrostomy and the intervention of specific antibiotics.

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice.

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Ma, Elise L; Smith, Allen D; Desai, Neemesh; Cheung, Lumei; Hanscom, Marie; Stoica, Bogdan A; Loane, David J; Shea-Donohue, Terez; Faden, Alan I

2017-11-01

Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. Moderate-level TBI was induced in C57BL/6mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglial-mediated inflammation. These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis.

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Wallon, Conny; Persborn, Mats; Jönsson, Maria; Wang, Arthur; Phan, Van; Lampinen, Maria; Vicario, Maria; Santos, Javier; Sherman, Philip M; Carlson, Marie; Ericson, Ann-Charlott; McKay, Derek M; Söderholm, Johan D

2011-05-01

Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropin-releasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers ((51)Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), α-helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility

International Nuclear Information System (INIS)

Aw, Tak Yee

2005-01-01

The intestine is a primary site of nutrient absorption and a critical defense barrier against dietary-derived mutagens, carcinogens, and oxidants. Accumulation of oxidants like peroxidized lipids in the gut lumen can contribute to impairment of mucosal metabolic pathways, enterocyte dysfunction independent of cell injury, and development of gut pathologies, such as inflammation and cancer. Despite this recognition, we know little of the pathways of intestinal transport, metabolism, and luminal disposition of dietary peroxides in vivo or of the underlying mechanisms of lipid peroxide-induced genesis of intestinal disease processes. This chapter summarizes our current understanding of the determinants of intestinal absorption and metabolism of peroxidized lipids. I will review experimental evidence from our laboratory and others (Table 1) supporting the pivotal role that glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play in mucosal transport and metabolism of lipid hydroperoxides and how reductant availability can be compromised under chronic stress such as hypoxia, and the influence of GSH on oxidative susceptibility, and redox contribution to genesis of gut disorders. The discussion is pertinent to understanding dietary lipid peroxides and GSH redox balance in intestinal physiology and pathophysiology and the significance of luminal GSH in preserving the integrity of the intestinal epithelium

The Mucosal Immune System of Teleost Fish

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Irene Salinas

2015-08-01

Full Text Available Teleost fish possess an adaptive immune system associated with each of their mucosal body surfaces. Evidence obtained from mucosal vaccination and mucosal infection studies reveal that adaptive immune responses take place at the different mucosal surfaces of teleost. The main mucosa-associated lymphoid tissues (MALT of teleosts are the gut-associated lymphoid tissue (GALT, skin-associated lymphoid tissue (SALT, the gill-associated lymphoid tissue (GIALT and the recently discovered nasopharynx-associated lymphoid tissue (NALT. Teleost MALT includes diffuse B cells and T cells with specific phenotypes different from their systemic counterparts that have co-evolved to defend the microbe-rich mucosal environment. Both B and T cells respond to mucosal infection or vaccination. Specific antibody responses can be measured in the gills, gut and skin mucosal secretions of teleost fish following mucosal infection or vaccination. Rainbow trout studies have shown that IgT antibodies and IgT+ B cells are the predominant B cell subset in all MALT and respond in a compartmentalized manner to mucosal infection. Our current knowledge on adaptive immunity in teleosts is limited compared to the mammalian literature. New research tools and in vivo models are currently being developed in order to help reveal the great intricacy of teleost mucosal adaptive immunity and help improve mucosal vaccination protocols for use in aquaculture.

Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity.

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Sya N Ukena

2007-12-01

Full Text Available Probiotics are proposed to positively modulate the intestinal epithelial barrier formed by intestinal epithelial cells (IECs and intercellular junctions. Disruption of this border alters paracellular permeability and is a key mechanism for the development of enteric infections and inflammatory bowel diseases (IBDs.To study the in vivo effect of probiotic Escherichia coli Nissle 1917 (EcN on the stabilization of the intestinal barrier under healthy conditions, germfree mice were colonized with EcN or K12 E. coli strain MG1655. IECs were isolated and analyzed for gene and protein expression of the tight junction molecules ZO-1 and ZO-2. Then, in order to analyze beneficial effects of EcN under inflammatory conditions, the probiotic was orally administered to BALB/c mice with acute dextran sodium sulfate (DSS induced colitis. Colonization of gnotobiotic mice with EcN resulted in an up-regulation of ZO-1 in IECs at both mRNA and protein levels. EcN administration to DSS-treated mice reduced the loss of body weight and colon shortening. In addition, infiltration of the colon with leukocytes was ameliorated in EcN inoculated mice. Acute DSS colitis did not result in an anion secretory defect, but abrogated the sodium absorptive function of the mucosa. Additionally, intestinal barrier function was severely affected as evidenced by a strong increase in the mucosal uptake of Evans blue in vivo. Concomitant administration of EcN to DSS treated animals resulted in a significant protection against intestinal barrier dysfunction and IECs isolated from these mice exhibited a more pronounced expression of ZO-1.This study convincingly demonstrates that probiotic EcN is able to mediate up-regulation of ZO-1 expression in murine IECs and confer protection from the DSS colitis-associated increase in mucosal permeability to luminal substances.

Role of the normal gut microbiota.

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Jandhyala, Sai Manasa; Talukdar, Rupjyoti; Subramanyam, Chivkula; Vuyyuru, Harish; Sasikala, Mitnala; Nageshwar Reddy, D

2015-08-07

Relation between the gut microbiota and human health is being increasingly recognised. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individual's life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbe-host interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Several factors play a role in shaping the normal gut microbiota. They include (1) the mode of delivery (vaginal or caesarean); (2) diet during infancy (breast milk or formula feeds) and adulthood (vegan based or meat based); and (3) use of antibiotics or antibiotic like molecules that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.

Gut-Associated Lymphoid Tissue: A Key Tissue Inside the Mucosal Immune System of Hens Immunized with Escherichia coli F4.

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Peralta, Maria F; Magnoli, Alejandra; Alustiza, Fabrisio; Nilson, Armando; Miazzo, Raúl; Vivas, Adriana

2017-01-01

Immunoglobulin Y (IgY) is the predominant antibody found in hen's ( Gallus domesticus ) egg yolk. This antibody, developed against several microorganisms in hen egg yolk, has been successfully used as an alternative to immunoglobulins from mammals for use in immunodiagnostics and immunotherapy. Enteropathogenic Escherichia coli (E.coli) F 4 is the main etiological agent associated with swine neonatal diarrhea, and it causes notable economic losses in swine production. The aim of the present study was to evaluate the relationship between humoral immune response and the activation of gut-associated lymphoid tissue (GALT) in laying hens intramuscularly immunized with E. coli F 4 . Adult laying Shaver hens were immunized with a bacterin based on an inactivated lysate E. coli F 4 strain that was originally isolated from neonatal piglet diarrhea, following a recommended schedule. The percentage of B lymphocytes in blood and spleen homogenates was determined by flow cytometry. Villi histomorphometry and the size of germinal centers (GC) activated in GALT and the spleen were measured in histological samples either stained with hematoxylin/eosin or through immunofluorescence. Antibody and isotype-specific antibodies in serum and egg yolk were measured using indirect enzyme-linked immunosorbent assay (ELISA). Secretory and serum immunoglobulin A (IgA) were measured by ELISA tests. Laying hen with intramuscular immunization with E. coli F 4 lysate, activated both mucosal and systemic protection. Mucosal protection was provided through B lymphocytes, and most of them were activated on Peyer's patches and esophageal tonsils, in GALT. Furthermore, increased B lymphocyte number in the lamina propria of the gut, and increased intraepithelial plasmatic cell number, produced high levels of mucosal IgA. Activated B lymphocytes interacted with absorptive cells, immune cells, and microbiota in the gut, producing signals that were translated into a powerful physical defense by producing

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms.

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Lechuga, Susana; Ivanov, Andrei I

2017-07-01

The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Lactobacillus casei Shirota Supplementation Does Not Restore Gut Microbiota Composition and Gut Barrier in Metabolic Syndrome: A Randomized Pilot Study.

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Vanessa Stadlbauer

Full Text Available Metabolic syndrome is associated with disturbances in gut microbiota composition. We aimed to investigate the effect of Lactobacillus casei Shirota (LcS on gut microbiota composition, gut barrier integrity, intestinal inflammation and serum bile acid profile in metabolic syndrome. In a single-centre, prospective, randomised controlled pilot study, 28 subjects with metabolic syndrome received either LcS for 12 weeks (n = 13 or no LcS (n = 15. Data were compared to healthy controls (n = 16. Gut microbiota composition was characterised from stool using 454 pyrosequencing of 16S rRNA genes. Serum bile acids were quantified by tandem mass spectrometry. Zonulin and calprotectin were measured in serum and stool by ELISA. Bacteroidetes/Firmicutes ratio was significantly higher in healthy controls compared to metabolic syndrome but was not influenced by LcS. LcS supplementation led to enrichment of Parabacteroides. Zonulin and calprotectin were increased in metabolic syndrome stool samples but not influenced by LcS supplementation. Serum bile acids were similar to controls and not influenced by LcS supplementation. Metabolic syndrome is associated with a higher Bacteroidetes/Firmicutes ratio and gut barrier dysfunction but LcS was not able to change this. LcS administration was associated with subtle microbiota changes at genus level.ClinicalTrials.gov NCT01182844.

HIV enteropathy and aging: gastrointestinal immunity, mucosal epithelial barrier, and microbial translocation.

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Wang, Hongyin; Kotler, Donald P

2014-07-01

Despite decreases in morbidity and mortality as a result of antiretroviral therapy, gastrointestinal dysfunction remains common in HIV infection. Treated patients are at risk for complications of 'premature' aging, such as cardiovascular disease, osteopenia, neurocognitive decline, malignancies, and frailty. This review summarizes recent observations in this field. Mucosal CD4 lymphocytes, especially Th17 cells, are depleted in acute HIV and simian immune deficiency virus (SIV) infections, although other cell types also are affected. Reconstitution during therapy often is incomplete, especially in mucosa. Mucosal barrier function is affected by both HIV infection and aging and includes paracellular transport via tight junctions and uptake through areas of apoptosis; other factors may affect systemic antigen exposure. The resultant microbial translocation is associated with systemic immune activation in HIV and SIV infections. There is evidence of immune activation and microbial translocation in the elderly. The immune phenotypes of immunosenescence in HIV infection and aging appear similar. There are several targets for intervention; blockage of residual mucosal virus replication, preventing antigen uptake, modulating the microbiome, improving T cell recovery, combining therapies aimed at mucosal integrity, augmenting mucosal immunity, and managing traditional risk factors for premature aging in the general population. Aging may interact with HIV enteropathy to enhance microbial translocation and immune activation.

Human immunodeficiency virus-associated disruption of mucosal barriers and its role in HIV transmission and pathogenesis of HIV/AIDS disease

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Tugizov, Sharof

2016-01-01

Abstract Oral, intestinal and genital mucosal epithelia have a barrier function to prevent paracellular penetration by viral, bacterial and other pathogens, including human immunodeficiency virus (HIV). HIV can overcome these barriers by disrupting the tight and adherens junctions of mucosal epithelia. HIV-associated disruption of epithelial junctions may also facilitate paracellular penetration and dissemination of other viral pathogens. This review focuses on possible molecular mechanisms of HIV-associated disruption of mucosal epithelial junctions and its role in HIV transmission and pathogenesis of HIV and acquired immune deficiency syndrome (AIDS). PMID:27583187

Immunomodulating effects of probiotics, prebiotics and synbiotics for pig gut health

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Roselli, Marianna; Pieper, Robert; Rogel-Gaillard, Claire

2017-01-01

Probiotics are live microorganisms that can confer a health benefit on the host, and amongst various mechanisms probiotics are believed to exert their effects by production of antimicrobial substances, competition with pathogens for adhesion sites and nutrients, enhancement of mucosal barrier...... integrity and immune modulation. Through these activities probiotics can support three core benefits for the host: supporting a healthy gut microbiota, a healthy digestive tract and a healthy immune system. More recently, the concept of combining probiotics and prebiotics, i.e. synbiotics......, for the beneficial effect on gut health of pigs has attracted major interest, and examples of probiotic and prebiotic benefits for pigs are pathogen inhibition and immunomodulation. Yet, it remains to be defined in pigs, what exactly is a healthy gut. Because of the high level of variability in growth and feed...

Comparison of the chloride channel activator lubiprostone and the oral laxative Polyethylene Glycol 3350 on mucosal barrier repair in ischemic-injured porcine intestine.

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Moeser, Adam-J; Nighot, Prashant-K; Roerig, Birgit; Ueno, Ryuji; Blikslager, Anthony-T

2008-10-21

To investigate the effects of lubiprostone and Polyethylene Glycol 3350 (PEG) on mucosal barrier repair in ischemic-injured porcine intestine. Ileum from 6 piglets (approximately 15 kg body weight) was subjected to ischemic conditions by occluding the local mesenteric circulation for 45 min in vivo. Ileal tissues from each pig were then harvested and mounted in Ussing chambers and bathed in oxygenated Ringer's solution in vitro. Intestinal barrier function was assessed by measuring transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of (3)H-mannitol and (14)C-inulin. Statistical analyses of data collected over a 120-min time course included 2-way ANOVA for the effects of time and treatment on indices of barrier function. Application of 1 micromol/L lubiprostone to the mucosal surface of ischemic-injured ileum in vitro induced significant elevations in TER compared to non-treated tissue. Lubiprostone also reduced mucosal-to-serosal fluxes of (3)H-mannitol and (14)C-inulin. Alternatively, application of a polyethylene laxative (PEG, 20 mmol/L) to the mucosal surface of ischemic tissues significantly increased flux of (3)H-mannitol and (14)C-inulin. This experiment demonstrates that lubiprostone stimulates recovery of barrier function in ischemic intestinal tissues whereas the PEG laxative had deleterious effects on mucosal repair. These results suggest that, unlike osmotic laxatives, lubiprostone stimulates repair of the injured intestinal barrier.

Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection.

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Andrew Leber

Full Text Available Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17 effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions.

Activation of IGF-1/IGFBP-3 signaling by berberine improves intestinal mucosal barrier of rats with acute endotoxemia.

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He, Yan; Yuan, Xiaoming; Zhou, Guangrong; Feng, Aiwen

2018-01-01

Insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) play a role in the maintenance of gut mucosal barrier function. Nevertheless, IGF-I/IGFBP-3 and tight junction protein (TJP) expression in small intestinal mucosa are often impaired during endotoxemia. In this model of acute endotoxemia, the regulatory effect of berberine on IGF-I/IGFBP-3 and TJP expression in ileal mucosa was evaluated. The findings revealed systemic injection of lipopolysaccharide (LPS) suppressed mRNA and protein expression of IGF-I and IGFBP-3, but berberine ameliorated their production. LPS injection inhibited occludin and claudin-1 protein generation, and this inhibitory effect of LPS was abolished by berberine. Inhibition of IGF-I/IGFBP-3 signaling by AG1024 or siRNAs reduced berberine-induced occludin and claudin-1 production. Additionally, GW9662 was found to repress berberine-induced IGF-I/IGFBP-3 expression, indicating of a cross-link between PPARγ and IGF-I/IGFBP-3 axis. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of adding butyric acid to PN on gut-associated lymphoid tissue and mucosal immunoglobulin A levels.

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Murakoshi, Satoshi; Fukatsu, Kazuhiko; Omata, Jiro; Moriya, Tomoyuki; Noguchi, Midori; Saitoh, Daizoh; Koyama, Isamu

2011-07-01

Parenteral nutrition (PN) causes intestinal mucosal atrophy, gut-associated lymphoid tissue (GALT) atrophy and dysfunction, leading to impaired mucosal immunity and increased susceptibility to infectious complications. Therefore, new PN formulations are needed to maintain mucosal immunity. Short-chain fatty acids have been demonstrated to exert beneficial effects on the intestinal mucosa. We examined the effects of adding butyric acid to PN on GALT lymphocyte numbers, phenotypes, mucosal immunoglobulin A (IgA) levels, and intestinal morphology in mice. Male Institute of Cancer Research mice (n = 103) were randomized to receive either standard PN (S-PN), butyric acid-supplemented PN (Bu-PN), or ad libitum chow (control) groups. The mice were fed these respective diets for 5 days. In experiment 1, cells were isolated from Peyer's patches (PPs) to determine lymphocyte numbers and phenotypes (αβTCR(+), γδTCR(+), CD4(+), CD8(+), B220(+) cells). IgA levels in small intestinal washings were also measured. In experiment 2, IgA levels in respiratory tract (bronchoalveolar and nasal) washings were measured. In experiment 3, small intestinal morphology was evaluated. Lymphocyte yields from PPs and small intestinal, bronchoalveolar, and nasal washing IgA levels were all significantly lower in the S-PN group than in the control group. Bu-PN moderately, but significantly, restored PP lymphocyte numbers, as well as intestinal and bronchoalveolar IgA levels, as compared with S-PN. Villous height and crypt depth in the small intestine were significantly decreased in the S-PN group vs the control group, however Bu-PN restored intestinal morphology. A new PN formula containing butyric acid is feasible and would ameliorate PN-induced impairment of mucosal immunity.

A polyphenol-enriched diet and Ascaris suum infection modulate mucosal immune responses and gut microbiota composition in pigs

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Williams, Andrew R.; Krych, Lukasz; Ahmad, Hajar Fauzan

2017-01-01

. suum for 14 days to assess parasite establishment, acquisition of local and systemic immune responses and effects on the gut microbiome. Despite in vitro anthelmintic activity of GP-extracts, numbers of parasite larvae in the intestine were not altered by GP-supplementation. However, the bioactive diet......Polyphenols are a class of bioactive plant secondary metabolites that are thought to have beneficial effects on gut health, such as modulation of mucosal immune and inflammatory responses and regulation of parasite burdens. Here, we examined the interactions between a polyphenol-rich diet...... supplement and infection with the enteric nematode Ascaris suum in pigs. Pigs were fed either a basal diet or the same diet supplemented with grape pomace (GP), an industrial by-product rich in polyphenols such as oligomeric proanthocyanidins. Half of the animals in each group were then inoculated with A...

Expert-led didactic versus self-directed audiovisual training of confocal laser endomicroscopy in evaluation of mucosal barrier defects.

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Huynh, Roy; Ip, Matthew; Chang, Jeff; Haifer, Craig; Leong, Rupert W

2018-01-01

 Confocal laser endomicroscopy (CLE) allows mucosal barrier defects along the intestinal epithelium to be visualized in vivo during endoscopy. Training in CLE interpretation can be achieved didactically or through self-directed learning. This study aimed to compare the effectiveness of expert-led didactic with self-directed audiovisual teaching for training inexperienced analysts on how to recognize mucosal barrier defects on endoscope-based CLE (eCLE).  This randomized controlled study involved trainee analysts who were taught how to recognize mucosal barrier defects on eCLE either didactically or through an audiovisual clip. After being trained, they evaluated 6 sets of 30 images. Image evaluation required the trainees to determine whether specific features of barrier dysfunction were present or not. Trainees in the didactic group engaged in peer discussion and received feedback after each set while this did not happen in the self-directed group. Accuracy, sensitivity, and specificity of both groups were compared. Trainees in the didactic group achieved a higher overall accuracy (87.5 % vs 85.0 %, P  = 0.002) and sensitivity (84.5 % vs 80.4 %, P  = 0.002) compared to trainees in the self-directed group. Interobserver agreement was higher in the didactic group (k = 0.686, 95 % CI 0.680 - 0.691, P  barrier defects on eCLE.

Mucosal immunity and B cells in teleosts: effect of vaccination and stress.

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David eParra

2015-07-01

Full Text Available Fish are subjected to several insults from the environment, which may endanger animal survival. Mucosal surfaces are the first line of defense against those threats and they act as a physical barrier to protect the animal but also function as immunologically active tissues. Thus, four mucosal-associated lymphoid tissues have been described in fish, which lead the immune responses in gut, skin, gills and nose. Humoral and cellular immunity, as well as its regulation and the factors that influence the response in these mucosal lymphoid tissues is still not well known in most of fish species. Mucosal B-lymphocytes and immunoglobulins (Igs are one of the key players in the immune response after vaccination. Recent findings about IgT in trout have delimited the compartmentalization of immune response in systemic and mucosal. The existence of IgT as a specialized mucosa Ig gives us the opportunity of measuring mucosal specific responses after vaccination, a fact that was not possible until recently in most of the fish species. Vaccination process is influenced by several factors, being stress one of the main stimuli determining the success of the vaccine. Thus, one of the major goals in a vaccination process is to avoid possible situations of stress, which might interfere with fish immune performance. However, the interaction between immune and neuroendocrine systems at mucosal tissues is still unknown. In this review we will summarized the latest findings about B-lymphocytes and immunoglobulins in mucosal immunity and the effect of stress and vaccines on B cell response at mucosal sites. It is important to point out that a small number of studies have been published regarding mucosal stress and very few about the influence of stress over mucosal B-lymphocytes.

Navy and black bean supplementation primes the colonic mucosal microenvironment to improve gut health.

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Monk, Jennifer M; Lepp, Dion; Wu, Wenqing; Pauls, K Peter; Robinson, Lindsay E; Power, Krista A

2017-11-01

Common beans (Phaseolus vulgaris L.) are enriched in non-digestible fermentable carbohydrates and phenolic compounds that can modulate the colonic microenvironment (microbiota and host epithelial barrier) to improve gut health. In a comprehensive assessment of the impact of two commonly consumed bean varieties (differing in levels and types of phenolic compounds) within the colonic microenvironment, C57Bl/6 mice were fed diets supplemented with 20% cooked navy bean (NB) or black bean (BB) flours or an isocaloric basal diet control (BD) for 3 weeks. NB and BB similarly altered the fecal microbiota community structure (16S rRNA sequencing) notably by increasing the abundance of carbohydrate fermenting bacteria such as Prevotella, S24-7 and Ruminococcus flavefaciens, which coincided with enhanced short chain fatty acid (SCFA) production (microbial-derived carbohydrate fermentation products) and colonic expression of the SCFA receptors GPR-41/-43/-109a. Both NB and BB enhanced multiple aspects of mucus and epithelial barrier integrity vs. BD including: (i) goblet cell number, crypt mucus content and mucin mRNA expression, (ii) anti-microbial defenses (Reg3γ), (iii) crypt length and epithelial cell proliferation, (iv) apical junctional complex components (occludin, JAM-A, ZO-1 and E-cadherin) mRNA expression and (v) reduced serum endotoxin concentrations. Interestingly, biomarkers of colon barrier integrity (crypt height, mucus content, cell proliferation and goblet cell number) were enhanced in BB vs. NB-fed mice, suggesting added benefits attributable to unique BB components (e.g., phenolics). Overall, NB and BB improved baseline colonic microenvironment function by altering the microbial community structure and activity and promoting colon barrier integrity and function; effects which may prove beneficial in attenuating gut-associated diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Disturbance of the gut-associated lymphoid tissue is associated with disease progression in chronic HIV infection.

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Hofer, Ursula; Speck, Roberto F

2009-07-01

Why and how HIV makes people sick is highly debated. Recent evidence implicates heightened immune activation due to breakdown of the gastrointestinal barrier as a determining factor of lentiviral pathogenesis. HIV-mediated loss of Th17 cells from the gut-associated lymphoid tissue (GALT) impairs mucosal integrity and innate defense mechanisms against gut microbes. Translocation of microbial products from the gut, in turn, correlates with increased immune activation in chronic HIV infection and may further damage the immune system by increasing viral and activation-induced T cell death, by reducing T cell reconstitution due to tissue scarring, and by impairing the function of other cell types, such as gammadelta T cells and epithelial cells. Maintaining a healthy GALT may be the key to reducing the pathogenic potential of HIV.

Mucosal vaccines: recent progress in understanding the natural barriers.

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Borges, Olga; Lebre, Filipa; Bento, Dulce; Borchard, Gerrit; Junginger, Hans E

2010-02-01

It has long been known that protection against pathogens invading the organism via mucosal surfaces correlates better with the presence of specific antibodies in local secretions than with serum antibodies. The most effective way to induce mucosal immunity is to administer antigens directly to the mucosal surface. The development of vaccines for mucosal application requires antigen delivery systems and immunopotentiators that efficiently facilitate the presentation of the antigen to the mucosal immune system. This review provides an overview of the events within mucosal tissues that lead to protective mucosal immune responses. The understanding of those biological mechanisms, together with knowledge of the technology of vaccines and adjuvants, provides guidance on important technical aspects of mucosal vaccine design. Not being exhaustive, this review also provides information related to modern adjuvants, including polymeric delivery systems and immunopotentiators.

Mucosal pathobiology and molecular signature of epithelial barrier dysfunction in the small intestine in irritable bowel syndrome.

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González-Castro, Ana M; Martínez, Cristina; Salvo-Romero, Eloísa; Fortea, Marina; Pardo-Camacho, Cristina; Pérez-Berezo, Teresa; Alonso-Cotoner, Carmen; Santos, Javier; Vicario, María

2017-01-01

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders in developed countries. Its etiology remains unknown; however, a common finding, regardless of IBS subtype, is the presence of altered intestinal barrier. In fact, signaling and location of cell-to-cell adhesion proteins, in connection with increased immune activity, seem abnormal in the intestinal epithelium of IBS patients. Despite that most research is performed on distal segments of the intestine, altered permeability has been reported in both, the small and the large bowel of all IBS subtypes. The small intestine carries out digestion and nutrient absorption and is also the site where the majority of immune responses to luminal antigens takes place. In fact, the upper intestine is more exposed to environmental antigens than the colon and is also a site of symptom generation. Recent studies have revealed small intestinal structural alterations of the epithelial barrier and mucosal immune activation in association with intestinal dysfunction, suggesting the commitment of the intestine as a whole in the pathogenesis of IBS. This review summarizes the most recent findings on mucosal barrier alterations and its relationship to symptoms arising from the small intestine in IBS, including epithelial structural abnormalities, mucosal immune activation, and microbial dysbiosis, further supporting the hypothesis of an organic origin of IBS. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics.

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Geurts, L; Neyrinck, A M; Delzenne, N M; Knauf, C; Cani, P D

2014-03-01

Crosstalk between organs is crucial for controlling numerous homeostatic systems (e.g. energy balance, glucose metabolism and immunity). Several pathological conditions, such as obesity and type 2 diabetes, are characterised by a loss of or excessive inter-organ communication that contributes to the development of disease. Recently, we and others have identified several mechanisms linking the gut microbiota with the development of obesity and associated disorders (e.g. insulin resistance, type 2 diabetes, hepatic steatosis). Among these, we described the concept of metabolic endotoxaemia (increase in plasma lipopolysaccharide levels) as one of the triggering factors leading to the development of metabolic inflammation and insulin resistance. Growing evidence suggests that gut microbes contribute to the onset of low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. We have demonstrated that enteroendocrine cells (producing glucagon-like peptide-1, peptide YY and glucagon-like peptide-2) and the endocannabinoid system control gut permeability and metabolic endotoxaemia. Recently, we hypothesised that specific metabolic dysregulations occurring at the level of numerous organs (e.g. gut, adipose tissue, muscles, liver and brain) rely from gut microbiota modifications. In this review, we discuss the mechanisms linking gut permeability, adipose tissue metabolism, and glucose homeostasis, and recent findings that show interactions between the gut microbiota, the endocannabinoid system and the apelinergic system. These specific systems are discussed in the context of the gut-to-peripheral organ axis (intestine, adipose tissue and brain) and impacts on metabolic regulation. In the present review, we also briefly describe the impact of a variety of non-digestible nutrients (i.e. inulin-type fructans, arabinoxylans, chitin glucans and polyphenols). Their effects on the composition of the gut microbiota and

Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet.

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MohanKumar, Krishnan; Killingsworth, Cheryl R; McIlwain, R Britt; Timpa, Joseph G; Jagadeeswaran, Ramasamy; Namachivayam, Kopperuncholan; Kurundkar, Ashish R; Kelly, David R; Garzon, Steven A; Maheshwari, Akhil

2014-02-01

Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass are at risk of developing a systemic inflammatory response syndrome with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Healthy 3-week-old piglets were subjected to ECMO for up to 8 h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression were investigated by immunohistochemistry, western blots, and reverse transcriptase-quantitative PCR. Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2 h of ECMO. After 8 h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. We conclude that epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO.

Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut.

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Mantis, N J; Rol, N; Corthésy, B

2011-11-01

Secretory IgA (SIgA) serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. Through a process known as immune exclusion, SIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus, and facilitating their removal by peristaltic and mucociliary activities. In addition, SIgA functions in mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed. In just the past several years, SIgA has been identified as having the capacity to directly quench bacterial virulence factors, influence composition of the intestinal microbiota by Fab-dependent and Fab-independent mechanisms, promote retro-transport of antigens across the intestinal epithelium to dendritic cell subsets in gut-associated lymphoid tissue, and, finally, to downregulate proinflammatory responses normally associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the intrinsic biological activities now associated with SIgA and their relationships with immunity and intestinal homeostasis.

IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut.

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Renga, Giorgia; Moretti, Silvia; Oikonomou, Vasilis; Borghi, Monica; Zelante, Teresa; Paolicelli, Giuseppe; Costantini, Claudio; De Zuani, Marco; Villella, Valeria Rachela; Raia, Valeria; Del Sordo, Rachele; Bartoli, Andrea; Baldoni, Monia; Renauld, Jean-Christophe; Sidoni, Angelo; Garaci, Enrico; Maiuri, Luigi; Pucillo, Carlo; Romani, Luigina

2018-05-08

Candida albicans is implicated in intestinal diseases. Identifying host signatures that discriminate between the pathogenic versus commensal nature of this human commensal is clinically relevant. In the present study, we identify IL-9 and mast cells (MCs) as key players of Candida commensalism and pathogenicity. By inducing TGF-β in stromal MCs, IL-9 pivotally contributes to mucosal immune tolerance via the indoleamine 2,3-dioxygenase enzyme. However, Candida-driven IL-9 and mucosal MCs also contribute to barrier function loss, dissemination, and inflammation in experimental leaky gut models and are upregulated in patients with celiac disease. Inflammatory dysbiosis occurs with IL-9 and MC deficiency, indicating that the activity of IL-9 and MCs may go beyond host immunity to include regulation of the microbiota. Thus, the output of the IL-9/MC axis is highly contextual during Candida colonization and reveals how host immunity and the microbiota finely tune Candida behavior in the gut. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Intestinal stromal cells in mucosal immunity and homeostasis.

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Owens, B M J; Simmons, A

2013-03-01

A growing body of evidence suggests that non-hematopoietic stromal cells of the intestine have multiple roles in immune responses and inflammation at this mucosal site. Despite this, many still consider gut stromal cells as passive structural entities, with past research focused heavily on their roles in fibrosis, tumor progression, and wound healing, rather than their contributions to immune function. In this review, we discuss our current knowledge of stromal cells in intestinal immunity, highlighting the many immunological axes in which stromal cells have a functional role. We also consider emerging data that broaden the potential scope of their contribution to immunity in the gut and argue that these so-called "non-immune" cells are reclassified in light of their diverse contributions to intestinal innate immunity and the maintenance of mucosal homeostasis.

Nutrition and Gut Mucositis in Pediatric Oncology

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Pontoppidan, Peter Erik Lotko

Childhood malignancies are the second most common cause of death in children. A major limitation of current therapies is the high toxicity. Alimentary tract toxicity (mucositis) is associated with increased risk of complication such as infections that may lead to death. In relation to HSCT, mucos...

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity

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Esposito Pasquale

2011-03-01

Full Text Available Abstract Background Celiac disease (CD is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders. Methods CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity. Results Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308, paralleled by significantly increased expression of claudin (CLDN 4 (P = 0.0286. Relative to controls, adaptive immunity markers interleukin (IL-6 (P = 0.0124 and IL-21 (P = 0.0572 were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR 2 was increased in GS but not in CD (P = 0.0295. Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325 and CD patients (P = 0.0293. Conclusions This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.

Specific inulin-type fructan fibers protect against autoimmune diabetes by modulating gut immunity, barrier function, and microbiota homeostasis.

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Chen, Kang; Chen, Hao; Faas, Marijke M; de Haan, Bart J; Li, Jiahong; Xiao, Ping; Zhang, Hao; Diana, Julien; de Vos, Paul; Sun, Jia

2017-08-01

Dietary fibers capable of modifying gut barrier and microbiota homeostasis affect the progression of type 1 diabetes (T1D). Here, we aim to compare modulatory effects of inulin-type fructans (ITFs), natural soluble dietary fibers with different degrees of fermentability from chicory root, on T1D development in nonobese diabetic mice. Female nonobese diabetic mice were weaned to long- and short-chain ITFs [ITF(l) and ITF(s), 5%] supplemented diet up to 24 weeks. T1D incidence, pancreatic-gut immune responses, gut barrier function, and microbiota composition were analyzed. ITF(l) but not ITF(s) supplementation dampened the incidence of T1D. ITF(l) promoted modulatory T-cell responses, as evidenced by increased CD25 + Foxp3 + CD4 + regulatory T cells, decreased IL17A + CD4 + Th17 cells, and modulated cytokine production profile in the pancreas, spleen, and colon. Furthermore, ITF(l) suppressed NOD like receptor protein 3 caspase-1-p20-IL-1β inflammasome in the colon. Expression of barrier reinforcing tight junction proteins occludin and claudin-2, antimicrobial peptides β-defensin-1, and cathelicidin-related antimicrobial peptide as well as short-chain fatty acid production were enhanced by ITF(l). Next-generation sequencing analysis revealed that ITF(l) enhanced Firmicutes/Bacteroidetes ratio to an antidiabetogenic balance and enriched modulatory Ruminococcaceae and Lactobacilli. Our data demonstrate that ITF(l) but not ITF(s) delays the development of T1D via modulation of gut-pancreatic immunity, barrier function, and microbiota homeostasis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs

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Adam J. Moeser

2017-12-01

Full Text Available The gastrointestinal (GI barrier serves a critical role in survival and overall health of animals and humans. Several layers of barrier defense mechanisms are provided by the epithelial, immune and enteric nervous systems. Together they act in concert to control normal gut functions (e.g., digestion, absorption, secretion, immunity, etc. whereas at the same time provide a barrier from the hostile conditions in the luminal environment. Breakdown of these critical GI functions is a central pathophysiological mechanism in the most serious GI disorders in pigs. This review will focus on the development and functional properties of the GI barrier in pigs and how common early life production stressors, such as weaning, can alter immediate and long-term barrier function and disease susceptibility. Specific stress-related pathophysiological mechanisms responsible for driving GI barrier dysfunction induced by weaning and the implications to animal health and performance will be discussed.

Bovine colostrum modulates myeloablative chemotherapy-induced gut toxicity in piglets

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Pontoppidan, Peter Erik Lotko; Shen, René Liang; Cilieborg, Malene Skovsted

2015-01-01

BACKGROUND: Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown. OBJECTIVE: We...

Gut Microbiota-Immune System Crosstalk and Pancreatic Disorders

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D. Pagliari

2018-01-01

Full Text Available Gut microbiota is key to the development and modulation of the mucosal immune system. It plays a central role in several physiological functions, in the modulation of inflammatory signaling and in the protection against infections. In healthy states, there is a perfect balance between commensal and pathogens, and microbiota and the immune system interact to maintain gut homeostasis. The alteration of such balance, called dysbiosis, determines an intestinal bacterial overgrowth which leads to the disruption of the intestinal barrier with systemic translocation of pathogens. The pancreas does not possess its own microbiota, and it is believed that inflammatory and neoplastic processes affecting the gland may be linked to intestinal dysbiosis. Increasing research evidence testifies a correlation between intestinal dysbiosis and various pancreatic disorders, but it remains unclear whether dysbiosis is the cause or an effect. The analysis of specific alterations in the microbiome profile may permit to develop novel tools for the early detection of several pancreatic disorders, utilizing samples, such as blood, saliva, and stools. Future studies will have to elucidate the mechanisms by which gut microbiota is modulated and how it tunes the immune system, in order to be able to develop innovative treatment strategies for pancreatic disorders.

Identification of potential biomarkers for gut barrier failure in broiler chickens

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Juxing eChen

2015-05-01

Full Text Available The objective of the present study was to identify potential biomarkers for gut barrier failure in chickens. A total of 144 day-of-hatch Ross 308 male broiler chickens were housed in 24 battery cages with 6 chicks per cage. Cages were randomly assigned to either a control group (CON or gut barrier failure (GBF group. During the first 13 d, birds in CON or GBF groups were fed a common corn-soy starter diet. On d 14, CON chickens were switched to a corn grower diet and GBF chickens were switched to rye-wheat-barley grower diet. In addition, on d 21, GBF chickens were orally challenged with a coccidiosis vaccine. At d 21 and d 28, birds were weighed by cage and feed intake was recorded to calculate feed conversion ratio. At d 28, one chicken from each cage was euthanized to collect intestinal samples for morphometric analysis, blood for serum, and intestinal mucosa scrapings for gene expression. Overall performance and feed efficiency was severely affected (P < 0.05 by a GBF model when compared with CON group at d 21 and d 28. Duodenum of GBF birds had wider villi, longer crypt depth, and higher crypt depth/villi height ratio than CON birds. Similarly, GBF birds had longer crypt depth in jejunum and ileum when compared with CON birds. An increase (P <0.05 in serum endotoxin, α1-acid glycoprotein (AGP, as well as interleukin (IL-8, IL-1β, transforming growth factor (TGF-β4 and fatty-acid-binding protein (FABP 6 mRNA levels were increased in GBF birds compared to CON; however, FABP2 mRNA levels were decreased (P <0.05 in GBF birds compared to CON. Occludin was numerically reduced by 24% (P = 0.107 and mucin 2 (MUC2 was reduced by 29 % (P = 0.088 in GBF birds compared to CON birds. The results from the present study suggest that serum endotoxin and AGP, as well as, gene expression of FABP2, FABP6, IL-8, IL-1β and TGF-β4 in mucosa may work as potential biomarkers for gut barrier health in chickens.

A polyphenol-enriched diet and Ascaris suum infection modulate mucosal immune responses and gut microbiota composition in pigs.

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Andrew R Williams

Full Text Available Polyphenols are a class of bioactive plant secondary metabolites that are thought to have beneficial effects on gut health, such as modulation of mucosal immune and inflammatory responses and regulation of parasite burdens. Here, we examined the interactions between a polyphenol-rich diet supplement and infection with the enteric nematode Ascaris suum in pigs. Pigs were fed either a basal diet or the same diet supplemented with grape pomace (GP, an industrial by-product rich in polyphenols such as oligomeric proanthocyanidins. Half of the animals in each group were then inoculated with A. suum for 14 days to assess parasite establishment, acquisition of local and systemic immune responses and effects on the gut microbiome. Despite in vitro anthelmintic activity of GP-extracts, numbers of parasite larvae in the intestine were not altered by GP-supplementation. However, the bioactive diet significantly increased numbers of eosinophils induced by A. suum infection in the duodenum, jejunum and ileum, and modulated gene expression in the jejunal mucosa of infected pigs. Both GP-supplementation and A. suum infection induced significant and apparently similar changes in the composition of the prokaryotic gut microbiota, and both also decreased concentrations of isobutyric and isovaleric acid (branched-chain short chain fatty acids in the colon. Our results demonstrate that while a polyphenol-enriched diet in pigs may not directly influence A. suum establishment, it significantly modulates the subsequent host response to helminth infection. Our results suggest an influence of diet on immune function which may potentially be exploited to enhance immunity to helminths.

Interactions between bacteria and the gut mucosa: Do enteric neurotransmitters acting on the mucosal epithelium influence intestinal colonization or infection?

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The intestinal epithelium is a critical barrier between the internal and external milieux of the mammalian host. Epithelial interactions between these two host environments have been shown to be modulated by several different, cross-communicating cell types residing in the gut mucosa. These include ...

Role of serotonin in the intestinal mucosal epithelium barrier in weaning mice undergoing stress-induced diarrhea.

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Dong, Yulan; Wang, Zixu; Qin, Zhuoming; Cao, Jing; Chen, Yaoxing

2018-02-01

Stress-induced diarrhea is a frequent and challenging threat to humans and domestic animals. Serotonin (5-HT) has been shown to be involved in the pathological process of stress-induced diarrhea. However, the role of 5-HT in stress-induced diarrhea remains unclear. A stress-induced diarrhea model was established in 21-day-old ICR weaning mice through an intragastric administration of 0.25 mL of 0.4 g/mL folium sennae and restraint of the hind legs with adhesive tape for 4 h to determine whether 5-HT regulates the mucosal barrier to cause diarrhea. Mice with decreased levels of 5-HT were pretreated with an intraperitoneal injection of 300 mg/kg p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor. After 5 days of treatment, the stress level, body weight and intestinal mucosal morphology indexes were measured. Compared to the controls, the mice with stress-induced diarrhea displayed a stress reaction, with increased corticosterone levels, as well as increased 5-HT-positive cells. However, the mice with stress-induced diarrhea exhibited decreased body weights, villus height to crypt depth ratios (V/C), and Occludin and Claudin1 expression. The PCPA injection reversed these effects in mice with different degrees of stress-induced diarrhea. Based on these findings, inhibition of 5-HT synthesis relieved the stress response and improved the health of the intestinal tract, including both the intestinal absorption capacity, as determined by the villus height and crypt depth, and the mucosal barrier function, as determined by the tight junction proteins of epithelial cell.

Interaction between gut immunity and polysaccharides.

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Huang, Xiaojun; Nie, Shaoping; Xie, Mingyong

2017-09-22

The human gut is colonized with a vast and diverse microbial ecosystem, and these bacteria play fundamental roles in the well being of our bodies. Gut-associated lymphoid tissues, the largest mucosal immune system, should never be overlooked for their profound effect in maintaining the host immunity. Therefore, we discussed the relationship between gut immunity and host health, primarily from two aspects: the homeostasis of gut microbiota, and the function of gut-associated lymphoid tissues. Polysaccharides, widely concerned as bioactive macromolecules in recent centuries, have been proved to benefit the intestinal health. Dietary polysaccharides can improve the ratio of probiotics, regulate the intestinal microenvironment like decreasing the gut pH, and stimulate the macrophages or lymphocytes in gut tissues to fight against diseases like cancer. Based on various experimental and clinical evidence, the impacts of dietary polysaccharides on intestinal health are summarized, in order to reveal the possible immunomodulatory mechanisms of polysaccharides.

Effects of Lactobacillus plantarum on gut barrier function in experimental obstructive jaundice

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Zhou, Yu-Kun; Qin, Huan-Long; Zhang, Ming; Shen, Tong-Yi; Chen, Hong-Qi; Ma, Yan-Lei; Chu, Zhao-Xin; Zhang, Peng; Liu, Zhi-Hua

2012-01-01

AIM: To investigate the mechanisms of Lactobacillus plantarum (L. plantarum) action on gut barrier in preoperative and postoperative experimental obstructive jaundice in rats. METHODS: Forty rats were randomly divided into groups of sham-operation, bile duct ligation (BDL), BDL + L. plantarum, BDL + internal biliary drainage (IBD), and BDL + IBD + L. plantarum. Ten days after L. plantarum administration, blood and ileal samples were collected from the rats for morphological examination, and intestinal barrier function, liver function, intestinal oxidative stress and protein kinase C (PKC) activity measurement. The distribution and expression of the PKC and tight junction (TJ) proteins, such as occludin, zonula occludens-1, claudin-1, claudin-4, junction adhesion molecule-A and F-actin, were examined by confocal laser scanning microscopy, immunohistochemistry, Western blotting, real-time fluorescent quantitative polymerase chain reaction assay. RESULTS: L. plantarum administration substantially restored gut barrier, decreased enterocyte apoptosis, improved intestinal oxidative stress, promoted the activity and expression of protein kinase (BDL vs BDL + L. plantarum, 0.295 ± 0.007 vs 0.349 ± 0.003, P plantarum, 0.407 ± 0.046 vs 0.465 ± 0.135, P plantarum, 0.266 ± 0.118 vs 0.326 ± 0.009, P plantarum was more prominent after internal biliary drainage ( BDL + IBD vs BDL + IBD + L. plantarum, 0.415 ± 0.105 vs 0.494 ± 0.145, P plantarum can decrease intestinal epithelial cell apoptosis, reduce oxidative stress, and prevent TJ disruption in biliary obstruction by activating the PKC pathway. PMID:22912548

Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications.

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Yarbrough, Victoria L; Winkle, Sean; Herbst-Kralovetz, Melissa M

2015-01-01

At the interface of the external environment and the mucosal surface of the female reproductive tract (FRT) lies a first-line defense against pathogen invasion that includes antimicrobial peptides (AMP). Comprised of a unique class of multifunctional, amphipathic molecules, AMP employ a wide range of functions to limit microbial invasion and replication within host cells as well as independently modulate the immune system, dampen inflammation and maintain tissue homeostasis. The role of AMP in barrier defense at the level of the skin and gut has received much attention as of late. Given the far reaching implications for women's health, maternal and fetal morbidity and mortality, and sexually transmissible and polymicrobial diseases, we herein review the distribution and function of key AMP throughout the female reproductive mucosa and assess their role as an essential immunological barrier to microbial invasion throughout the reproductive cycle of a woman's lifetime. A comprehensive search in PubMed/Medline was conducted related to AMP general structure, function, signaling, expression, distribution and barrier function of AMP in the FRT, hormone regulation of AMP, the microbiome of the FRT, and AMP in relation to implantation, pregnancy, fertility, pelvic inflammatory disease, complications of pregnancy and assisted reproductive technology. AMP are amphipathic peptides that target microbes for destruction and have been conserved throughout all living organisms. In the FRT, several major classes of AMP are expressed constitutively and others are inducible at the mucosal epithelium and by immune cells. AMP expression is also under the influence of sex hormones, varying throughout the menstrual cycle, and dependent on the vaginal microbiome. AMP can prevent infection with sexually transmissible and opportunistic pathogens of the female reproductive tissues, although emerging understanding of vaginal dysbiosis suggests induction of a unique AMP profile with increased

Mucosal Immune Regulation in Intestinal Disease. The role of bacterial products, food components and drugs

NARCIS (Netherlands)

Bol-Schoenmakers, M.

2009-01-01

The challenge of the mucosal gut associated immune system is to remain unresponsive to food products and commensal microbiota, while mounting an appropriate immune response towards pathogens. This implicates the necessity of tight immune regulation within the gut associated lymphoid tissue (GALT).

Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection.

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Byrareddy, Siddappa N; Kallam, Brianne; Arthos, James; Cicala, Claudia; Nawaz, Fatima; Hiatt, Joseph; Kersh, Ellen N; McNicholl, Janet M; Hanson, Debra; Reimann, Keith A; Brameier, Markus; Walter, Lutz; Rogers, Kenneth; Mayne, Ann E; Dunbar, Paul; Villinger, Tara; Little, Dawn; Parslow, Tristram G; Santangelo, Philip J; Villinger, Francois; Fauci, Anthony S; Ansari, Aftab A

2014-12-01

α4β7 integrin-expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.

Gut microbiota and probiotics in modulation of epithelium and gut-associated lymphoid tissue function.

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Sanz, Yolanda; De Palma, Giada

2009-01-01

The intestinal tract mucosa is exposed to a vast number of environmental antigens and a large community of commensal bacteria. The mucosal immune system has to provide both protection against pathogens and tolerance to harmless bacteria. Immune homeostasis depends on the interaction of indigenous commensal and transient bacteria (probiotics) with various components of the epithelium and the gut-associated lymphoid tissue. Herein, an update is given of the mechanisms by which the gut microbiota and probiotics are translocated through the epithelium, sensed via pattern-recognition receptors, and activate innate and adaptive immune responses.

Gas tonometry for evaluation of gastrointestinal mucosal perfusion: experimental models of trauma, shock and complex surgical maneuvers - Part 1

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Figueiredo Luiz Francisco Poli de

2002-01-01

Full Text Available Substantial clinical and animal evidences indicate that the mesenteric circulatory bed, particularly the gut mucosa, is highly vulnerable to reductions in oxygen supply and prone to early injury in the course of hemodynamic changes induced by trauma, shock, sepsis and several complex surgical maneuvers. Gut hypoxia or ischemia is one possible contributing factor to gastrointestinal tract barrier dysfunction that may be associated with the development of systemic inflammatory response and multiple organ dysfunction syndrome, a common cause of death after trauma, sepsis or major surgeries. Monitoring gut perfusion during experiments may provide valuable insights over new interventions and therapies highly needed to reduce trauma and sepsis-related morbidity and mortality. We present our experience with gas tonometry as a monitor of the adequacy of gastrointestinal mucosal perfusion in clinical and experimental models of trauma, shock and surgical maneuvers associated with abrupt hemodynamic changes, such as aortic occlusion and hepatic vascular exclusion. Next issue we will be presenting our experience with gas tonometry in experimental and clinical sepsis.

Toward improving mucosal barrier defenses: rhG-CSF plus IgG antibody.

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Simmonds, Aryeh; LaGamma, Edmund F

2006-11-01

Epithelial cell functions ultimately define the ability of the extremely low birth weight human fetus to survive outside of the uterus. These specialized epithelial cell capacities manage all human interactions with the ex utero world including: (i) lung mechanics, surface chemistry and gas exchange, (ii) renal tubular balance of fluid and electrolytes, (iii) barrier functions of the intestine and skin for keeping bacteria out and water in, plus enabling intestinal digestion, as well as (iv) maintaining an intact neuroepithelium lining of the ventricles of the brain and retina. In Part I of this two part review, the authors describe why the gut barrier is a clinically relevant model system for studying the complex interplay between innate and adaptive immunity, dendritic &epithelial cell interactions, intraepithelial lymphocytes, M-cells, as well as the gut associated lymphoid tissues where colonization after birth, clinician feeding practices, use of antibiotics as well as exposure to prebiotics, probiotics and maternal vaginal flora all program the neonate for a life-time of immune competence distinguishing "self" from foreign antigens. These barrier defense capacities become destructive during disease processes like necrotizing enterocolitis (NEC) when an otherwise maturationally normal, yet dysregulated and immature, immune defense system is associated with high levels of certain inflammatory mediators like TNFa. In Part II the authors discuss the rationale for why rhG-CSF has theoretical advantages in managing NEC or sepsis by augmenting neonatal neutrophil number, neutrophil expression of Fcg and complement receptors, as well as phagocytic function and oxidative burst. rhG-CSF also has potent anti-TNFa functions that may serve to limit extension of tissue destruction while not impairing bacterial killing capacity. Healthy, non-infected neutropenic and septic neonates differ in their ability to respond to rhG-CSF; however, no neonatal clinical trials to date

Understanding the gut microbiome of dairy calves: Opportunities to improve early-life gut health.

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Malmuthuge, Nilusha; Guan, Le Luo

2017-07-01

Early gut microbiota plays a vital role in the long-term health of the host. However, understanding of these microbiota is very limited in livestock species, especially in dairy calves. Neonatal calves are highly susceptible to enteric infections, one of the major causes of calf death, so approaches to improving gut health and overall calf health are needed. An increasing number of studies are exploring the microbial composition of the gut, the mucosal immune system, and early dietary interventions to improve the health of dairy calves, revealing possibilities for effectively reducing the susceptibility of calves to enteric infections while promoting growth. Still, comprehensive understanding of the effect of dietary interventions on gut microbiota-one of the key aspects of gut health-is lacking. Such knowledge may provide in-depth understanding of the mechanisms behind functional changes in response to dietary interventions. Understanding of host-microbial interactions with dietary interventions and the role of the gut microbiota during pathogenesis at the site of infection in early life is vital for designing effective tools and techniques to improve calf gut health. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication

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Takahashi, Yasushi; Uno, Kaname; Iijima, Katsunori; Abe, Yasuhiko; Koike, Tomoyuki; Asano, Naoki; Asanuma, Kiyotaka; Shimosegawa, Tooru

2018-01-01

Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endoscopic resection for GC, identified later than 24 months after eradication, and took biopsies by Congo-red chromoendoscopy to distinguish AA and ANA (UMIN00018967). The mucosal barrier function was investigated using a mini-Ussing chamber system and molecular biological methods. The reduction in mucosal impedance in ANA after stimulation was significantly larger than that in AA, 79.6% vs. 87.9%, respectively. The decrease of zonula occludens-1 (ZO-1) and let-7a and the increase of snail in ANA were significant compared to those in AA. In an in vitro study, the restoration of ZO-1 and let-7a as well as the induction of snail were observed after stimulation. High mobility group A2 (HMGA2)-snail activation, MTT proliferation, and cellular infiltration capacity were significantly increased in AGS transfected with let-7a inhibitor, and vice versa. Accordingly, using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to ANA might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammation-associated carcinogenesis even after eradication. PMID:29719591

Food allergens and mucosal immune systems with special reference to recognition of food allergens by gut-associated lymphoid tissue

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Shuichi Kaminogawa

1999-01-01

Full Text Available Food allergy, triggered by an aberrant immune response elicited by orally ingested food allergens, is generated through a complicated mechanism because the allergen interacts with the mucosal immune system (the gut- associated lymphoid tissue, GALT and the resulting immune response affects the generation of allergy. This review will describe the process by which antigens or allergens are recognized by the GALT and the characteristic immune responses induced thereafter. Orally administered antigens induce distinct immune responses in the Peyer's patches, lamina propria and the intestinal epithelium. In addition to these local immune responses in the gut, ingested antigens are known to affect systemic immunity. These may induce a suppressed state of systemic immune responsiveness, which is called oral tolerance, or in some cases they may elicit a systemic IgE antibody response which may lead to allergic reactions. Information on the regions on food allergens recognized by T cells and IgE antibodies is important in understanding the fates of food allergens after being recognized by the GALT. The structure of T and B cell epitopes on food allergens and the possibility of modulation of allergic reactions by amino-acid substituted analogs of allergen- derived peptides will also be discussed.

Infant Nutritional Status, Feeding Practices, Enteropathogen Exposure, Socioeconomic Status, and Illness Are Associated with Gut Barrier Function As Assessed by the Lactulose Mannitol Test in the MAL-ED Birth Cohort.

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Lee, Gwenyth O; McCormick, Benjamin J J; Seidman, Jessica C; Kosek, Margaret N; Haque, Rashidul; Olortegui, Maribel Paredes; Lima, Aldo A M; Bhutta, Zulfiqar A; Kang, Gagandeep; Samie, Amidou; Amour, Caroline; Mason, Carl J; Ahmed, Tahmeed; Yori, Pablo Peñataro; Oliveira, Domingos B; Alam, Didar; Babji, Sudhir; Bessong, Pascal; Mduma, Estomih; Shrestha, Sanjaya K; Ambikapathi, Ramya; Lang, Dennis R; Gottlieb, Michael; Guerrant, Richard L; Caulfield, Laura E; For The Mal-Ed Network Investigators

2017-07-01

The lactulose mannitol (LM) dual sugar permeability test is the most commonly used test of environmental enteropathy in developing countries. However, there is a large but conflicting literature on its association with enteric infection and host nutritional status. We conducted a longitudinal cohort using a single field protocol and comparable laboratory procedures to examine intestinal permeability in multiple, geographically diverse pediatric populations. Using a previously published systematic review to guide the selection of factors potentially associated with LM test results, we examined the relationships between these factors and mucosal breach, represented by percent lactulose excretion; absorptive area, represented by percent mannitol excretion; and gut barrier function, represented by the L/M ratio. A total of 6,602 LM tests were conducted in 1,980 children at 3, 6, 9, and 15 months old; percent lactulose excretion, percent mannitol excretion, and the L/M ratio were expressed as age- and sex-specific normalized values using the Brazil cohort as the reference population. Among the factors considered, recent severe diarrhea, lower socioeconomic status, and recent asymptomatic enteropathogen infections were associated with decreased percent mannitol excretion and higher L/M ratios. Poorer concurrent weight-for-age, infection, and recent breastfeeding were associated with increased percent lactulose excretion and increased L/M ratios. Our results support previously reported associations between the L/M ratio and factors related to child nutritional status and enteropathogen exposure. These results were remarkably consistent across sites and support the hypothesis that the frequency of these exposures in communities living in poverty leads to alterations in gut barrier function.

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells.

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Benedek, Gil; Zhang, Jun; Nguyen, Ha; Kent, Gail; Seifert, Hilary A; Davin, Sean; Stauffer, Patrick; Vandenbark, Arthur A; Karstens, Lisa; Asquith, Mark; Offner, Halina

2017-09-15

Sex hormones promote immunoregulatory effects on multiple sclerosis. In the current study we evaluated the composition of the gut microbiota and the mucosal-associated regulatory cells in estrogen or sham treated female mice before and after autoimmune encephalomyelitis (EAE) induction. Treatment with pregnancy levels of estrogen induces changes in the composition and diversity of gut microbiota. Additionally, estrogen prevents EAE-associated changes in the gut microbiota and might promote the enrichment of bacteria that are associated with immune regulation. Our results point to a possible cross-talk between the sex hormones and the gut microbiota, which could promote neuroprotection. Copyright © 2017 Elsevier B.V. All rights reserved.

Splenectomy attenuates severe thermal trauma-induced intestinal barrier breakdown in rats.

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Liu, Xiang-dong; Chen, Zhen-yong; Yang, Peng; Huang, Wen-guang; Jiang, Chun-fang

2015-12-01

The severe local thermal trauma activates a number of systemic inflammatory mediators, such as TNF-α, NF-κB, resulting in a disruption of gut barrier. The gastrointestinal tight junction (TJ) is highly regulated by membrane-associated proteins including zonula occludens protein-1 (ZO-1) and occludin, which can be modulated by inflammatory cytokines. As splenectomy has been shown to reduce secretion of cytokines, we hypothesized that (1) severe scald injury up-regulates TNF-α and NF-κB, meanwhile down-regulates expression of ZO-1 and occludin, leading to the increased intestinal permeability, and (2) splenectomy can prevent the burn-induced decrease in ZO-1 and occludin expression, resulting in improved intestinal barrier. Wistar rats undergoing a 30% total body surface area (TBSA) thermal trauma were randomized to receive an accessorial splenectomy meanwhile or not. Intestinal injury was assessed by histological morphological analysis, and serum endotoxin levels, TNF-α, NF-κB, ZO-1 and occludin levels were detected by Western blotting in the terminal ileum mucosal tissue. 30% TBSA burn caused a significant increase in serum endotoxin levels, but NF-κB, and TNF-α, and the average intestinal villus height and mucosal thickness were decreased significantly. Burn injury could also markedly decrease the levels of ZO-1 and occludin in terminal ileum mucosal tissue (all PSplenectomy at 7th day after burn significantly reversed the burn-induced breakdown of ZO-1 and occludin (all PSplenectomy may provide a therapeutic benefit in restoring burn-induced intestinal barrier by decreasing the release of inflammatory cytokines and recovering TJ proteins.

Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice.

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Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G; Smokvina, Tamara; Langella, Philippe

2016-01-01

Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4(+) lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4(+) Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability.

Protective effect of lactobacillus acidophilus and isomaltooligosaccharide on intestinal mucosal barriers in rat models of antibiotic-associated diarrhea

International Nuclear Information System (INIS)

Du Dan; Fang Lichao; Chen Bingbo; Wei Hong

2008-01-01

Objective: To investigate the protective effect of synbiotics combined lactobacillus acidophilus and iso-malto-oligosaccharide (IMO) on intestinal mucosal barriers in rat models of antibiotic-associated diarrhea(AAD). Methods: Rat models of AAD were prepared with lincomycin gavage for 5 days. The synbiotics was orally administered to the AAD rats daily at three different strengths for 7 days. The intestinal flora and intestinal mucus SIgA levels were determined on d6, d9 and d13. The histopathological changes of ileal mucosa were studied on d13. Results: In the prepared AAD model rats (on d6) there were lower intestinal mucus SIgA levels and intestinal flora disorders were demonstrated. The intestinal floras of the rats administering synbiotics were readjusted to the similar pattern of healthy rats with bacterial translocation corrected on d13 and the levels of SIgA were not significantly different from of the control (P>0.05). The histopathological picture was basically normal in the treated models on d13. Conclusion: The synbiotics combined lactobacillus acidophilus and isomaltooligosaccharide possessed good protective effect on the intestinal mucosal barrier in lincomycin induced rat models of AAD. (authors)

Primary and Chronic HIV Infection Differently Modulates Mucosal Vδ1 and Vδ2 T-Cells Differentiation Profile and Effector Functions.

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Eleonora Cimini

Full Text Available Gut-associated immune system has been identified as a major battlefield during the early phases of HIV infection. γδ T-cells, deeply affected in number and function after HIV infection, are able to act as a first line of defence against invading pathogens by producing antiviral soluble factors and by killing infected cells. Despite the relevant role in mucosal immunity, few data are available on gut-associated γδ T-cells during HIV infection. Aim of this work was to evaluate how primary (P-HIV and chronic (C-HIV HIV infection affects differentiation profile and functionality of circulating and gut-associated Vδ1 and Vδ2 T-cells. In particular, circulating and mucosal cells were isolated from respectively whole blood and residual gut samples from HIV-infected subjects with primary and chronic infection and from healthy donors (HD. Differentiation profile and functionality were analyzed by multiparametric flow cytometry. P-HIV and C-HIV were characterized by an increase in the frequency of effector Vδ1-T cells both in circulating and mucosal compartments. Moreover, during P-HIV mucosal Vδ1 T-cells expressed high levels of CD107a, suggesting a good effector cytotoxic capability of these cells in the early phase of infection that was lost in C-HIV. P-HIV induced an increase in circulating effector Vδ2 T-cells in comparison to C-HIV and HD. Notably, P-HIV as well as HD were characterized by the ability of mucosal Vδ2 T-cells to spontaneously produce IFN-γ that was lost in C-HIV. Altogether, our data showed for the first time a functional capability of mucosal Vδ1 and Vδ2 T-cells during P-HIV that was lost in C-HIV, suggesting exhaustion mechanisms induced by persistent stimulation.

Enterochromaffin cells of the human gut: sensors for spices and odorants.

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Braun, Thomas; Voland, Petra; Kunz, Lars; Prinz, Christian; Gratzl, Manfred

2007-05-01

Release of serotonin from mucosal enterochromaffin cells triggered by luminal substances is the key event in the regulation of gut motility and secretion. We were interested to know whether nasal olfactory receptors are also expressed in the human gut mucosa by enterochromaffin cells and whether their ligands and odorants present in spices, fragrances, detergents, and cosmetics cause serotonin release. Receptor expression was studied by the reverse-transcription polymerase chain reaction method in human mucosal enterochromaffin cells isolated by laser microdissection and in a cell line derived from human enterochromaffin cells. Activation of the cells by odorants was investigated by digital fluorescence imaging using the fluorescent Ca(2+) indicator Fluo-4. Serotonin release was measured in culture supernatants by a serotonin enzyme immunoassay and amperometry using carbon fiber microelectrodes placed on single cells. We found expression of 4 olfactory receptors in microdissected human mucosal enterochromaffin cells and in a cell line derived from human enterochromaffin cells. Ca(2+) imaging studies revealed that odorant ligands of the identified olfactory receptors cause Ca(2+) influx, elevation of intracellular free Ca(2+) levels, and, consequently, serotonin release. Our results show that odorants present in the luminal environment of the gut may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells. Serotonin controls both gut motility and secretion and is implicated in pathologic conditions such as vomiting, diarrhea, and irritable bowel syndrome. Thus, olfactory receptors are potential novel targets for the treatment of gastrointestinal diseases and motility disorders.

Probiotics, Prebiotics and Immunomodulation of Gut Mucosal Defences: Homeostasis and Immunopathology

Science.gov (United States)

Hardy, Holly; Harris, Jennifer; Lyon, Eleanor; Beal, Jane; Foey, Andrew D.

2013-01-01

Probiotics are beneficial microbes that confer a realistic health benefit on the host, which in combination with prebiotics, (indigestible dietary fibre/carbohydrate), also confer a health benefit on the host via products resulting from anaerobic fermentation. There is a growing body of evidence documenting the immune-modulatory ability of probiotic bacteria, it is therefore reasonable to suggest that this is potentiated via a combination of prebiotics and probiotics as a symbiotic mix. The need for probiotic formulations has been appreciated for the health benefits in “topping up your good bacteria” or indeed in an attempt to normalise the dysbiotic microbiota associated with immunopathology. This review will focus on the immunomodulatory role of probiotics and prebiotics on the cells, molecules and immune responses in the gut mucosae, from epithelial barrier to priming of adaptive responses by antigen presenting cells: immune fate decision—tolerance or activation? Modulation of normal homeostatic mechanisms, coupled with findings from probiotic and prebiotic delivery in pathological studies, will highlight the role for these xenobiotics in dysbiosis associated with immunopathology in the context of inflammatory bowel disease, colorectal cancer and hypersensitivity. PMID:23760057

Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 prevents CCl4-induced liver cirrhosis by protecting the intestinal barrier in rats.

Science.gov (United States)

Shi, Ding; Lv, Longxian; Fang, Daiqiong; Wu, Wenrui; Hu, Chenxia; Xu, Lichen; Chen, Yanfei; Guo, Jing; Hu, Xinjun; Li, Ang; Guo, Feifei; Ye, Jianzhong; Li, Yating; Andayani, Dewi; Li, Lanjuan

2017-07-31

Alterations in the gut microbiome have been reported in liver cirrhosis, and probiotic interventions are considered a potential treatment strategy. This study aimed to evaluate the effects and mechanisms of Lactobacillus salivarius LI01, Pediococcus pentosaceus LI05, Lactobacillus rhamnosus GG, Clostridium butyricum MIYAIRI and Bacillus licheniformis Zhengchangsheng on CCl 4 -induced cirrhotic rats. Only administration of LI01 or LI05 prevented liver fibrosis and down-regulated the hepatic expression of profibrogenic genes. Serum endotoxins, bacterial translocations (BTs), and destruction of intestinal mucosal ultrastructure were reduced in rats treated with LI01 or LI05, indicating maintenance of the gut barrier as a mechanism; this was further confirmed by the reduction of not only hepatic inflammatory cytokines, such as TNF-α, IL-6, and IL-17A, but also hepatic TLR2, TLR4, TLR5 and TLR9. Metagenomic sequencing of 16S rRNA gene showed an increase in potential beneficial bacteria, such as Elusimicrobium and Prevotella, and a decrease in pathogenic bacteria, such as Escherichia. These alterations in gut microbiome were correlated with profibrogenic genes, gut barrier markers and inflammatory cytokines. In conclusion, L. salivarius LI01 and P. pentosaceus LI05 attenuated liver fibrosis by protecting the intestinal barrier and promoting microbiome health. These results suggest novel strategies for the prevention of liver cirrhosis.

Dietary flaxseed modulates the colonic microenvironment in healthy C57Bl/6 male mice which may alter susceptibility to gut-associated diseases.

Science.gov (United States)

Power, Krista A; Lepp, Dion; Zarepoor, Leila; Monk, Jennifer M; Wu, Wenqing; Tsao, Rong; Liu, Ronghua

2016-02-01

Understanding how dietary components alter the healthy baseline colonic microenvironment is important in determining their roles in influencing gut health and gut-associated diseases. Dietary flaxseed (FS) has demonstrated anti-colon cancer effects in numerous rodent models, however, exacerbated acute colonic mucosal injury and inflammation in a colitis model. This study investigates whether FS alters critical aspects of gut health in healthy unchallenged mice, which may help explain some of the divergent effects observed following different gut-associated disease challenges. Four-week-old C57Bl/6 male mice were fed an AIN-93G basal diet (BD) or an isocaloric BD+10% ground FS diet for 3 weeks. FS enhanced colon goblet cell density, mucus production, MUC2 mRNA expression, and cecal short chain fatty acid levels, indicative of beneficial intestinal barrier integrity responses. Additionally, FS enhanced colonic regenerating islet-derived protein 3 gamma (RegIIIγ) and reduced MUC1 and resistin-like molecule beta (RELMβ) mRNA expression which may indicate altered responses in regulating microbial defense and injury repair responses. FS diet altered the fecal microbial community structure (16S rRNA gene profiling), including a 20-fold increase in Prevotella spp. and a 30-fold reduction in Akkermansia muciniphila abundance. A 10-fold reduction in A. muciniphila abundance by FS was also demonstrated in the colon tissue-associated microbiota (quantitative PCR). Furthermore, fecal branched chain fatty acids were increased by FS, indicative of increased microbial-derived putrefactive compounds. In conclusion, consumption of a FS-supplemented diet alters the baseline colonic microenvironment of healthy mice which may modify subsequent mucosal microbial defense and injury-repair responses leading to altered susceptibility to different gut-associated diseases. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Effects of Lactobacillus johnsonii and Lactobacillus reuteri on gut barrier function and heat shock proteins in intestinal porcine epithelial cells.

Science.gov (United States)

Liu, Hao-Yu; Roos, Stefan; Jonsson, Hans; Ahl, David; Dicksved, Johan; Lindberg, Jan Erik; Lundh, Torbjörn

2015-04-01

Heat shock proteins (HSPs) are a set of highly conserved proteins that can serve as intestinal gate keepers in gut homeostasis. Here, effects of a probiotic, Lactobacillus rhamnosus GG (LGG), and two novel porcine isolates, Lactobacillus johnsonii strain P47-HY and Lactobacillus reuteri strain P43-HUV, on cytoprotective HSP expression and gut barrier function, were investigated in a porcine IPEC-J2 intestinal epithelial cell line model. The IPEC-J2 cells polarized on a permeable filter exhibited villus-like cell phenotype with development of apical microvilli. Western blot analysis detected HSP expression in IPEC-J2 and revealed that L. johnsonii and L. reuteri strains were able to significantly induce HSP27, despite high basal expression in IPEC-J2, whereas LGG did not. For HSP72, only the supernatant of L. reuteri induced the expression, which was comparable to the heat shock treatment, which indicated that HSP72 expression was more stimulus specific. The protective effect of lactobacilli was further studied in IPEC-J2 under an enterotoxigenic Escherichia coli (ETEC) challenge. ETEC caused intestinal barrier destruction, as reflected by loss of cell-cell contact, reduced IPEC-J2 cell viability and transepithelial electrical resistance, and disruption of tight junction protein zonula occludens-1. In contrast, the L. reuteri treatment substantially counteracted these detrimental effects and preserved the barrier function. L. johnsonii and LGG also achieved barrier protection, partly by directly inhibiting ETEC attachment. Together, the results indicate that specific strains of Lactobacillus can enhance gut barrier function through cytoprotective HSP induction and fortify the cell protection against ETEC challenge through tight junction protein modulation and direct interaction with pathogens. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis

NARCIS (Netherlands)

Persborn, M.; Gerritsen, J.; Wallon, C.; Carlsson, A.; Akkermans, L.M.A.; Soderholm, J.D.

2013-01-01

Background A total of 10-15% of patients with an ileoanal pouch develop severe pouchitis necessitating long-term use of antibiotics or pouch excision. Probiotics reduce the risk of recurrence of pouchitis, but mechanisms behind these effects are not fully understood. Aim To examine mucosal barrier

Chitosan-Based Nanoparticles for Mucosal Delivery of RNAi Therapeutics

DEFF Research Database (Denmark)

Martirosyan, Alina; Olesen, Morten Jarlstad; Howard, Kenneth A.

2014-01-01

of the polysaccharide chitosan have been used to facilitate delivery of siRNA across mucosal surfaces following local administration. This chapter describes the mucosal barriers that need to be addressed in order to design an effective mucosal delivery strategy and the utilization of the mucoadhesive properties...... of chitosan. Focus is given to preparation methods and the preclinical application of chitosan nanoparticles for respiratory and oral delivery of siRNA....

Specific inulin-type fructan fibers protect against autoimmune diabetes by modulating gut immunity, barrier function, and microbiota homeostasis

NARCIS (Netherlands)

Chen, Kang; Chen, Hao; Faas, Marijke M; de Haan, Bart J; Li, Jiahong; Xiao, Ping; Zhang, Hao; Diana, Julien; de Vos, Paul; Sun, Jia

Scope: Dietary fibers capable of modifying gut barrier and microbiota homeostasis affect the progression of type 1 diabetes (T1D). Here, we aim to compare modulatory effects of inulin-type fructans (ITFs), natural soluble dietary fibers with different degrees of fermentability from chicory root, on

Electroacupuncture at Zusanli Prevents Severe Scalds-Induced Gut Ischemia and Paralysis by Activating the Cholinergic Pathway

Directory of Open Access Journals (Sweden)

Huan Wang

2015-01-01

Full Text Available Severe burn injuries may result in gastrointestinal paralysis, and barrier dysfunction due to gut ischemia and lowered vagus excitability. In this study we investigate whether electroacupuncture (EA at Zusanli (ST36 could prevent severe scalds-induced gut ischemia, paralysis, and barrier dysfunction and whether the protective role of EA at ST36 is related to the vagus nerve. 35% burn area rats were divided into six groups: (a EAN: EA nonchannel acupoints followed by scald injury; (b EA: EA at ST36 after scald injury; (c VGX/EA: vagotomy (VGX before EA at ST36 and scald injury; (d VGX/EAN: VGX before EAN and scald injury; (e atropine/EA: applying atropine before scald injury and then EA at ST36; (f atropine/EAN: applying atropine before scald injury and then EA at nonchannel acupoints. EA at the Zusanli point significantly promoted the intestinal impelling ratio and increased the amount of mucosal blood flow after scald injury. The plasma diamine oxidase (DAO and intestinal permeability decreased significantly after scald injury in the EA group compared with others. However, EA after atropine injection or cervical vagotomy failed to improve intestinal motility and mucosa blood flow suggesting that the mechanism of EA may be related to the activation of the cholinergic nerve pathway.

Human colorectal mucosal microbiota correlates with its host niche physiology revealed by endomicroscopy.

Science.gov (United States)

Wang, Ai-Hua; Li, Ming; Li, Chang-Qing; Kou, Guan-Jun; Zuo, Xiu-Li; Li, Yan-Qing

2016-02-26

The human gut microbiota plays a pivotal role in the maintenance of health, but how the microbiota interacts with the host at the colorectal mucosa is poorly understood. We proposed that confocal laser endomicroscopy (CLE) might help to untangle this relationship by providing in vivo physiological information of the mucosa. We used CLE to evaluate the in vivo physiology of human colorectal mucosa, and the mucosal microbiota was quantified using 16 s rDNA pyrosequencing. The human mucosal microbiota agglomerated to three major clusters dominated by Prevotella, Bacteroides and Lactococcus. The mucosal microbiota clusters did not significantly correlate with the disease status or biopsy sites but closely correlated with the mucosal niche physiology, which was non-invasively revealed by CLE. Inflammation tilted two subnetworks within the mucosal microbiota. Infiltration of inflammatory cells significantly correlated with multiple components in the predicted metagenome, such as the VirD2 component of the type IV secretory pathway. Our data suggest that a close correlation exists between the mucosal microbiota and the colorectal mucosal physiology, and CLE is a clinically available tool that can be used to facilitate the study of the in vivo correlation between colorectal mucosal physiology and the mucosal microbiota.

Barrier effect of Esoxx® on esophageal mucosal damage: experimental study on ex-vivo swine model

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Di Simone MP

2012-06-01

Full Text Available Massimo P Di Simone,1 Fabio Baldi,2,3 Valentina Vasina,4 Fabrizio Scorrano,5 Maria Laura Bacci,5 Antonella Ferrieri,6 Gilberto Poggioli11Department of General Surgery and Transplants, 2Centre for the Study and Therapy of the Esophageal Diseases, 3GVM Care and Research, MCH Cotignola (RA, 4Department of Pharmacology, Alma Mater Studiorum, University of Bologna, Bologna, 5Department of Veterinary Medical Science – DMSVET – University of Bologna, Bologna, 6Clinical Research Department, Alfa Wassermann Spa, Bologna, ItalyAbstract: The aim of the present study was to assess the potential barrier effect of Esoxx®, a new nonprescription medication under development for the relief of gastroesophageal reflux symptoms. Esoxx is based on a mixture of hyaluronic acid and chondroitin sulfate in a bioadhesive suspension of Lutrol® F 127 polymer (poloxamer 407 which facilitates the product adhesion on the esophageal mucosa. The mucosal damage was induced by 15 to 90 minutes of perfusion with an acidic solution (HCl, pH 1.47 with or without pepsin (2000 U/mL, acidified to pH 2; Sigma-Aldrich. Mucosal esophageal specimens were histologically evaluated and Evans blue dye solution was used to assess the permeability of the swine mucosa after the chemical injury. The results show that: (1 esophageal mucosal damage is related to the perfusion time and to the presence of pepsin, (2 mucosal damage is associated with an increased permeability, documented by an evident Evans blue staining, (3 perfusion with Esoxx is able to reduce the permeability of the injured mucosa, even after saline washing of the swine esophagus. These preliminary results support further clinical studies of Esoxx in the topical treatment of gastroesophageal reflux symptoms.Keywords: bioadhesion, hyaluronic acid, Evans blue dye, animal model, esophagus, reflux esophagitis

Multiscale modeling of mucosal immune responses

Science.gov (United States)

2015-01-01

Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM. Background Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Implementation Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. Conclusion We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut

Multiscale modeling of mucosal immune responses.

Science.gov (United States)

Mei, Yongguo; Abedi, Vida; Carbo, Adria; Zhang, Xiaoying; Lu, Pinyi; Philipson, Casandra; Hontecillas, Raquel; Hoops, Stefan; Liles, Nathan; Bassaganya-Riera, Josep

2015-01-01

Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation.Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T

Mucosal immunogenicity of plant lectins in mice

Science.gov (United States)

Lavelle, E C; Grant, G; Pusztai, A; Pfüller, U; O’Hagan, D T

2000-01-01

The mucosal immunogenicity of a number of plant lectins with different sugar specificities was investigated in mice. Following intranasal (i.n.) or oral administration, the systemic and mucosal antibody responses elicited were compared with those induced by a potent mucosal immunogen (cholera toxin; CT) and a poorly immunogenic protein (ovalbumin; OVA). After three oral or i.n. doses of CT, high levels of specific serum antibodies were measured and specific IgA was detected in the serum, saliva, vaginal wash, nasal wash and gut wash of mice. Immunization with OVA elicited low titres of serum IgG but specific IgA was not detected in mucosal secretions. Both oral and i.n. delivery of all five plant lectins investigated [Viscum album (mistletoe lectin 1; ML‐1), Lycospersicum esculentum (tomato lectin; LEA), Phaseolus vulgaris (PHA), Triticum vulgaris (wheat germ agglutinin (WGA), Ulex europaeus I (UEA‐1)] stimulated the production of specific serum IgG and IgA antibody after three i.n. or oral doses. Immunization with ML‐1 induced high titres of serum IgG and IgA in addition to specific IgA in mucosal secretions. The response to orally delivered ML‐1 was comparable to that induced by CT, although a 10‐fold higher dose was administered. Immunization with LEA also induced high titres of serum IgG, particularly after i.n. delivery. Low specific IgA titres were also detected to LEA in mucosal secretions. Responses to PHA, WGA and UEA‐1 were measured at a relatively low level in the serum, and little or no specific mucosal IgA was detected. PMID:10651938

Probiotics and the Gut Immune System: Indirect Regulation.

Science.gov (United States)

La Fata, Giorgio; Weber, Peter; Mohajeri, M Hasan

2018-03-01

The gastrointestinal tract (GIT) represents the largest interface between the human organism and the external environment. In the lumen and upper part of the mucus layer, this organ hosts an enormous number of microorganisms whose composition affects the functions of the epithelial barrier and the gut immune system. Consequentially, the microorganisms in the GIT influence the health status of the organism. Probiotics are living microorganisms which, in specific conditions, confer a health benefit to the host. Among others, probiotics have immunomodulatory properties that usually act directly by (a) increasing the activity of macrophages or natural killer cells, (b) modulating the secretion of immunoglobulins or cytokines, or indirectly by (c) enhancing the gut epithelial barrier, (d) altering the mucus secretion, and (e) competitive exclusion of other (pathogenic) bacteria. This review focuses on specific bacteria strains with indirect immunomodulatory properties. Particularly, we describe here the mechanisms through which specific probiotics enhance the gut epithelial barrier and modulate mucus production. Moreover, we describe the antimicrobial properties of specific bacteria strains. Recent data suggest that multiple pathologies are associated with an unbalanced gut microflora (dysbiosis). Although the cause-effect relationship between pathology and gut microflora is not yet well established, consumption of specific probiotics may represent a powerful tool to re-establish gut homeostasis and promote gut health.

Effect of feeding soybean meal and differently processed peas on the gut mucosal immune system of broilers.

Science.gov (United States)

Röhe, I; Göbel, T W; Goodarzi Boroojeni, F; Zentek, J

2017-07-01

Peas are traditionally used as a protein source for poultry. However, peas contain antinutritional factors (ANF), which are associated with the initiation of local and systemic immune reactions. The current study examined the effect of feeding raw or differently processed peas in comparison with feeding a soybean meal (SBM) based control diet (C) on the gut mucosal immune system of broilers in a 35 day feeding trial. In six replicates, a total of 360 one-day-old male broilers were randomly allocated to four different groups receiving C, or three treatment diets containing raw, fermented, and enzymatically pre-digested peas, each supplying 30% of required crude protein. After slaughtering, jejunal samples were taken for immunohistochemical, flow cytometric, and gene expression analyses. Investigations were focused on the topological distribution of intraepithelial leukocytes (villus tip, villus mid, and crypt region) as well as on the further characterization of the different intraepithelial lymphocytes (IEL) and concomitant pro- and anti-inflammatory cytokines. Broilers receiving the raw or processed pea diets had higher numbers of intraepithelial CD45+ leukocytes in the tip (P = 0.004) and mid region (P pea containing diets in comparison with those fed C. The flow cytometric phenotyping showed a similar relative distribution of IEL among the feeding groups. The expression of intestinal pro- and anti-inflammatory cytokines was affected by feeding the different diets only to a minor extent. To conclude, feeding of diets formulated with raw and processed peas in comparison with feeding a SBM control diet initiated mucosal immune responses in the jejunum of broilers indicated by a quantitative increase of intraepithelial T cells. Further research is needed in order to ascertain the specific factors which are responsible for observed local immune reactions and how these local reactions might affect the immune status and health of broilers. © 2017 Poultry Science

Stress-related IBS | Outhoff | South African Family Practice

African Journals Online (AJOL)

The gastrointestinal tract is exquisitely sensitive to different physical and psychological stressors. Irritable ... but also other potentially important factors such as gut motility, intestinal mucosal permeability and barrier functioning, visceral sensitivity, mucosal blood flow, immune cell reactivity and enteric microbiota composition.

The Treg/Th17 axis: A dynamic balance regulated by the gut microbiome

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Sara eOmenetti

2015-12-01

Full Text Available T-helper 17 (Th17 and T-regulatory (Treg cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naïve T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFβ, IL-6 and all-trans retinoic acid (RA. Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate, and downstream adaptive, immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1β, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease (IBD. In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease.

Effect of early-life gut mucosal compromise on disease progression in NOD mice

DEFF Research Database (Denmark)

Bendtsen, Katja M.; Hansen, Camilla HF; Krych, Lukasz

2017-01-01

Disease expression in spontaneous nonobese diabetic (NOD) mice depends on environmental stimuli such as stress, diet, and gut microbiota composition. We evaluated a brief, early-life gut intervention in which pups were weaned to low-dose dextran sulfate sodium (DSS). We hypothesized that the mucus...

Exposure to bacterial DNA before hemorrhagic shock strongly aggravates systemic inflammation and gut barrier loss via an IFN-gamma-dependent route

NARCIS (Netherlands)

Luyer, Misha D.; Buurman, Wim A.; Hadfoune, M.'hamed; Wolfs, T.; van't Veer, Cornelis; Jacobs, Jan A.; Dejong, Cornelis H.; Greve, Jan Willem M.

2007-01-01

OBJECTIVE: To investigate the role of bacterial DNA in development of an excessive inflammatory response and loss of gut barrier loss following systemic hypotension. SUMMARY BACKGROUND DATA: Bacterial infection may contribute to development of inflammatory complications following major surgery;

Roles of Mucosal Immunity against Mycobacterium tuberculosis Infection

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Wu Li

2012-01-01

Full Text Available Mycobacterium tuberculosis (Mtb, the causative agent of tuberculosis (TB, is one of the world's leading infectious causes of morbidity and mortality. As a mucosal-transmitted pathogen, Mtb infects humans and animals mainly through the mucosal tissue of the respiratory tract. Apart from providing a physical barrier against the invasion of pathogen, the major function of the respiratory mucosa may be to serve as the inductive sites to initiate mucosal immune responses and sequentially provide the first line of defense for the host to defend against this pathogen. A large body of studies in the animals and humans have demonstrated that the mucosal immune system, rather than the systemic immune system, plays fundamental roles in the host’s defense against Mtb infection. Therefore, the development of new vaccines and novel delivery routes capable of directly inducing respiratory mucosal immunity is emphasized for achieving enhanced protection from Mtb infection. In this paper, we outline the current state of knowledge regarding the mucosal immunity against Mtb infection, including the development of TB vaccines, and respiratory delivery routes to enhance mucosal immunity are discussed.

Alterations in Gut Microbiome Composition and Barrier Function Are Associated with Reproductive and Metabolic Defects in Women with Polycystic Ovary Syndrome (PCOS: A Pilot Study.

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Lisa Lindheim

Full Text Available Polycystic ovary syndrome (PCOS is a common female endocrinopathy of unclear origin characterized by hyperandrogenism, oligo-/anovulation, and ovarian cysts. Women with PCOS frequently display overweight, insulin resistance, and systemic low-grade inflammation. We hypothesized that endotoxemia resulting from a leaky gut is associated with inflammation, insulin resistance, fat accumulation, and hyperandrogenemia in PCOS. In this pilot study, we compared the stool microbiome, gut permeability, and inflammatory status of women with PCOS and healthy controls.16S rRNA gene amplicon sequencing was performed on stool samples from 24 PCOS patients and 19 healthy controls. Data processing and microbiome analysis were conducted in mothur and QIIME using different relative abundance cut-offs. Gut barrier integrity, endotoxemia, and inflammatory status were evaluated using serum and stool markers and associations with reproductive, metabolic, and anthropometric parameters were investigated.The stool microbiome of PCOS patients showed a lower diversity and an altered phylogenetic composition compared to controls. We did not observe significant differences in any taxa with a relative abundance>1%. When looking at rare taxa, the relative abundance of bacteria from the phylum Tenericutes, the order ML615J-28 (phylum Tenericutes and the family S24-7 (phylum Bacteroidetes was significantly lower and associated with reproductive parameters in PCOS patients. Patients showed alterations in some, but not all markers of gut barrier function and endotoxemia.Patients with PCOS have a lower diversity and an altered phylogenetic profile in their stool microbiome, which is associated with clinical parameters. Gut barrier dysfunction and endotoxemia were not driving factors in this patient cohort, but may contribute to the clinical phenotype in certain PCOS patients.

Alterations in Gut Microbiome Composition and Barrier Function Are Associated with Reproductive and Metabolic Defects in Women with Polycystic Ovary Syndrome (PCOS): A Pilot Study.

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Lindheim, Lisa; Bashir, Mina; Münzker, Julia; Trummer, Christian; Zachhuber, Verena; Leber, Bettina; Horvath, Angela; Pieber, Thomas R; Gorkiewicz, Gregor; Stadlbauer, Vanessa; Obermayer-Pietsch, Barbara

2017-01-01

Polycystic ovary syndrome (PCOS) is a common female endocrinopathy of unclear origin characterized by hyperandrogenism, oligo-/anovulation, and ovarian cysts. Women with PCOS frequently display overweight, insulin resistance, and systemic low-grade inflammation. We hypothesized that endotoxemia resulting from a leaky gut is associated with inflammation, insulin resistance, fat accumulation, and hyperandrogenemia in PCOS. In this pilot study, we compared the stool microbiome, gut permeability, and inflammatory status of women with PCOS and healthy controls. 16S rRNA gene amplicon sequencing was performed on stool samples from 24 PCOS patients and 19 healthy controls. Data processing and microbiome analysis were conducted in mothur and QIIME using different relative abundance cut-offs. Gut barrier integrity, endotoxemia, and inflammatory status were evaluated using serum and stool markers and associations with reproductive, metabolic, and anthropometric parameters were investigated. The stool microbiome of PCOS patients showed a lower diversity and an altered phylogenetic composition compared to controls. We did not observe significant differences in any taxa with a relative abundance>1%. When looking at rare taxa, the relative abundance of bacteria from the phylum Tenericutes, the order ML615J-28 (phylum Tenericutes) and the family S24-7 (phylum Bacteroidetes) was significantly lower and associated with reproductive parameters in PCOS patients. Patients showed alterations in some, but not all markers of gut barrier function and endotoxemia. Patients with PCOS have a lower diversity and an altered phylogenetic profile in their stool microbiome, which is associated with clinical parameters. Gut barrier dysfunction and endotoxemia were not driving factors in this patient cohort, but may contribute to the clinical phenotype in certain PCOS patients.

Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

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Tornai, Tamas; Palyu, Eszter; Vitalis, Zsuzsanna; Tornai, Istvan; Tornai, David; Antal-Szalmas, Peter; Norman, Gary L; Shums, Zakera; Veres, Gabor; Dezsofi, Antal; Par, Gabriella; Par, Alajos; Orosz, Peter; Szalay, Ferenc; Lakatos, Peter Laszlo; Papp, Maria

2017-01-01

AIM To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients. METHODS Sera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various anti-microbial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls. RESULTS A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG (P < 0.001, for both) and AGA IgG (P = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), P = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), P = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies (P < 0.001 for EndoCab IgA and P = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABPAAA IgA pos vs neg: 365 vs 166 pg/mL, P = 0.011), but not with serum LBP level. CONCLUSION Presence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

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Donjete Statovci

2017-07-01

Full Text Available Recent findings point toward diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host’s physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota, and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fiber, represent a growing health risk contributing to the increased occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory bowel diseases (IBD and asthma are chronic mucosal inflammatory conditions of unknown etiology with increasing prevalence worldwide. These conditions have a multifactorial etiology including genetic factors, environmental factors, and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibers, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma.

MicroRNA-orchestrated pathophysiologic control in gut homeostasis and inflammation.

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Lee, Juneyoung; Park, Eun Jeong; Kiyono, Hiroshi

2016-05-01

The intestine represents the largest and most elaborate immune system organ, in which dynamic and reciprocal interplay among numerous immune and epithelial cells, commensal microbiota, and external antigens contributes to establishing both homeostatic and pathologic conditions. The mechanisms that sustain gut homeostasis are pivotal in maintaining gut health in the harsh environment of the gut lumen. Intestinal epithelial cells are critical players in creating the mucosal platform for interplay between host immune cells and luminal stress inducers. Thus, knowledge of the epithelial interface between immune cells and the luminal environment is a prerequisite for a better understanding of gut homeostasis and pathophysiologies such as inflammation. In this review, we explore the importance of the epithelium in limiting or promoting gut inflammation (e.g., inflammatory bowel disease). We also introduce recent findings on how small RNAs such as microRNAs orchestrate pathophysiologic gene regulation. [BMB Reports 2016; 49(5): 263-269].

Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila.

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Lee, Kyung-Ah; Kim, Sung-Hee; Kim, Eun-Kyoung; Ha, Eun-Mi; You, Hyejin; Kim, Boram; Kim, Min-Ji; Kwon, Youngjoo; Ryu, Ji-Hwan; Lee, Won-Jae

2013-05-09

All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions. Copyright © 2013 Elsevier Inc. All rights reserved.

Trypanosome infection establishment in the tsetse fly gut is influenced by microbiome-regulated host immune barriers.

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Brian L Weiss

Full Text Available Tsetse flies (Glossina spp. vector pathogenic African trypanosomes, which cause sleeping sickness in humans and nagana in domesticated animals. Additionally, tsetse harbors 3 maternally transmitted endosymbiotic bacteria that modulate their host's physiology. Tsetse is highly resistant to infection with trypanosomes, and this phenotype depends on multiple physiological factors at the time of challenge. These factors include host age, density of maternally-derived trypanolytic effector molecules present in the gut, and symbiont status during development. In this study, we investigated the molecular mechanisms that result in tsetse's resistance to trypanosomes. We found that following parasite challenge, young susceptible tsetse present a highly attenuated immune response. In contrast, mature refractory flies express higher levels of genes associated with humoral (attacin and pgrp-lb and epithelial (inducible nitric oxide synthase and dual oxidase immunity. Additionally, we discovered that tsetse must harbor its endogenous microbiome during intrauterine larval development in order to present a parasite refractory phenotype during adulthood. Interestingly, mature aposymbiotic flies (Gmm(Apo present a strong immune response earlier in the infection process than do WT flies that harbor symbiotic bacteria throughout their entire lifecycle. However, this early response fails to confer significant resistance to trypanosomes. Gmm(Apo adults present a structurally compromised peritrophic matrix (PM, which lines the fly midgut and serves as a physical barrier that separates luminal contents from immune responsive epithelial cells. We propose that the early immune response we observe in Gmm(Apo flies following parasite challenge results from the premature exposure of gut epithelia to parasite-derived immunogens in the absence of a robust PM. Thus, tsetse's PM appears to regulate the timing of host immune induction following parasite challenge. Our results

Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

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Bleier, Benjamin S; Kohman, Richie E; Feldman, Rachel E; Ramanlal, Shreshtha; Han, Xue

2013-01-01

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

Gut microbiota and metabolic syndrome.

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Festi, Davide; Schiumerini, Ramona; Eusebi, Leonardo Henry; Marasco, Giovanni; Taddia, Martina; Colecchia, Antonio

2014-11-21

Gut microbiota exerts a significant role in the pathogenesis of the metabolic syndrome, as confirmed by studies conducted both on humans and animal models. Gut microbial composition and functions are strongly influenced by diet. This complex intestinal "superorganism" seems to affect host metabolic balance modulating energy absorption, gut motility, appetite, glucose and lipid metabolism, as well as hepatic fatty storage. An impairment of the fine balance between gut microbes and host's immune system could culminate in the intestinal translocation of bacterial fragments and the development of "metabolic endotoxemia", leading to systemic inflammation and insulin resistance. Diet induced weight-loss and bariatric surgery promote significant changes of gut microbial composition, that seem to affect the success, or the inefficacy, of treatment strategies. Manipulation of gut microbiota through the administration of prebiotics or probiotics could reduce intestinal low grade inflammation and improve gut barrier integrity, thus, ameliorating metabolic balance and promoting weight loss. However, further evidence is needed to better understand their clinical impact and therapeutic use.

Colonic transit time is related to bacterial metabolism and mucosal turnover in the human gut

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Roager, Henrik Munch; Hansen, Lea Benedicte Skov; Bahl, Martin Iain

Little is known about how colonic transit time relates to human colonic metabolism, and its importance for host health, although stool consistency, a proxy for colonic transit time, has recently been negatively associated with gut microbial richness. To address the relationships between colonic t...... imply a healthy gut microbial ecosystem and points at colonic transit time as a highly important factor to consider in microbiome and metabolomics studies.......Little is known about how colonic transit time relates to human colonic metabolism, and its importance for host health, although stool consistency, a proxy for colonic transit time, has recently been negatively associated with gut microbial richness. To address the relationships between colonic...... transit time and the gut microbial composition and metabolism, we assessed the colonic transit time of 98 subjects using radiopaque markers, and profiled their gut microbiota by16S rRNA gene sequencing and their urine metabolome by ultra performance liquid chromatography mass spectrometry. Based...

A molecular analysis of fecal and mucosal bacterial communities in irritable bowel syndrome.

LENUS (Irish Health Repository)

Codling, Caroline

2010-02-01

The objectives of this study were, firstly, to determine the diversity of the host\\'s gut microbiota in irritable bowel syndrome (IBS) using a culture-independent method (DGGE of the 16S rRNA gene) and, secondly, to examine mucosal biopsies of IBS patients and compare them to their own fecal microbiota.

Intestinal barrier: A gentlemen's agreement between microbiota and immunity.

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Caricilli, Andrea Moro; Castoldi, Angela; Câmara, Niels Olsen Saraiva

2014-02-15

Our body is colonized by more than a hundred trillion commensals, represented by viruses, bacteria and fungi. This complex interaction has shown that the microbiome system contributes to the host's adaptation to its environment, providing genes and functionality that give flexibility of diet and modulate the immune system in order not to reject these symbionts. In the intestine, specifically, the microbiota helps developing organ structures, participates of the metabolism of nutrients and induces immunity. Certain components of the microbiota have been shown to trigger inflammatory responses, whereas others, anti-inflammatory responses. The diversity and the composition of the microbiota, thus, play a key role in the maintenance of intestinal homeostasis and explain partially the link between intestinal microbiota changes and gut-related disorders in humans. Tight junction proteins are key molecules for determination of the paracellular permeability. In the context of intestinal inflammatory diseases, the intestinal barrier is compromised, and decreased expression and differential distribution of tight junction proteins is observed. It is still unclear what is the nature of the luminal or mucosal factors that affect the tight junction proteins function, but the modulation of the immune cells found in the intestinal lamina propria is hypothesized as having a role in this modulation. In this review, we provide an overview of the current understanding of the interaction of the gut microbiota with the immune system in the development and maintenance of the intestinal barrier.

Colonic transit time is related to bacterial metabolism and mucosal turnover in the gut

DEFF Research Database (Denmark)

Roager, Henrik Munch; Hansen, Lea Benedicte Skov; Bahl, Martin Iain

2016-01-01

Little is known about how colonic transit time relates to human colonic metabolism and its importance for host health, although a firm stool consistency, a proxy for a long colonic transit time, has recently been positively associated with gut microbial richness. Here, we show that colonic transi...... does not per se imply a healthy gut microbial ecosystem and points at colonic transit time as a highly important factor to consider in microbiome and metabolomics studies.......Little is known about how colonic transit time relates to human colonic metabolism and its importance for host health, although a firm stool consistency, a proxy for a long colonic transit time, has recently been positively associated with gut microbial richness. Here, we show that colonic transit...... time in humans, assessed using radio-opaque markers, is associated with overall gut microbial composition, diversity and metabolism. We find that a long colonic transit time associates with high microbial richness and is accompanied by a shift in colonic metabolism from carbohydrate fermentation...

Colonization and effector functions of innate lymphoid cells in mucosal tissues

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Kim, Myunghoo; Kim, Chang H.

2016-01-01

Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. PMID:27365193

Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice

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Pineton de Chambrun, G; Body-Malapel, M; Frey-Wagner, I; Djouina, M; Deknuydt, F; Atrott, K; Esquerre, N; Altare, F; Neut, C; Arrieta, M C; Kanneganti, T-D; Rogler, G; Colombel, J-F; Cortot, A; Desreumaux, P; Vignal, C

2014-01-01

The increasing incidence of inflammatory bowel diseases (IBDs) in developing countries has highlighted the critical role of environmental pollutants as causative factors in their pathophysiology. Despite its ubiquity and immune toxicity, the impact of aluminum in the gut is not known. This study aimed to evaluate the effects of environmentally relevant intoxication with aluminum in murine models of colitis and to explore the underlying mechanisms. Oral administration of aluminum worsened intestinal inflammation in mice with 2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis and chronic colitis in interleukin 10-negative (IL10−/−) mice. Aluminum increased the intensity and duration of macroscopic and histologic inflammation, colonic myeloperoxidase activity, inflammatory cytokines expression, and decreased the epithelial cell renewal compared with control animals. Under basal conditions, aluminum impaired intestinal barrier function. In vitro, aluminum induced granuloma formation and synergized with lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial cells. Deleterious effects of aluminum on intestinal inflammation and mucosal repair strongly suggest that aluminum might be an environmental IBD risk factor. PMID:24129165

Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.

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Lorentz, C Adam; Liang, Zhe; Meng, Mei; Chen, Ching-Wen; Yoseph, Benyam P; Breed, Elise R; Mittal, Rohit; Klingensmith, Nathan J; Farris, Alton B; Burd, Eileen M; Koval, Michael; Ford, Mandy L; Coopersmith, Craig M

2017-06-07

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK -/- and wild type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK -/- mice (95% vs. 24%, p<0.0001). Intestinal permeability increased in septic WT mice compared to unmanipulated mice. In contrast, permeability in septic MLCK -/- mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK -/- mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8, 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK -/- mice; however, survival was similar between septic MLCK -/- mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

Gut-associated lymphoid tissue contains the molecular machinery to support T-cell-dependent and T-cell-independent class switch recombination.

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Barone, F; Patel, P; Sanderson, J D; Spencer, J

2009-11-01

A PRoliferation-Inducing Ligand (APRIL) is a secreted cytokine member of the tumor necrosis factor family. It is a B-cell survival factor that also induces class switch recombination (CSR) toward immunoglobulin A (IgA), independent of T cells. It is therefore an important contributor to the maintenance of the mucosal immunological barrier, which has been linked to a putative extrafollicular inductive phase of the IgA response in lamina propria. By immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) on microdissected tissue from normal human gut, we observed APRIL expression, together with TACI (transmembrane activator and CAML interactor) and BCMA (B-cell maturation antigen), in gut-associated lymphoid tissue (GALT), lamina propria, and in the epithelium of stomach, small and large intestine, and rectum. However, no activation-induced cytidine deaminase (AID) expression (an absolute requirement for class switching) was detected in lamina propria by IHC or qRT-PCR. APRIL and its receptors were only observed alongside AID in GALT, showing that GALT contains the apparatus to support both T-independent and T-dependent routes to IgA CSR.

Dietary Lactobacillus rhamnosus GG Supplementation Improves the Mucosal Barrier Function in the Intestine of Weaned Piglets Challenged by Porcine Rotavirus.

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Xiangbing Mao

Full Text Available Lactobacillus rhamnosus GG (LGG has been regarded as a safe probiotic strain. The aim of this study was to investigate whether dietary LGG supplementation could alleviate diarrhea via improving jejunal mucosal barrier function in the weaned piglets challenged by RV, and further analyze the potential roles for apoptosis of jejunal mucosal cells and intestinal microbiota. A total of 24 crossbred barrows weaned at 21 d of age were assigned randomly to 1 of 2 diets: the basal diet and LGG supplementing diet. On day 11, all pigs were orally infused RV or the sterile essential medium. RV infusion increased the diarrhea rate, increased the RV-Ab, NSP4 and IL-2 concentrations and the Bax mRNA levels of jejunal mucosa (P<0.05, decreased the villus height, villus height: crypt depth, the sIgA, IL-4 and mucin 1 concentrations and the ZO-1, occludin and Bcl-2 mRNA levels of jejunal mucosa (P<0.05, and affected the microbiota of ileum and cecum (P<0.05 in the weaned pigs. Dietary LGG supplementation increased the villus height and villus height: crypt depth, the sIgA, IL-4, mucin 1 and mucin 2 concentrations, and the ZO-1, occludin and Bcl-2 mRNA levels of the jejunal mucosa (P<0.05 reduced the Bax mRNA levels of the jejunal mucosa (P<0.05 in weaned pigs. Furthermore, dietary LGG supplementation alleviated the increase of diarrhea rate in the weaned pigs challenged by RV (P<0.05, and relieve the effect of RV infection on the villus height, crypt depth and the villus height: crypt depth of the jejunal mucosa (P<0.05, the NSP4, sIgA, IL-2, IL-4, mucin 1 and mucin 2 concentrations of jejunal mucosa (P<0.05, the ZO-1, occludin, Bax and Bcl-2 mRNA levels of the jejunal mucosa (P<0.05, and the microbiota of ileum and cecum (P<0.05 in the weaned pigs challenged by RV. These results suggest that supplementing LGG in diets alleviated the diarrhea of weaned piglets challenged by RV via inhibiting the virus multiplication and improving the jejunal mucosal barrier

Side chain variations radically alter the diffusion of poly(2-alkyl-2-oxazoline) functionalised nanoparticles through a mucosal barrier.

Science.gov (United States)

Mansfield, Edward D H; de la Rosa, Victor R; Kowalczyk, Radoslaw M; Grillo, Isabelle; Hoogenboom, Richard; Sillence, Katy; Hole, Patrick; Williams, Adrian C; Khutoryanskiy, Vitaliy V

2016-08-16

Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in particular, mucus penetrating nanoparticles may improve drug bioavailability via the oral route. To date, few polymers have been investigated for their muco-penetration, and the effects of systematic structural changes to polymer architectures on the penetration and diffusion of functionalised nanomaterials through mucosal tissue have not been reported. We investigated the influence of poly(2-oxazoline) alkyl side chain length on nanoparticle diffusion; poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), and poly(2-n-propyl-2-oxazoline) were grafted onto the surface of thiolated silica nanoparticles and characterised by FT-IR, Raman and NMR spectroscopy, thermogravimetric analysis, and small angle neutron scattering. Diffusion coefficients were determined in water and in a mucin dispersion (using Nanoparticle Tracking Analysis), and penetration through a mucosal barrier was assessed using an ex vivo fluorescence technique. The addition of a single methylene group in the side chain significantly altered the penetration and diffusion of the materials in both mucin dispersions and mucosal tissue. Nanoparticles functionalised with poly(2-methyl-2-oxazoline) were significantly more diffusive than particles with poly(2-ethyl-2-oxazoline) while particles with poly(2-n-propyl-2-oxazoline) showed no significant increase compared to the unfunctionalised particles. These data show that variations in the polymer structure can radically alter their diffusive properties with clear implications for the future design of mucus penetrating systems.

Development of the intrinsic and extrinsic innervation of the gut.

Science.gov (United States)

Uesaka, Toshihiro; Young, Heather M; Pachnis, Vassilis; Enomoto, Hideki

2016-09-15

The gastrointestinal (GI) tract is innervated by intrinsic enteric neurons and by extrinsic efferent and afferent nerves. The enteric (intrinsic) nervous system (ENS) in most regions of the gut consists of two main ganglionated layers; myenteric and submucosal ganglia, containing numerous types of enteric neurons and glial cells. Axons arising from the ENS and from extrinsic neurons innervate most layers of the gut wall and regulate many gut functions. The majority of ENS cells are derived from vagal neural crest cells (NCCs), which proliferate, colonize the entire gut, and first populate the myenteric region. After gut colonization by vagal NCCs, the extrinsic nerve fibers reach the GI tract, and Schwann cell precursors (SCPs) enter the gut along the extrinsic nerves. Furthermore, a subpopulation of cells in myenteric ganglia undergoes a radial (inward) migration to form the submucosal plexus, and the intrinsic and extrinsic innervation to the mucosal region develops. Here, we focus on recent progress in understanding the developmental processes that occur after the gut is colonized by vagal ENS precursors, and provide an up-to-date overview of molecular mechanisms regulating the development of the intrinsic and extrinsic innervation of the GI tract. Copyright © 2016 Elsevier Inc. All rights reserved.

High-Altitude-Induced alterations in Gut-Immune Axis: A review.

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Khanna, Kunjan; Mishra, K P; Ganju, Lilly; Kumar, Bhuvnesh; Singh, Shashi Bala

2018-03-04

High-altitude sojourn above 8000 ft is increasing day by day either for pilgrimage, mountaineering, holidaying or for strategic reasons. In India, soldiers are deployed to these high mountains for their duty or pilgrims visit to the holy places, which are located at very high altitude. A large population also resides permanently in high altitude regions. Every year thousands of pilgrims visit Holy cave of Shri Amarnath ji, which is above 15 000 ft. The poor acclimatization to high altitude may cause alteration in immunity. The low oxygen partial pressure may cause alterations in gut microbiota, which may cause changes in gut immunity. Effect of high altitude on gut-associated mucosal system is new area of research. Many studies have been carried out to understand the physiology and immunology behind the high-altitude-induced gut problems. Few interventions have also been discovered to circumvent the problems caused due to high-altitude conditions. In this review, we have discussed the effects of high-altitude-induced changes in gut immunity particularly peyer's patches, NK cells and inflammatory cytokines, secretary immunoglobulins and gut microbiota. The published articles from PubMed and Google scholar from year 1975 to 2017 on high-altitude hypoxia and gut immunity are cited in this review.

Colonization and effector functions of innate lymphoid cells in mucosal tissues.

Science.gov (United States)

Kim, Myunghoo; Kim, Chang H

2016-10-01

Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Keeping gut lining at bay: impact of emulsifiers.

Science.gov (United States)

Cani, Patrice D; Everard, Amandine

2015-06-01

Obesity is associated with altered gut microbiota and low-grade inflammation. Both dietary habits and food composition contribute to the onset of such diseases. Emulsifiers, compounds commonly used in a variety of foods, were shown to induce body weight gain, low-grade inflammation and metabolic disorders. These dietary compounds promote gut microbiota alteration and gut barrier dysfunction leading to negative metabolic alterations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mucosal IgA Responses: Damaged in Established HIV Infection—Yet, Effective Weapon against HIV Transmission

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Viraj Kulkarni

2017-11-01

Full Text Available HIV infection not only destroys CD4+ T cells but also inflicts serious damage to the B-cell compartment, such as lymphadenopathy, destruction of normal B-cell follicle architecture, polyclonal hypergammaglobulinemia, increased apoptosis of B cells, and irreversible loss of memory B-cell responses with advanced HIV disease. Subepithelial B cells and plasma cells are also affected, which results in loss of mucosal IgG and IgA antibodies. This leaves the mucosal barrier vulnerable to bacterial translocation. The ensuing immune activation in mucosal tissues adds fuel to the fire of local HIV replication. We postulate that compromised mucosal antibody defenses also facilitate superinfection of HIV-positive individuals with new HIV strains. This in turn sets the stage for the generation of circulating recombinant forms of HIV. What can the mucosal B-cell compartment contribute to protect a healthy, uninfected host against mucosal HIV transmission? Here, we discuss proof-of-principle studies we have performed using passive mucosal immunization, i.e., topical administration of preformed anti-HIV monoclonal antibodies (mAbs as IgG1, dimeric IgA1 (dIgA1, and dIgA2 isotypes, alone or in combination. Our data indicate that mucosally applied anti-HIV envelope mAbs can provide potent protection against mucosal transmission of simian-human immunodeficiency virus. Our review also discusses the induction of mucosal antibody defenses by active vaccination and potential strategies to interrupt the vicious cycle of bacterial translocation, immune activation, and stimulation of HIV replication in individuals with damaged mucosal barriers.

Toxin-mediated effects on the innate mucosal defenses: implications for enteric vaccines

DEFF Research Database (Denmark)

Glenn, Gregory M; Francis, David H; Danielsen, E Michael

2009-01-01

mucosal barrier as a key step in enteric pathogen survival. We review key observations relevant to the roles of LT and cholera toxin in protective immunity and the effects of these toxins on innate mucosal defenses. We suggest either that toxin-mediated fluid secretion mechanically disrupts the mucus...... layer or that toxins interfere with innate mucosal defenses by other means. Such a breach gives pathogens access to the enterocyte, leading to binding and pathogenicity by enterotoxigenic E. coli (ETEC) and other organisms. Given the common exposure to LT(+) ETEC by humans visiting or residing...... unexpectedly broad protective effects against LT(+) ETEC and mixed infections when using a toxin-based enteric vaccine. If toxins truly exert barrier-disruptive effects as a key step in pathogenesis, then a return to classic toxin-based vaccine strategies for enteric disease is warranted and can be expected...

The Mucosal Immune System and Its Regulation by Autophagy.

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Kabat, Agnieszka M; Pott, Johanna; Maloy, Kevin J

2016-01-01

The gastrointestinal tract presents a unique challenge to the mucosal immune system, which has to constantly monitor the vast surface for the presence of pathogens, while at the same time maintaining tolerance to beneficial or innocuous antigens. In the intestinal mucosa, specialized innate and adaptive immune components participate in directing appropriate immune responses toward these diverse challenges. Recent studies provide compelling evidence that the process of autophagy influences several aspects of mucosal immune responses. Initially described as a "self-eating" survival pathway that enables nutrient recycling during starvation, autophagy has now been connected to multiple cellular responses, including several aspects of immunity. Initial links between autophagy and host immunity came from the observations that autophagy can target intracellular bacteria for degradation. However, subsequent studies indicated that autophagy plays a much broader role in immune responses, as it can impact antigen processing, thymic selection, lymphocyte homeostasis, and the regulation of immunoglobulin and cytokine secretion. In this review, we provide a comprehensive overview of mucosal immune cells and discuss how autophagy influences many aspects of their physiology and function. We focus on cell type-specific roles of autophagy in the gut, with a particular emphasis on the effects of autophagy on the intestinal T cell compartment. We also provide a perspective on how manipulation of autophagy may potentially be used to treat mucosal inflammatory disorders.

Evidence for the effects of yogurt on gut health and obesity.

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Pei, Ruisong; Martin, Derek A; DiMarco, Diana M; Bolling, Bradley W

2017-05-24

Obesity is associated with increased risk for chronic diseases, and affects both developed and developing nations. Yogurt is a nutrient-dense food that may benefit individuals with lactose intolerance, constipation and diarrheal diseases, hypertension, cardiovascular diseases, diabetes, and certain types of cancer. Emerging evidence suggests that yogurt consumption might also improve the health of obese individuals. Obesity is often accompanied by chronic, low-grade inflammation perpetuated by adipose tissue and the gut. In the gut, obesity-associated dysregulation of microbiota and impaired gut barrier function may increase endotoxin exposure. Intestinal barrier function can be compromised by pathogens, inflammatory cytokines, endocannabinoids, diet, exercise, and gastrointestinal peptides. Yogurt consumption may improve gut health and reduce chronic inflammation by enhancing innate and adaptive immune responses, intestinal barrier function, lipid profiles, and by regulating appetite. While this evidence suggests that yogurt consumption is beneficial for obese individuals, randomized-controlled trials are needed to further support this hypothesis.

Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis.

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Alexandra L Whittaker

Full Text Available Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8. Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg and NSAID (carprofen; 15mg/kg in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg. Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001. Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis.

Leaky Gut As a Danger Signal for Autoimmune Diseases

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Qinghui Mu

2017-05-01

Full Text Available The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease. Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required. Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.

The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia

NARCIS (Netherlands)

Schuijt, Tim J.; Lankelma, Jacqueline M.; Scicluna, Brendon P.; de Sousa E Melo, Felipe; Roelofs, Joris J. T. H.; de Boer, J. Daan; Hoogendijk, Arjan J.; de Beer, Regina; de Vos, Alex; Belzer, Clara; de Vos, Willem M.; van der Poll, Tom; Wiersinga, W. Joost

2016-01-01

Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is

The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia

NARCIS (Netherlands)

Schuijt, T.J.; Lankelma, J.M.; Scicluna, B.P.; Melo, e F.S.; Roelofs, J.J.; Boer, de J.D.; Hoogendijk, A.J.; Beer, de R.; Vos, de A.; Belzer, C.; Vos, de W.M.; Poll, van der T.; Wiersinga, W.J.

2016-01-01

OBJECTIVE: Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia,

Microbes vs. chemistry in the origin of the anaerobic gut lumen.

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Friedman, Elliot S; Bittinger, Kyle; Esipova, Tatiana V; Hou, Likai; Chau, Lillian; Jiang, Jack; Mesaros, Clementina; Lund, Peder J; Liang, Xue; FitzGerald, Garret A; Goulian, Mark; Lee, Daeyeon; Garcia, Benjamin A; Blair, Ian A; Vinogradov, Sergei A; Wu, Gary D

2018-04-17

The succession from aerobic and facultative anaerobic bacteria to obligate anaerobes in the infant gut along with the differences between the compositions of the mucosally adherent vs. luminal microbiota suggests that the gut microbes consume oxygen, which diffuses into the lumen from the intestinal tissue, maintaining the lumen in a deeply anaerobic state. Remarkably, measurements of luminal oxygen levels show nearly identical pO 2 (partial pressure of oxygen) profiles in conventional and germ-free mice, pointing to the existence of oxygen consumption mechanisms other than microbial respiration. In vitro experiments confirmed that the luminal contents of germ-free mice are able to chemically consume oxygen (e.g., via lipid oxidation reactions), although at rates significantly lower than those observed in the case of conventionally housed mice. For conventional mice, we also show that the taxonomic composition of the gut microbiota adherent to the gut mucosa and in the lumen throughout the length of the gut correlates with oxygen levels. At the same time, an increase in the biomass of the gut microbiota provides an explanation for the reduction of luminal oxygen in the distal vs. proximal gut. These results demonstrate how oxygen from the mammalian host is used by the gut microbiota, while both the microbes and the oxidative chemical reactions regulate luminal oxygen levels, shaping the composition of the microbial community throughout different regions of the gut.

Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut

OpenAIRE

Kim, Myung H.; Taparowsky, Elizabeth J.; Kim, Chang H.

2015-01-01

Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2 and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a `switch' in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term po...

Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis.

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Obata, Takashi; Goto, Yoshiyuki; Kunisawa, Jun; Sato, Shintaro; Sakamoto, Mitsuo; Setoyama, Hiromi; Matsuki, Takahiro; Nonaka, Kazuhiko; Shibata, Naoko; Gohda, Masashi; Kagiyama, Yuki; Nochi, Tomonori; Yuki, Yoshikazu; Fukuyama, Yoshiko; Mukai, Akira; Shinzaki, Shinichiro; Fujihashi, Kohtaro; Sasakawa, Chihiro; Iijima, Hideki; Goto, Masatoshi; Umesaki, Yoshinori; Benno, Yoshimi; Kiyono, Hiroshi

2010-04-20

The indigenous bacteria create natural cohabitation niches together with mucosal Abs in the gastrointestinal (GI) tract. Here we report that opportunistic bacteria, largely Alcaligenes species, specifically inhabit host Peyer's patches (PPs) and isolated lymphoid follicles, with the associated preferential induction of antigen-specific mucosal IgA Abs in the GI tract. Alcaligenes were identified as the dominant bacteria on the interior of PPs from naïve, specific-pathogen-free but not from germ-free mice. Oral transfer of intratissue uncultured Alcaligenes into germ-free mice resulted in the presence of Alcaligenes inside the PPs of recipients. This result was further supported by the induction of antigen-specific Ab-producing cells in the mucosal (e.g., PPs) but not systemic compartment (e.g., spleen). The preferential presence of Alcaligenes inside PPs and the associated induction of intestinal secretory IgA Abs were also observed in both monkeys and humans. Localized mucosal Ab-mediated symbiotic immune responses were supported by Alcaligenes-stimulated CD11c(+) dendritic cells (DCs) producing the Ab-enhancing cytokines TGF-beta, B-cell-activating factor belonging to the TNF family, and IL-6 in PPs. These CD11c(+) DCs did not migrate beyond the draining mesenteric lymph nodes. In the absence of antigen-specific mucosal Abs, the presence of Alcaligenes in PPs was greatly diminished. Thus, indigenous opportunistic bacteria uniquely inhabit PPs, leading to PP-DCs-initiated, local antigen-specific Ab production; this may involve the creation of an optimal symbiotic environment on the interior of the PPs.

The Potential Role of Probiotics in the Management of Childhood Autism Spectrum Disorders

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J. William Critchfield

2011-01-01

Full Text Available Gastrointestinal (GI dysfunction has been reported in a substantial number of children with autism spectrum disorders (ASD. Activation of the mucosal immune response and the presence of abnormal gut microbiota are repeatedly observed in these children. In children with ASD, the presence of GI dysfunction is often associated with increased irritability, tantrums, aggressive behaviour, and sleep disturbances. Moreover, modulating gut bacteria with short-term antibiotic treatment can lead to temporary improvement in behavioral symptoms in some individuals with ASD. Probiotics can influence microbiota composition and intestinal barrier function and alter mucosal immune responses. The administration of probiotic bacteria to address changes in the microbiota might, therefore, be a useful novel therapeutic tool with which to restore normal gut microbiota, reduce inflammation, restore epithelial barrier function, and potentially ameliorate behavioural symptoms associated with some children with ASD. In this review of the literature, support emerges for the clinical testing of probiotics in ASD, especially in the context of addressing GI symptoms.

Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease.

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Barbara, Giovanni; Scaioli, Eleonora; Barbaro, Maria Raffaella; Biagi, Elena; Laghi, Luca; Cremon, Cesare; Marasco, Giovanni; Colecchia, Antonio; Picone, Gianfranco; Salfi, Nunzio; Capozzi, Francesco; Brigidi, Patrizia; Festi, Davide

2017-07-01

The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1 H nuclear magnetic resonance. Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia . Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease. Published by the BMJ Publishing Group Limited

Proximal Gut Mucosal Epithelial Homeostasis in Aged IL-1 Type I Receptor Knockout Mice After Starvation

Science.gov (United States)

2011-08-01

increases whole-body lean mass and insulin sensitivity in elderly subjects with sarcopenia . Am J Cardiol. 2008; 101:69E. [PubMed: 18157968] 11. Iwakiri R...nutritional deficiencies in the elderly can be corrected by nutritional supplementation [5-7], especially among patients who are fed enterally [8-10...mechanistic approach regarding intestinal cell dysfunction in the elderly . Starvation causes mucosal atrophy and loss of mucosal height [32], and glutamine

Exogenous ghrelin regulates proliferation and apoptosis in the hypotrophic gut mucosa of the rat.

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de Segura, Ignacio A Gómez; Vallejo-Cremades, María Teresa; Lomas, Jesús; Sánchez, Miriam F; Caballero, María Isabel; Largo, Carlota; De Miguel, Enrique

2010-04-01

Ghrelin is the natural endogenous ligand for growth hormone secretagogue receptors. This peptide regulates energy homeostasis and expenditure and is a potential link between gut absorptive function and growth. We hypothesized that ghrelin may induce a proliferative and antiapoptotic action promoting the recovery of the hypotrophic gut mucosa. Therefore, the aim of the study was to determine the action of exogenous ghrelin following gut mucosal hypotrophia in rats fed an elemental diet. An elemental diet provides readily absorbable simple nutrients and is usually given to patients with absorptive dysfunction. Male Wistar rats (n = 48) were fed the elemental diet for one week to induce mucosal hypotrophy and then treated for another week with systemic ghrelin and pair-fed with either a normoproteic or hyperproteic isocaloric liquid diet. Another group received a standard diet instead of the elemental diet and served as control (normotrophy). The elemental diet induced intestinal hypotrophia characterized by decreased proliferation in the ileum and increased apoptosis in jejunum and ileum. Ghrelin administration restored normal levels of proliferation in the ileum and apoptosis in the jejunum, with partial apoptosis restoration in the ileum. Ghrelin levels in plasma and fundus were increased in all groups, although the highest levels were found in rats treated with exogenous ghrelin. Ghrelin administration has a positive effect in the hypotrophic gut, regulating both proliferation and apoptosis towards a physiological balance counteracting the negative changes induced by an elemental diet in the intestines.

Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

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Fasano, Alessio

2008-01-01

The anatomical and functional arrangement of the gastrointestinal tract suggests that this organ, beside its digestive and absorptive functions, regulates the trafficking of macromolecules between the environment and the host through a barrier mechanism. Under physiological circumstances, this trafficking is safeguarded by the competency of intercellular tight junctions, structures whose physiological modulation is mediated by, among others, the recently described protein zonulin. To prevent harm and minimize inflammation, the same paracellular pathway, in concert with the gut-associated lymphoid tissue and the neuroendocrine network, controls the equilibrium between tolerance and immunity to nonself antigens. The zonulin pathway has been exploited to deliver drugs, macromolecules, or vaccines that normally would not be absorbed through the gastrointestinal mucosal barrier. However, if the tightly regulated trafficking of macromolecules is jeopardized secondary to prolonged zonulin up-regulation, the excessive flow of nonself antigens in the intestinal submucosa can cause both intestinal and extraintestinal autoimmune disorders in genetically susceptible individuals. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier competency. Understanding the role of zonulin-dependent intestinal barrier dysfunction in the pathogenesis of autoimmune diseases is an area of translational research that encompasses many fields. PMID:18832585

Decreased colonization of fecal Clostridium coccoides/Eubacterium rectale species from ulcerative colitis patients in an in vitro dynamic gut model with mucin environment.

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Vermeiren, Joan; Van den Abbeele, Pieter; Laukens, Debby; Vigsnaes, Louise Kristine; De Vos, Martine; Boon, Nico; Van de Wiele, Tom

2012-03-01

The mucus layer in the colon, acting as a barrier to prevent invasion of pathogens, is thinner and discontinuous in patients with ulcerative colitis (UC). A recent developed in vitro dynamic gut model, the M-SHIME, was used to compare long-term colonization of the mucin layer by the microbiota from six healthy volunteers (HV) and six UC patients and thus distinguish the mucin adhered from the luminal microbiota. Although under the same nutritional conditions, short-chain fatty acid production by the luminal communities from UC patients showed a tendency toward a lower butyrate production. A more in-depth community analysis of those microbial groups known to produce butyrate revealed that the diversity of the Clostridium coccoides/Eubacterium rectale and Clostridium leptum group, and counts of Faecalibacterium prausnitzii were lower in the luminal fractions of the UC samples. Counts of Roseburia spp. were lower in the mucosal fractions of the UC samples. qPCR analysis for butyryl-CoA:acetate CoA transferase, responsible for butyrate production, displayed a lower abundance in both the luminal and mucosal fractions of the UC samples. The M-SHIME model revealed depletion in butyrate producing microbial communities not restricted to the luminal but also in the mucosal samples from UC patients compared to HV. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Impact of removing mucosal barrier injury laboratory-confirmed bloodstream infections from central line-associated bloodstream infection rates in the National Healthcare Safety Network, 2014.

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See, Isaac; Soe, Minn M; Epstein, Lauren; Edwards, Jonathan R; Magill, Shelley S; Thompson, Nicola D

2017-03-01

Central line-associated bloodstream infection (CLABSI) event data reported to the National Healthcare Safety Network from 2014, the first year of required use of the mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI) definition, were analyzed to assess the impact of removing MBI-LCBI events from CLABSI rates. CLABSI rates decreased significantly in some location types after removing MBI-LCBI events, and MBI-LCBI events will be removed from publicly reported CLABSI rates. Published by Elsevier Inc.

Gut microbiota, low-grade inflammation, and metabolic syndrome.

Science.gov (United States)

Chassaing, Benoit; Gewirtz, Andrew T

2014-01-01

The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. Alterations in gut microbiota composition are associated with a variety of disease states including obesity, diabetes, and inflammatory bowel disease (IBD). Transplant of microbiota from diseased persons (or mice) to germfree mice transfers some aspects of disease phenotype, indicating that altered microbiota plays a role in disease establishment and manifestation. There are myriad potential mechanisms by which alterations in gut microbiota might promote disease, including increasing energy harvest, production of toxic metabolites, and molecular mimicry of host proteins. However, our research indicates that an overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation. More specifically, we hypothesize that the histopathologically evident gut inflammation that defines IBD is a severe but relatively rare outcome of an altered host-microbiota relationship, while a much more common consequence of such disturbances is "low-grade" inflammation characterized by elevated proinflammatory gene expression that associates with, and may promote, metabolic syndrome. In this context, a variety of chronic inflammatory diseases may stem from inability of the mucosal immune system to properly manage a stable healthy relationship with the gut microbiota. While one's ability to manage their gut microbiota is dictated in part by genetics, it can be markedly influenced by the composition of the microbiota one inherits from their early environment. Moreover, the host-microbiota relationship can be perturbed by instigator bacteria or dietary components, which may prove to play a role in promoting chronic inflammatory disease states.

Mucus as a Barrier to Drug Delivery

DEFF Research Database (Denmark)

Bøgh, Marie; Nielsen, Hanne Mørck

2015-01-01

Viscoelastic mucus lines all mucosal surfaces of the body and forms a potential barrier to mucosal drug delivery. Mucus is mainly composed of water and mucins; high-molecular weight glycoproteins forming an entangled network. Consequently, mucus forms a steric barrier and due to its negative charge...... barrier to drug delivery. Current knowledge of mucus characteristics and barrier properties, as achieved by state-of-the-art methodologies, is the topic of this MiniReview emphasizing the gastrointestinal mucus and an overall focus on oral drug delivery. Cell culture-based in vitro models are well......, studies of peptide and protein drug diffusion in and through mucus and studies of mucus-penetrating nanoparticles are included to illustrate the mucus as a potentially important barrier to obtain sufficient bioavailability of orally administered drugs, and thus an important parameter to address...

Cardiovascular and Antiobesity Effects of Resveratrol Mediated through the Gut Microbiota.

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Bird, Julia K; Raederstorff, Daniel; Weber, Peter; Steinert, Robert E

2017-11-01

Encouraging scientific research into the health effects of dietary bioactive resveratrol has been confounded by its rapid first-pass metabolism, which leads to low in vivo bioavailability. Preliminary studies have shown that resveratrol can modulate gut microbiota composition, undergo biotransformation to active metabolites via the intestinal microbiota, or affect gut barrier function. In rodents, resveratrol can modify the relative Bacteroidetes:Firmicutes ratio and reverse the gut microbial dysbiosis caused by a high-fat diet. By upregulating the expression of genes involved in maintaining tight junctions between intestinal cells, resveratrol contributes to gut barrier integrity. The composition of the gut microbiome and rapid metabolism of resveratrol determines the production of resveratrol metabolites, which are found at greater concentrations in humans after ingestion than their parent molecule and can have similar biological effects. Resveratrol may affect cardiovascular risk factors such as elevated blood cholesterol or trimethylamine N -oxide concentrations. Modulating the composition of the gut microbiota by resveratrol may affect central energy metabolism and modify concentrations of satiety hormones to produce antiobesity effects. Encouraging research from animal models could be tested in humans. © 2017 American Society for Nutrition.

Mucosal Interactions Between Genetics, Diet And Microbiome In Inflammatory Bowel Diseases

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Abigail Basson

2016-08-01

Full Text Available Numerous reviews have discussed gut microbiota composition changes during inflammatory bowel diseases (IBD, particularly Crohn’s disease (CD. However, most studies address the observed effects by focusing on studying the univariate connection between disease and dietary-induced alterations to gut microbiota composition. The possibility that these effects may reflect a number of other interconnected (i.e. pantropic mechanisms, activated in parallel, particularly concerning various bacterial metabolites, is in the process of been elucidated. Progress seems however hampered by various difficult-to-study factors interacting at the mucosal level. Here we highlight some of such factors that merit consideration, namely; 1 the contribution of host genetics and diet in altering gut microbiome, and in turn, the crosstalk among secondary metabolic pathways; 2 the interdependence between the amount of dietary fat, the fatty acid composition, the effects of timing and route of administration on gut microbiota community, and the impact of microbiota-derived fatty acids; 3 the effect of diet on bile acid composition, and the modulator role of bile acids on the gut microbiota; 4 the impact of endogenous and exogenous intestinal micronutrients and metabolites, and 5 the need to consider food associated toxins and chemicals which can introduce confounding immune modulating elements (e.g., antioxidant and phytochemicals in oils and proteins. These concepts, which are not mutually exclusive, are herein illustrated paying special emphasis on physiologically inter-related processes.

Structure and function of the healthy pre-adolescent pediatric gut microbiome.

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Hollister, Emily B; Riehle, Kevin; Luna, Ruth Ann; Weidler, Erica M; Rubio-Gonzales, Michelle; Mistretta, Toni-Ann; Raza, Sabeen; Doddapaneni, Harsha V; Metcalf, Ginger A; Muzny, Donna M; Gibbs, Richard A; Petrosino, Joseph F; Shulman, Robert J; Versalovic, James

2015-08-26

The gut microbiome influences myriad host functions, including nutrient acquisition, immune modulation, brain development, and behavior. Although human gut microbiota are recognized to change as we age, information regarding the structure and function of the gut microbiome during childhood is limited. Using 16S rRNA gene and shotgun metagenomic sequencing, we characterized the structure, function, and variation of the healthy pediatric gut microbiome in a cohort of school-aged, pre-adolescent children (ages 7-12 years). We compared the healthy pediatric gut microbiome with that of healthy adults previously recruited from the same region (Houston, TX, USA). Although healthy children and adults harbored similar numbers of taxa and functional genes, their composition and functional potential differed significantly. Children were enriched in Bifidobacterium spp., Faecalibacterium spp., and members of the Lachnospiraceae, while adults harbored greater abundances of Bacteroides spp. From a functional perspective, significant differences were detected with respect to the relative abundances of genes involved in vitamin synthesis, amino acid degradation, oxidative phosphorylation, and triggering mucosal inflammation. Children's gut communities were enriched in functions which may support ongoing development, while adult communities were enriched in functions associated with inflammation, obesity, and increased risk of adiposity. Previous studies suggest that the human gut microbiome is relatively stable and adult-like after the first 1 to 3 years of life. Our results suggest that the healthy pediatric gut microbiome harbors compositional and functional qualities that differ from those of healthy adults and that the gut microbiome may undergo a more prolonged development than previously suspected.

Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells.

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Masashi Ohno

Full Text Available Curcumin is a hydrophobic polyphenol derived from turmeric, a traditional Indian spice. Curcumin exhibits various biological functions, but its clinical application is limited due to its poor absorbability after oral administration. A newly developed nanoparticle curcumin shows improved absorbability in vivo. In this study, we examined the effects of nanoparticle curcumin (named Theracurmin on experimental colitis in mice.BALB/c mice were fed with 3% dextran sulfate sodium (DSS in water. Mucosal cytokine expression and lymphocyte subpopulation were analyzed by real-time PCR and flow cytometry, respectively. The profile of the gut microbiota was analyzed by real-time PCR.Treatment with nanoparticle curcumin significantly attenuated body weight loss, disease activity index, histological colitis score and significantly improved mucosal permeability. Immunoblot analysis showed that NF-κB activation in colonic epithelial cells was significantly suppressed by treatment with nanoparticle curcumin. Mucosal mRNA expression of inflammatory mediators was significantly suppressed by treatment with nanoparticle curcumin. Treatment with nanoparticle curcumin increased the abundance of butyrate-producing bacteria and fecal butyrate level. This was accompanied by increased expansion of CD4+ Foxp3+ regulatory T cells and CD103+ CD8α- regulatory dendritic cells in the colonic mucosa.Treatment with nanoparticle curcumin suppressed the development of DSS-induced colitis potentially via modulation of gut microbial structure. These responses were associated with induction of mucosal immune cells with regulatory properties. Nanoparticle curcumin is one of the promising candidates as a therapeutic option for the treatment of IBD.

Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant

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Shailbala Singh

2014-10-01

Full Text Available Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer, a synthetic glycolipid agonist of natural killer T (NKT cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.

Oral and intestinal mucositis - causes and possible treatments.

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Duncan, M; Grant, G

2003-11-01

Chemotherapy and radiotherapy, whilst highly effective in the treatment of neoplasia, can also cause damage to healthy tissue. In particular, the alimentary tract may be badly affected. Severe inflammation, lesioning and ulceration can occur. Patients may experience intense pain, nausea and gastro-enteritis. They are also highly susceptible to infection. The disorder (mucositis) is a dose-limiting toxicity of therapy and affects around 500 000 patients world-wide annually. Oral and intestinal mucositis is multi-factorial in nature. The disruption or loss of rapidly dividing epithelial progenitor cells is a trigger for the onset of the disorder. However, the actual dysfunction that manifests and its severity and duration are greatly influenced by changes in other cell populations, immune responses and the effects of oral/gut flora. This complexity has hampered the development of effective palliative or preventative measures. Recent studies have concentrated on the use of bioactive/growth factors, hormones or interleukins to modify epithelial metabolism and reduce the susceptibility of the tract to mucositis. Some of these treatments appear to have considerable potential and are at present under clinical evaluation. This overview deals with the cellular changes and host responses that may lead to the development of mucositis of the oral cavity and gastrointestinal tract, and the potential of existing and novel palliative measures to limit or prevent the disorder. Presently available treatments do not prevent mucositis, but can limit its severity if used in combination. Poor oral health and existing epithelial damage predispose patients to mucositis. The elimination of dental problems or the minimization of existing damage to the alimentary tract, prior to the commencement of therapy, lowers their susceptibility. Measures that reduce the flora of the tract, before therapy, can also be helpful. Increased production of free radicals and the induction of inflammation are

Structural Change in Microbiota by a Probiotic Cocktail Enhances the Gut Barrier and Reduces Cancer via TLR2 Signaling in a Rat Model of Colon Cancer.

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Kuugbee, Eugene Dogkotenge; Shang, Xueqi; Gamallat, Yaser; Bamba, Djibril; Awadasseid, Annoor; Suliman, Mohammed Ahmed; Zang, Shizhu; Ma, Yufang; Chiwala, Gift; Xin, Yi; Shang, Dong

2016-10-01

Structural change in the gut microbiota is implicated in cancer. The beneficial modulation of the microbiota composition with probiotics and prebiotics prevents diseases. We investigated the effect of oligofructose-maltodextrin-enriched Lactobacillus acidophilus, Bifidobacteria bifidum, and Bifidobacteria infantum (LBB), on the gut microbiota composition and progression of colorectal cancer. Sprague Dawley rats were acclimatized, given ampicillin (75 mg/kg), and treated as follows; GCO: normal control; GPR: LBB only; GPC: LBB+ 1,2-dimethylhydrazine dihydrochloride (DMH); and GCA: DMH only (cancer control). 16S V4 Pyrosequencing for gut microbiota analysis, tumor studies, and the expression of MUC2, ZO-1, occludin, TLR2, TLR4, caspase 3, COX-2, and β-catenin were conducted at the end of experiment. Probiotic LBB treatment altered the gut microbiota. The relative abundance of genera Pseudomonas, Congregibacter, Clostridium, Candidactus spp., Phaeobacter, Escherichia, Helicobacter, and HTCC was decreased (P cancer control. The altered gut microbiota was associated with decreased tumor incidence (80 % in GPC vs. 100 % in GCA, P = 0.0001), tumor volume (GPC 84.23 (42.75-188.4) mm(3) vs. GCA 243 (175.5-344.5) mm(3), P cancer control GCA (P colon cancer development by decreasing tumor incidence, multiplicity/count, and volume via enhanced TLR2-improved gut mucosa epithelial barrier integrity and suppression of apoptosis and inflammation.

Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases.

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Yarandi, Shadi S; Peterson, Daniel A; Treisman, Glen J; Moran, Timothy H; Pasricha, Pankaj J

2016-04-30

Gut microbiome is an integral part of the Gut-Brain axis. It is becoming increasingly recognized that the presence of a healthy and diverse gut microbiota is important to normal cognitive and emotional processing. It was known that altered emotional state and chronic stress can change the composition of gut microbiome, but it is becoming more evident that interaction between gut microbiome and central nervous system is bidirectional. Alteration in the composition of the gut microbiome can potentially lead to increased intestinal permeability and impair the function of the intestinal barrier. Subsequently, neuro-active compounds and metabolites can gain access to the areas within the central nervous system that regulate cognition and emotional responses. Deregulated inflammatory response, promoted by harmful microbiota, can activate the vagal system and impact neuropsychological functions. Some bacteria can produce peptides or short chain fatty acids that can affect gene expression and inflammation within the central nervous system. In this review, we summarize the evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.

Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota.

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Peterson, C T; Sharma, V; Elmén, L; Peterson, S N

2015-03-01

The distal gut harbours ∼10(13) bacteria, representing the most densely populated ecosystem known. The functional diversity expressed by these communities is enormous and relatively unexplored. The past decade of research has unveiled the profound influence that the resident microbial populations bestow to host immunity and metabolism. The evolution of these communities from birth generates a highly adapted and highly personalized microbiota that is stable in healthy individuals. Immune homeostasis is achieved and maintained due in part to the extensive interplay between the gut microbiota and host mucosal immune system. Imbalances of gut microbiota may lead to a number of pathologies such as obesity, type I and type II diabetes, inflammatory bowel disease (IBD), colorectal cancer (CRC) and inflammaging/immunosenscence in the elderly. In-depth understanding of the underlying mechanisms that control homeostasis and dysbiosis of the gut microbiota represents an important step in our ability to reliably modulate the gut microbiota with positive clinical outcomes. The potential of microbiome-based therapeutics to treat epidemic human disease is of great interest. New therapeutic paradigms, including second-generation personalized probiotics, prebiotics, narrow spectrum antibiotic treatment and faecal microbiome transplantation, may provide safer and natural alternatives to traditional clinical interventions for chronic diseases. This review discusses host-microbiota homeostasis, consequences of its perturbation and the associated challenges in therapeutic developments that lie ahead. © 2014 British Society for Immunology.

Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection.

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Quispe Calla, N E; Vicetti Miguel, R D; Boyaka, P N; Hall-Stoodley, L; Kaur, B; Trout, W; Pavelko, S D; Cherpes, T L

2016-11-01

Depot-medroxyprogesterone acetate (DMPA) is a hormonal contraceptive especially popular in areas with high prevalence of HIV and other sexually transmitted infections (STI). Although observational studies identify DMPA as an important STI risk factor, mechanisms underlying this connection are undefined. Levonorgestrel (LNG) is another progestin used for hormonal contraception, but its effect on STI susceptibility is much less explored. Using a mouse model of genital herpes simplex virus type 2 (HSV-2) infection, we herein found that DMPA and LNG similarly reduced genital expression of the desmosomal cadherin desmoglein-1α (DSG1α), enhanced access of inflammatory cells to genital tissue by increasing mucosal epithelial permeability, and increased susceptibility to viral infection. Additional studies with uninfected mice revealed that DMPA-mediated increases in mucosal permeability promoted tissue inflammation by facilitating endogenous vaginal microbiota invasion. Conversely, concomitant treatment of mice with DMPA and intravaginal estrogen restored mucosal barrier function and prevented HSV-2 infection. Evaluating ectocervical biopsy tissue from women before and 1 month after initiating DMPA remarkably revealed that inflammation and barrier protection were altered by treatment identically to changes seen in progestin-treated mice. Together, our work reveals DMPA and LNG diminish the genital mucosal barrier; a first-line defense against all STI, but may offer foundation for new contraceptive strategies less compromising of barrier protection.

Impaired barrier function by dietary fructo-oligosaccharides (FOS in rats is accompanied by increased colonic mitochondrial gene expression

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Kramer Evelien

2008-03-01

Full Text Available Abstract Background Dietary non-digestible carbohydrates stimulate the gut microflora and are therefore presumed to improve host resistance to intestinal infections. However, several strictly controlled rat infection studies showed that non-digestible fructo-oligosaccharides (FOS increase, rather than decrease, translocation of Salmonella towards extra-intestinal sites. In addition, it was shown that FOS increases intestinal permeability already before infection. The mechanism responsible for this adverse effect of FOS is unclear. Possible explanations are altered mucosal integrity due to changes in tight junctions or changes in expression of defense molecules such as antimicrobials and mucins. To examine the mechanisms underlying weakening of the intestinal barrier by FOS, a controlled dietary intervention study was performed. Two groups of 12 rats were adapted to a diet with or without FOS. mRNA was collected from colonic mucosa and changes in gene expression were assessed for each individual rat using Agilent rat whole genome microarrays. Results Among the 997 FOS induced genes we observed less mucosal integrity related genes than expected with the clear permeability changes. FOS did not induce changes in tight junction genes and only 8 genes related to mucosal defense were induced by FOS. These small effects are unlikely the cause for the clear increase in intestinal permeability that is observed. FOS significantly increased expression of 177 mitochondria-related genes. More specifically, induced expression of genes involved in all five OXPHOS complexes and the TCA cycle was observed. These results indicate that dietary FOS influences intestinal mucosal energy metabolism. Furthermore, increased expression of 113 genes related to protein turnover, including proteasome genes, ribosomal genes and protein maturation related genes, was seen. FOS upregulated expression of the peptide hormone proglucagon gene, in agreement with previous studies, as

β-1,3/1,6-Glucan alleviated intestinal mucosal barrier impairment of broiler chickens challenged with Salmonella enterica serovar Typhimurium.

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Shao, Yujing; Guo, Yuming; Wang, Zhong

2013-07-01

This study investigated the protective effect of β-1,3/1,6-glucan on gut morphology, intestinal epithelial tight junctions, and bacterial translocation of broiler chickens challenged with Salmonella enterica serovar Typhimurium. Ninety Salmonella-free Arbor Acre male broiler chickens were randomly divided into 3 groups: negative control group (NC), Salmonella Typhimurium-infected positive group (PC), and the Salmonella Typhimurium-infected group with dietary 100 mg/kg of β-1,3/1,6-glucan supplementation (T) to determine the effect of β-1,3/1,6-glucan on intestinal barrier function. Salmonella Typhimurium challenge alone significantly decreased villus height (P chickens challenged with Salmonella Typhimurium.

The Gut Microbiome and HIV-1 Pathogenesis: A Two Way Street

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Dillon, Stephanie M.; Frank, Daniel N.; Wilson, Cara C.

2016-01-01

HIV-1 infection is associated with substantial damage to the gastrointestinal (GI) tract resulting in structural impairment of the epithelial barrier and a disruption of intestinal homeostasis. The accompanying translocation of microbial products and potentially microbes themselves from the lumen into systemic circulation has been linked to immune activation, inflammation, and HIV-1 disease progression. The importance of microbial translocation in the setting of HIV-1 infection has led to a recent focus on understanding how the communities of microbes that make up the intestinal microbiome are altered during HIV-1 infection and how they interact with mucosal immune cells to contribute to inflammation. This review details the dysbiotic intestinal communities associated with HIV-1 infection and their potential link to HIV-1 pathogenesis. We detail studies that begin to address the mechanisms driving microbiota-associated immune activation and inflammation and the various treatment strategies aimed at correcting dysbiosis and improving the overall health of HIV-1 infected individuals. Finally, we discuss how this relatively new field of research can advance to provide a more comprehensive understanding of the contribution of the gut microbiome to HIV-1 pathogenesis. PMID:27755100

Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse

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Holgersen, Kristine; Kvist, Peter Helding; Markholst, Helle

2014-01-01

Background: In inflammatory bowel disease a defective mucosal barrier, a dysregulated immune response and an excessive reactivity against the gut microbiota are assumed to cause a breakdown of the intestinal homeostasis and lead to chronic inflammation. Piroxicam treatment is a method for inducti...

Gut TFH and IgA: key players for regulation of bacterial communities and immune homeostasis.

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Kato, Lucia M; Kawamoto, Shimpei; Maruya, Mikako; Fagarasan, Sidonia

2014-01-01

The main function of the immune system is to protect the host against pathogens. However, unlike the systemic immune system, the gut immune system does not eliminate, but instead nourishes complex bacterial communities and establishes advanced symbiotic relationships. Immunoglobulin A (IgA) is the most abundant antibody isotype in mammals, produced mainly in the gut. The primary function of IgA is to maintain homeostasis at mucosal surfaces, and studies in mice have demonstrated that IgA diversification has an essential role in the regulation of gut microbiota. Dynamic diversification and constant adaptation of IgA responses to local microbiota require expression of activation-induced cytidine deaminase by B cells and control from T follicular helper and Foxp3(+) T cells in germinal centers (GCs). We discuss the finely tuned regulatory mechanisms for IgA synthesis in GCs of Peyer's patches and emphasize the roles of CD4(+) T cells for IgA selection and the maintenance of appropriate gut microbial communities required for immune homeostasis.

Postnatal hematopoiesis and gut microbiota in NOD mice deviate from C57BL/6 mice

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Damlund, Dina Silke Malling; Metzdorff, Stine Broeng; Hasselby, Jane Preuss

2016-01-01

, a distinct splenic cell profile high in a granulocytic phenotype was evident in the neonatal NOD mice whereas neonatal C57BL/6 mice showed a profile rich in monocytes. Neonatal expression of Reg3g and Muc2 in the gut was deviating in NOD mice and coincided with fewer bacteria attaching to the Mucosal surface...

Anti-allergic role of cholinergic neuronal pathway via α7 nicotinic ACh receptors on mucosal mast cells in a murine food allergy model.

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Takeshi Yamamoto

Full Text Available The prevalence of food allergy (FA has increased in developed countries over the past few decades. However, no effective drug therapies are currently available. Therefore, we investigated cholinergic anti-inflammatory pathway as a regulatory system to ameliorate disrupted mucosal immune homeostasis in the gut based on the pathophysiological elucidation of mucosal mast cells (MMCs in a murine FA model. BALB/c mice sensitized with ovalbumin received repeated oral ovalbumin for the development of FA. FA mice developed severe allergic diarrhea and exhibited enhanced type 2 helper T (Th2 cell immune responses in both systemic immunity and mucosal immunity, along with MMCs hyperplasia in the colon. MMCs were localized primarily in the strategic position of the mucosal epithelium. Furthermore, the allergic symptoms did not develop in p85α disrupted phosphoinositide-3 kinase-deficient mice that lacked mast cells in the gut. Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR agonists (nicotine and α7 nAChR agonist GTS-21 alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by α7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via α7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA.

From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation.

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Bajic, Juliana E; Johnston, Ian N; Howarth, Gordon S; Hutchinson, Mark R

2018-01-01

The central nervous system and gastrointestinal tract form the primary targets of chemotherapy-induced toxicities. Symptoms associated with damage to these regions have been clinically termed chemotherapy-induced cognitive impairment and mucositis. Whilst extensive literature outlines the complex etiology of each pathology, to date neither chemotherapy-induced side-effect has considered the potential impact of one on the pathogenesis of the other disorder. This is surprising considering the close bidirectional relationship shared between each organ; the gut-brain axis. There are complex multiple pathways linking the gut to the brain and vice versa in both normal physiological function and disease. For instance, psychological and social factors influence motility and digestive function, symptom perception, and behaviors associated with illness and pathological outcomes. On the other hand, visceral pain affects central nociception pathways, mood and behavior. Recent interest highlights the influence of functional gut disorders, such as inflammatory bowel diseases and irritable bowel syndrome in the development of central comorbidities. Gut-brain axis dysfunction and microbiota dysbiosis have served as key portals in understanding the potential mechanisms associated with these functional gut disorders and their effects on cognition. In this review we will present the role gut-brain axis dysregulation plays in the chemotherapy setting, highlighting peripheral-to-central immune signaling mechanisms and their contribution to neuroimmunological changes associated with chemotherapy exposure. Here, we hypothesize that dysregulation of the gut-brain axis plays a major role in the intestinal, psychological and neurological complications following chemotherapy. We pay particular attention to evidence surrounding microbiota dysbiosis, the role of intestinal permeability, damage to nerves of the enteric and peripheral nervous systems and vagal and humoral mediated changes.

Protein energy malnutrition alters mucosal IgA responses and reduces mucosal vaccine efficacy in mice.

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Rho, Semi; Kim, Heejoo; Shim, Seung Hyun; Lee, Seung Young; Kim, Min Jung; Yang, Bo-Gie; Jang, Myoung Ho; Han, Byung Woo; Song, Man Ki; Czerkinsky, Cecil; Kim, Jae-Ouk

2017-10-01

Oral vaccine responsiveness is often lower in children from less developed countries. Childhood malnutrition may be associated with poor immune response to oral vaccines. The present study was designed to investigate whether protein energy malnutrition (PEM) impairs B cell immunity and ultimately reduces oral vaccine efficacy in a mouse model. Purified isocaloric diets containing low protein (1/10 the protein of the control diet) were used to determine the effect of PEM. PEM increased both nonspecific total IgA and oral antigen-specific IgA in serum without alteration of gut permeability. However, PEM decreased oral antigen-specific IgA in feces, which is consistent with decreased expression of polymeric Immunoglobulin receptor (pIgR) in the small intestine. Of note, polymeric IgA was predominant in serum under PEM. In addition, PEM altered B cell development status in the bone marrow and increased the frequency of IgA-secreting B cells, as well as IgA secretion by long-lived plasma cells in the small intestinal lamina propria. Moreover, PEM reduced the protective efficacy of the mucosally administered cholera vaccine and recombinant attenuated Salmonella enterica serovar Typhimurium vaccine in a mouse model. Our results suggest that PEM can impair mucosal immunity where IgA plays an important role in host protection and may partly explain the reduced efficacy of oral vaccines in malnourished subjects. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Effects of plasma CGRP and NPY level changes on intestinal mucosal barrier injury after scald in rats

International Nuclear Information System (INIS)

Shao Lijian; Zhu Qingxian; He Ming; Zhang Hongyan

2004-01-01

Objective: To investigate the significance of plasma CGRP and NPY levels changes immediately after scald in rats. Methods: Thirty-two rat models of 30% TBSA III degree scald were prepared. Eight animals each were sacrificed at 3, 6,12 and 24 hrs; taking blood samples for determination of plasma CGRP, NPY levels and 5 cm of ileum for pathologic study. As controls, eight animals without scald were treated in the same way. Results: Plasma CGRP levels were decreased significantly after scald, reaching bottom value at 12 hr and remained lower than those in controls at 24 hr (p 0.05). Plasma levels of CGRP were negatively correlated to plasma NPY levels (p<0.01). Ileum mucosal injuries presented as edema, congestion with necrosis and slough of epithelium were most marked at 12 hr. Conclusion: Plasma CGRP and NPY levels changed significantly after scald and were mutually negatively correlated. Post-scald intestinal mucosa barrier injuries were possibly related to the changes of levels of those vasoactive peptides

Cocoa and cocoa fibre differentially modulate IgA and IgM production at mucosal sites.

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Massot-Cladera, Malen; Franch, Àngels; Pérez-Cano, Francisco J; Castell, Margarida

2016-05-01

Previous studies have shown that a 10 % cocoa (C10) diet, containing polyphenols and fibre among others, modifies intestinal and systemic Ig production. The present study aimed at evaluating the impact of C10 on IgA and IgM production in the intestinal and extra-intestinal mucosal compartments, establishing the involvement of cocoa fibre (CF) in such effects. Mechanisms by which C10 intake may affect IgA synthesis in the salivary glands were also studied. To this effect, rats were fed either a standard diet, a diet containing C10, CF or inulin. Intestinal (the gut wash (GW), Peyer's patches (PP) and mesenteric lymph nodes (MLN)) and extra-intestinal (salivary glands) mucosal tissues and blood samples were collected for IgA and IgM quantification. The gene expressions of IgA production- and homing-related molecules were studied in the salivary glands. The C10 diet decreased intestinal IgA and IgM production. Although the CF diet decreased the GW IgA concentration, it increased PP, MLN and serum IgA concentrations. Both the C10 and the CF diets produced a down-regulatory effect on IgA secretion in the extra-intestinal tissues. The C10 diet interacted with the mechanisms involved in IgA synthesis, whereas the CF showed particular effects on the homing and transcytosis of IgA across the salivary glands. Overall, CF was able to up-regulate IgA production in the intestinal-inductor compartments, whereas it down-regulated its production at the mucosal-effector ones. Further studies must be directed to ascertain the mechanisms involved in the effect of particular cocoa components on gut-associated lymphoid tissue.

Lactobacillus reuteri strains protect epithelial barrier integrity of IPEC-J2 monolayers from the detrimental effect of enterotoxigenic Escherichia coli.

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Karimi, Shokoufeh; Jonsson, Hans; Lundh, Torbjörn; Roos, Stefan

2018-01-01

Lactobacillus reuteri is an inhabitant of the gastrointestinal (GI) tract of mammals and birds and several strains of this species are known to be effective probiotics. The mechanisms by which L. reuteri confers its health-promoting effects are far from being fully understood, but protection of the mucosal barrier is thought to be important. Leaky gut is a state of abnormal intestinal permeability with implications for the pathophysiology of various gastrointestinal disorders. Enterotoxigenic Escherichia coli (ETEC) can invade the intestinal mucosa and induce changes in barrier function by producing enterotoxin or by direct invasion of the intestinal epithelium. Our hypothesis was that L. reuteri can protect the mucosal barrier, and the goal of the study was to challenge this hypothesis by monitoring the protective effect of L. reuteri strains on epithelial dysfunction caused by ETEC. Using an infection model based on the porcine intestinal cell line IPEC-J2, it was demonstrated that pretreatment of the cells with human-derived L. reuteri strains (ATCC PTA 6475, DSM 17938 and 1563F) and a rat strain (R2LC) reduced the detrimental effect of ETEC in a dose-dependent manner, as monitored by permeability of FITC-dextran and transepithelial electrical resistance (TEER). Moreover, the results revealed that ETEC upregulated proinflammatory cytokines IL-6 and TNFα and decreased expression of the shorter isoform of ZO-1 (187 kDa) and E-cadherin. In contrast, pretreatment with L. reuteri DSM 17938 and 1563F downregulated expression of IL-6 and TNFα, and led to an increase in production of the longer isoform of ZO-1 (195 kDa) and maintained E-cadherin expression. Interestingly, expression of ZO-1 (187 kDa) was preserved only when the infected cells were pretreated with strain 1563F. These findings demonstrate that L. reuteri strains exert a protective effect against ETEC-induced mucosal integrity disruption. © 2018 The Authors. Physiological Reports published by

Mucin glycan foraging in the human gut microbiome

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Tailford, Louise E.; Crost, Emmanuelle H.; Kavanaugh, Devon; Juge, Nathalie

2015-01-01

The availability of host and dietary carbohydrates in the gastrointestinal (GI) tract plays a key role in shaping the structure-function of the microbiota. In particular, some gut bacteria have the ability to forage on glycans provided by the mucus layer covering the GI tract. The O-glycan structures present in mucin are diverse and complex, consisting predominantly of core 1-4 mucin-type O-glycans containing α- and β- linked N-acetyl-galactosamine, galactose and N-acetyl-glucosamine. These core structures are further elongated and frequently modified by fucose and sialic acid sugar residues via α1,2/3/4 and α2,3/6 linkages, respectively. The ability to metabolize these mucin O-linked oligosaccharides is likely to be a key factor in determining which bacterial species colonize the mucosal surface. Due to their proximity to the immune system, mucin-degrading bacteria are in a prime location to influence the host response. However, despite the growing number of bacterial genome sequences available from mucin degraders, our knowledge on the structural requirements for mucin degradation by gut bacteria remains fragmented. This is largely due to the limited number of functionally characterized enzymes and the lack of studies correlating the specificity of these enzymes with the ability of the strain to degrade and utilize mucin and mucin glycans. This review focuses on recent findings unraveling the molecular strategies used by mucin-degrading bacteria to utilize host glycans, adapt to the mucosal environment, and influence human health. PMID:25852737

Intestinal barrier integrity and inflammatory bowel disease

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Holmberg, Fredrik Eric Olof; Pedersen, Jannie; Jørgensen, Peter

2018-01-01

Disruption of normal barrier function is a fundamental factor in the pathogenesis of inflammatory bowel disease, which includes increased epithelial cell death, modified mucus configuration, altered expression and distribution of tight junction-proteins, along with a decreased expression of antim......Disruption of normal barrier function is a fundamental factor in the pathogenesis of inflammatory bowel disease, which includes increased epithelial cell death, modified mucus configuration, altered expression and distribution of tight junction-proteins, along with a decreased expression...... of antimicrobial peptides. Inflammatory bowel disease is associated with life-long morbidity for affected patients, and both the incidence and prevalence is increasing globally, resulting in substantial economic strain for society. Mucosal healing and re-establishment of barrier integrity is associated......, novel treatment strategies to accomplish mucosal healing and to re-establish normal barrier integrity in inflammatory bowel disease are warranted, and luminal stem cell-based approaches might have an intriguing potential. Transplantation of in vitro expanded intestinal epithelial stem cells derived...

Retinoic Acid Differentially Regulates the Migration of Innate Lymphoid Cell Subsets to the Gut.

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Kim, Myung H; Taparowsky, Elizabeth J; Kim, Chang H

2015-07-21

Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2, and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a "switch" in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term population and effector function of ILCs in the intestine. Only ILC1 and ILC3, but not ILC2, undergo the RA-dependent homing receptor switch in gut-associated lymphoid tissues. In contrast, ILC2 acquire gut homing receptors in a largely RA-independent manner during their development in the bone marrow and can migrate directly to the intestine. Thus, distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

Gut proteases target Yersinia invasin in vivo

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Freund Sandra

2011-04-01

Full Text Available Abstract Background Yersinia enterocolitica is a common cause of food borne gastrointestinal disease. After oral uptake, yersiniae invade Peyer's patches of the distal ileum. This is accomplished by the binding of the Yersinia invasin to β1 integrins on the apical surface of M cells which overlie follicle associated lymphoid tissue. The gut represents a barrier that severely limits yersiniae from reaching deeper tissues such as Peyer's patches. We wondered if gut protease attack on invasion factors could contribute to the low number of yersiniae invading Peyer's patches. Findings Here we show that invasin is rapidly degraded in vivo by gut proteases in the mouse infection model. In vivo proteolytic degradation is due to proteolysis by several gut proteases such as trypsin, α-chymotrypsin, pancreatic elastase, and pepsin. Protease treated yersiniae are shown to be less invasive in a cell culture model. YadA, another surface adhesin is cleaved by similar concentrations of gut proteases but Myf was not cleaved, showing that not all surface proteins are equally susceptible to degradation by gut proteases. Conclusions We demonstrate that gut proteases target important Yersinia virulence factors such as invasin and YadA in vivo. Since invasin is completely degraded within 2-3 h after reaching the small intestine of mice, it is no longer available to mediate invasion of Peyer's patches.

Gastric mucosal defence mechanism during stress of pyloric obstruction in albino rats.

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Somasundaram, K; Ganguly, A K

1987-04-01

1. The integrity of the gastric mucosa and its ability to secrete mucus are believed to be essential for protection of gastric mucosa against ulceration induced by aggressive factors active in any stress situation. This study involves a three-compartmental analysis of gastric mucosal barrier in pylorus-ligated albino rats. 2. Quantitative analyses of histologically identifiable gastric mucosal epithelial neutral glycoproteins and gastric adherent mucus from oxyntic and pyloric gland areas, and components of non-dialysable mucosubstances in gastric secretion were made under stress of pyloric obstruction for 4, 8, and 16 h durations. Epithelial mucin was identified by periodic acid-Schiff (PAS) staining technique and assessed from the ratio of gastric mucosal thickness to the depth of PAS positive materials in it. The remaining visible mucus adhered to the gastric mucosa was estimated by Alcian blue binding technique. The results were compared with that of identical control groups. 3. A significant reduction in mucosal epithelial PAS positive materials after 8 or 16 h of pylorus ligation was observed. 4. The Alcian blue binding capacity of the pyloric gland area was increased significantly after 4 h of pylorus ligation, while after 8 or 16 h it was reduced in both oxyntic and pyloric gland areas. 5. Significant reductions in the rate of gastric secretion and volume, as well as concentration of the components of non-dialysable mucosubstances, were observed, indicating decreased synthesis of mucus glycoproteins. 6. Disruption of the mucosal barrier may have occurred due to decreased mucus synthesis and acid-pepsin accumulation; both could be due to stress associated with gastric distension. 7. The present findings confirm the role of mucus in protecting the underlying gastric epithelium during stress. The adherent mucus offers a first line of defence and epithelial mucus a second line of defence.

Colonic transit time relates to bacterial metabolism and mucosal turnover in the human gut

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Roager, Henrik Munch; Hansen, Lea Benedicte Skov; Bahl, Martin Iain

catabolism as reflected by microbial metabolites in urine. This results in a number of potentially deleterious protein-derived metabolites. Additionally, longer colonic transit time correlates with metabolites likely reflecting reduced renewal of the colonic mucosa. Together, this suggests that a high gut...

Xyloglucan, a Plant Polymer with Barrier Protective Properties over the Mucous Membranes: An Overview

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Núria Piqué

2018-02-01

Full Text Available Disruption of the epithelial barrier function has been recently associated with a variety of diseases, mainly at intestinal level, but also affecting the respiratory epithelium and other mucosal barriers. Non-pharmacological approaches such as xyloglucan, with demonstrated protective barrier properties, are proposed as new alternatives for the management of a wide range of diseases, for which mucosal disruption and, particularly, tight junction alterations, is a common characteristic. Xyloglucan, a natural polysaccharide derived from tamarind seeds, possesses a “mucin-like” molecular structure that confers mucoadhesive properties, allowing xyloglucan formulations to act as a barrier capable of reducing bacterial adherence and invasion and to preserve tight junctions and paracellular flux, as observed in different in vitro and in vivo studies. In clinical trials, xyloglucan has been seen to reduce symptoms of gastroenteritis in adults and children, nasal disorders and dry eye syndrome. Similar mucosal protectors containing reticulated proteins have also been useful for the treatment of irritable bowel syndrome and urinary tract infections. The role of xyloglucan in other disorders with mucosal disruption, such as dermatological or other infectious diseases, deserves further research. In conclusion, xyloglucan, endowed with film-forming protective barrier properties, is a safe non-pharmacological alternative for the management of different diseases, such as gastrointestinal and nasal disorders.

Langerin-expressing dendritic cells in gut-associated lymphoid tissues.

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Chang, Sun-Young; Kweon, Mi-Na

2010-03-01

Dendritic cells (DCs) are key regulators of the immune system. They act as professional antigen-presenting cells and are capable of activating naive T cells and stimulating the growth and differentiation of B cells. According to their molecular expression, DCs can be divided into several subsets with different functions. We focus on DC subsets expressing langerin, a C-type lectin. Langerin expression is predominant in skin DCs, but langerin-expressing DCs also exist in mucosal tissue and can be induced by immunization and sometimes by nutrient deficiency. Topical transcutaneous immunization induces langerin(+)CD8 alpha(-) DCs in mesenteric lymph nodes (MLNs), which mediate the production of antigen-specific immunoglobulin A antibody in the intestine. Yet, in one recent study, langerin(+) DCs were generated in gut-associated lymphoid tissue and contributed to the suppressive intestinal immune environment in the absence of retinoic acid. In this review, we focus on the phenotypic and functional characteristics of langerin(+) DCs in the mucosal tissues, especially MLNs.

Immunological effects of reduced mucosal integrity in the early life of BALB/c mice

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Bendtsen, Katja Maria Bangsgaard; Hansen, Camilla Hartmann Friis; Krych, Łukasz

2017-01-01

Certain stimuli at the gut barrier may be necessary in early life to establish a proper balance of immune tolerance. We evaluated a compromised barrier in juvenile mice in relation to microbiota and local and systemic immunity. BALB/c mice were treated with a low dose of dextran sulfate sodium (D...

The impact of the postnatal gut microbiota on animal models

DEFF Research Database (Denmark)

Hansen, Axel Jacob Kornerup; Ejsing-Duun, Maria; Aasted, Bent

2007-01-01

Quality control of laboratory animals has been mostly concentrated on eliminating and securing the absence of specific infections, but event barrier bred laboratory animals harbour a huge number of gut bacteria. There is scientific evidence that the nature of the gut microbiota especially in early...... correlated to factors related to early exposure to microorganisms, e.g. the so-called hygiene hypothesis claims that the increasing human incidence of allergy. T1D, RA and IBD may be due to the lack of such exposure. It is possible today by various molecular techniques to profile the gut microbiota...

Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults : results of the "COPA" pilot randomized trial

NARCIS (Netherlands)

Gori, A.; Rizzardini, G.; van't Land, B.; Amor, K. B.; van Schaik, J.; Torti, C.; Quirino, T.; Tincati, C.; Bandera, A.; Knol, J.; Benlhassan-Chahour, K.; Trabattoni, D.; Bray, D.; Vriesema, A.; Welling, G.; Garssen, J.; Clerici, M.

Intestinal mucosal immune system is an early target for human immunodeficiency virus type 1 (HIV-1) infection, resulting in CD4(+) T-cell depletion, deterioration of gut lining, and fecal microbiota composition. We evaluated the effects of a prebiotic oligosaccharide mixture in highly active

Prebiotics: A Potential Treatment Strategy for the Chemotherapy-damaged Gut?

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Wang, Hanru; Geier, Mark S; Howarth, Gordon S

2016-01-01

Mucositis, characterized by ulcerative lesions along the alimentary tract, is a common consequence of many chemotherapy regimens. Chemotherapy negatively disrupts the intestinal microbiota, resulting in increased numbers of potentially pathogenic bacteria, such as Clostridia and Enterobacteriaceae, and decreased numbers of "beneficial" bacteria, such as Lactobacilli and Bifidobacteria. Agents capable of restoring homeostasis in the bowel microbiota could, therefore, be applicable to mucositis. Prebiotics are indigestible compounds, commonly oligosaccharides, that seek to reverse chemotherapy-induced intestinal dysbiosis through selective colonization of the intestinal microbiota by probiotic bacteria. In addition, evidence is emerging that certain prebiotics contribute to nutrient digestibility and absorption, modulate intestinal barrier function through effects on mucin expression, and also modify mucosal immune responses, possibly via inflammasome-mediated processes. This review examines the known mechanisms of prebiotic action, and explores their potential for reducing the severity of chemotherapy-induced mucositis in the intestine.

Crosstalk between Inflammation and ROCK/MLCK Signaling Pathways in Gastrointestinal Disorders with Intestinal Hyperpermeability

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Lijun Du

2016-01-01

Full Text Available The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn’s disease (CD, ulcerative colitis (UC, celiac disease, and irritable bowel syndrome (IBS. Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploring in vitro and in vivo model system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK- and myosin light chain kinase- (MLCK- mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability.

Duodenal mucosal protein kinase C-δ regulates glucose production in rats.

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Kokorovic, Andrea; Cheung, Grace W C; Breen, Danna M; Chari, Madhu; Lam, Carol K L; Lam, Tony K T

2011-11-01

Activation of protein kinase C (PKC) enzymes in liver and brain alters hepatic glucose metabolism, but little is known about their role in glucose regulation in the gastrointestinal tract. We investigated whether activation of PKC-δ in the duodenum is sufficient and necessary for duodenal nutrient sensing and regulates hepatic glucose production through a neuronal network in rats. In rats, we inhibited duodenal PKC and evaluated whether nutrient-sensing mechanisms, activated by refeeding, have disruptions in glucose regulation. We then performed gain- and loss-of-function pharmacologic and molecular experiments to target duodenal PKC-δ; we evaluated the impact on glucose production regulation during the pancreatic clamping, while basal levels of insulin were maintained. PKC-δ was detected in the mucosal layer of the duodenum; intraduodenal infusion of PKC inhibitors disrupted glucose homeostasis during refeeding, indicating that duodenal activation of PKC-δ is necessary and sufficient to regulate glucose homeostasis. Intraduodenal infusion of the PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) specifically activated duodenal mucosal PKC-δ and a gut-brain-liver neuronal pathway to reduce glucose production. Molecular and pharmacologic inhibition of duodenal mucosal PKC-δ negated the ability of duodenal OAG and lipids to reduce glucose production. In the duodenal mucosa, PKC-δ regulates glucose homeostasis. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Capsaicin-sensitive intestinal mucosal afferent mechanism and body fat distribution.

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Leung, Felix W

2008-07-04

This report summarizes clinical and experimental data in support of the hypothesis that capsaicin-sensitive intestinal mucosal afferent mechanism plays a role in regulating body fat distribution. Epidemiological data have revealed that the consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Rural Thai people consume diets containing 0.014% capsaicin. Rodents fed a diet containing 0.014% capsaicin showed no change in caloric intake but a significant 24% and 29% reduction in the visceral (peri-renal) fat weight. Increase in intestinal blood flow facilitates nutrient energy absorption and decrease in adipose tissue blood flow facilitates storage of nutrient energy in adipose tissue. Stimulation of intestinal mucosal afferent nerves increases intestinal blood flow, but decreases visceral (mesenteric) adipost tissue blood flow. In in vitro cell studies capsaicin has a direct effect on adipocytes. Intravenous capsaicin produces measurable plasma level and subcutaneous capsaicin retards accumulation of adipose tissue. The data on a direct effect of oral capsaicin on adipose tissue at remote sites, however, are conflicting. Capsaicin absorbed from the gut lumen is almost completely metabolized before reaching the general circulation. Oral capsaicin significantly increases transient receptor potential vanilloid type-1 (TRPV1) channel expression as well as TRPV1 messenger ribonucleic acid (mRNA) in visceral adipose tissue. In TRPV1 knockout mice on a high fat diet the body weight was not significantly different in the absence or presence of oral capsaicin. In rodent experiments, daily intragastric administration of capsaicin for two weeks led to defunctionalization of intestinal mucosal afferent nerves, manifested by loss of acute mucosal capsaicin-induced effects; but not the corneal afferent nerves, with preservation of the paw wiping reflex of the eye exposed briefly to dilute capsaicin. The latter indicated the absence of an oral

Impact of feed additives on surface mucosal health and columnaris susceptibility in channel catfish fingerlings, Ictalurus punctatus.

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Zhao, Honggang; Li, Chao; Beck, Benjamin H; Zhang, Ran; Thongda, Wilawan; Davis, D Allen; Peatman, Eric

2015-10-01

One of the highest priority areas for improvement in aquaculture is the development of dietary additives and formulations which provide for complete mucosal health and protection of fish raised in intensive systems. Far greater attention has been paid to dietary impact on gut health than to protective effects at other mucosal surfaces such as skin and gill. These exterior surfaces, however, are important primary targets for pathogen attachment and invasion. Flavobacterium columnare, the causative agent of columnaris disease, is among the most prevalent of all freshwater disease-causing bacteria, impacting global aquaculture of catfish, salmonids, baitfish and aquaria-trade species among others. This study evaluated whether the feeding of a standard catfish diet supplemented with Alltech dietary additives Actigen(®), a concentrated source of yeast cell wall-derived material and/or Allzyme(®) SSF, a fermented strain of Aspergillus niger, could offer protection against F. columnare mortality. A nine-week feeding trial of channel catfish fingerlings with basal diet (B), B + Allzyme(®) SSF, B + Actigen(®) and B + Actigen(®)+Allzyme(®) SSF revealed good growth in all conditions (FCR additives may provide protection extending beyond the gut to surface mucosa. Copyright © 2015 Elsevier Ltd. All rights reserved.

Separate effects of irradiation and of graft-versus-host reaction on rat mucosal mast cells

International Nuclear Information System (INIS)

Cummins, A.G.; Munro, G.H.; Huntley, J.F.; Miller, H.R.P.; Ferguson, A.

1989-01-01

T cell mediated immune responses in the gut can produce enteropathy and malabsorption. The authors investigated the relevance of mucosal mast cells (MMC) to the mechanisms of this enteropathy by using graft-versus-host reaction (GvHR) in the rat as a model of mucosal delayed type hypersensitivity. x-irradiation, with or without GvHR, led to the virtual disappearance of jejunal MMC, undetectable jejunal rat mast cell protease (RMCPII) and very low levels of RMCPII in serum (all p<0.01 when compared with unirradiated controls). These experiments show that there is a modest expansion in jejunal MMC in unirradiated rats with semiallogeneic GvHR, whereas irradiation, alone or associated with GvHR, profoundly depletes MMC for at least two weeks. The enteropathy of GvHR can evolve in the virtual absence of MMC. (author)

Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating Disorders.

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Lam, Yan Y; Maguire, Sarah; Palacios, Talia; Caterson, Ian D

2017-06-14

Traditionally recognized as mental illnesses, eating disorders are increasingly appreciated to be biologically-driven. There is a growing body of literature that implicates a role of the gut microbiota in the etiology and progression of these conditions. Gut bacteria may act on the gut-brain axis to alter appetite control and brain function as part of the genesis of eating disorders. As the illnesses progress, extreme feeding patterns and psychological stress potentially feed back to the gut ecosystem that can further compromise physiological, cognitive, and social functioning. Given the established causality between dysbiosis and metabolic diseases, an altered gut microbial profile is likely to play a role in the co-morbidities of eating disorders with altered immune function, short-chain fatty acid production, and the gut barrier being the key mechanistic links. Understanding the role of the gut ecosystem in the pathophysiology of eating disorders will provide critical insights into improving current treatments and developing novel microbiome-based interventions that will benefit patients with eating disorders.

Unexpected High Digestion Rate of Cooked Starch by the Ct-Maltase-Glucoamylase Small Intestine Mucosal α-Glucosidase Subunit

Science.gov (United States)

Lin, Amy Hui-Mei; Nichols, Buford L.; Quezada-Calvillo, Roberto; Avery, Stephen E.; Sim, Lyann; Rose, David R.; Naim, Hassan Y.; Hamaker, Bruce R.

2012-01-01

For starch digestion to glucose, two luminal α-amylases and four gut mucosal α-glucosidase subunits are employed. The aim of this research was to investigate, for the first time, direct digestion capability of individual mucosal α-glucosidases on cooked (gelatinized) starch. Gelatinized normal maize starch was digested with N- and C-terminal subunits of recombinant mammalian maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) of varying amounts and digestion periods. Without the aid of α-amylase, Ct-MGAM demonstrated an unexpected rapid and high digestion degree near 80%, while other subunits showed 20 to 30% digestion. These findings suggest that Ct-MGAM assists α-amylase in digesting starch molecules and potentially may compensate for developmental or pathological amylase deficiencies. PMID:22563462

Innate Lymphoid Cells in HIV/SIV Infections.

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Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R; Reeves, R Keith

2017-01-01

Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

Innate Lymphoid Cells in HIV/SIV Infections

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Spandan V. Shah

2017-12-01

Full Text Available Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia.

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Schuijt, Tim J; Lankelma, Jacqueline M; Scicluna, Brendon P; de Sousa e Melo, Felipe; Roelofs, Joris J T H; de Boer, J Daan; Hoogendijk, Arjan J; de Beer, Regina; de Vos, Alex; Belzer, Clara; de Vos, Willem M; van der Poll, Tom; Wiersinga, W Joost

2016-04-01

Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections. We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses. We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-α and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae. This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infections. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Gastroenterology issues in schizophrenia: why the gut matters.

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Severance, Emily G; Prandovszky, Emese; Castiglione, James; Yolken, Robert H

2015-05-01

Genetic and environmental studies implicate immune pathologies in schizophrenia. The body's largest immune organ is the gastrointestinal (GI) tract. Historical associations of GI conditions with mental illnesses predate the introduction of antipsychotics. Current studies of antipsychotic-naïve patients support that gut dysfunction may be inherent to the schizophrenia disease process. Risk factors for schizophrenia (inflammation, food intolerances, Toxoplasma gondii exposure, cellular barrier defects) are part of biological pathways that intersect those operant in the gut. Central to GI function is a homeostatic microbial community, and early reports show that it is disrupted in schizophrenia. Bioactive and toxic products derived from digestion and microbial dysbiosis activate adaptive and innate immunity. Complement C1q, a brain-active systemic immune component, interacts with gut-related schizophrenia risk factors in clinical and experimental animal models. With accumulating evidence supporting newly discovered gut-brain physiological pathways, treatments to ameliorate brain symptoms of schizophrenia should be supplemented with therapies to correct GI dysfunction.

The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction.

Science.gov (United States)

Chen, Lanfen; Chen, Zhangguo; Baker, Kristi; Halvorsen, Elizabeth M; da Cunha, Andre Pires; Flak, Magdalena B; Gerber, Georg; Huang, Yu-Hwa; Hosomi, Shuhei; Arthur, Janelle C; Dery, Ken J; Nagaishi, Takashi; Beauchemin, Nicole; Holmes, Kathryn V; Ho, Joshua W K; Shively, John E; Jobin, Christian; Onderdonk, Andrew B; Bry, Lynn; Weiner, Howard L; Higgins, Darren E; Blumberg, Richard S

2012-11-16

Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of positive acceleration exposure on intestinal mucosal barrier and sIgA level in rats

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Jie QIU

2016-10-01

Full Text Available Objective 　To explore the effect of positive acceleration (+Gz on immune barrier of intestinal mucosa in rats. Methods 　Thirty two male SD rats were randomly divided into 4 groups (8 each: Group A (control group, Group B (+5Gz group, Group C (+10Gz group and Group D (repeated exposure group. The animal centrifuge was used to simulate the exposure of acceleration. Group A was no disposed. +5Gz group and +10Gz group were subjected to centrifugal force of +5Gz and +10Gz respectively for 5min; repeated exposure group was continuously exposed to 1.5min under +5Gz value, 2min under +10Gz value and 1.5min under +5Gz. All groups were exposed to the respective acceleration once daily for 5 days. The damage of intestinal mucosa was observed by light microscopy after the experiment was finished, and the content of sIgA in intestinal mucosa was detected by ELISA. Results 　Except for group A, intestinal mucosal injury was observed in the other three groups. Group D was shown as the most serious one, followed by group C and group B. Compared with group A, the level of sIgA was significantly lower in other three groups (P<0.05. The level of sIgA in group C was significantly lower than that in group B (P<0.05 and higher than that in group D (P<0.05. Conclusion 　+Gz exposure can result in intestinal injury and weaken the function of immune barrier of intestinal mucosa in rats. DOI: 10.11855/j.issn.0577-7402.2016.10.14

The role of gut microbiota in health and disease: In vitro modeling of host-microbe interactions at the aerobe-anaerobe interphase of the human gut.

Science.gov (United States)

von Martels, Julius Z H; Sadaghian Sadabad, Mehdi; Bourgonje, Arno R; Blokzijl, Tjasso; Dijkstra, Gerard; Faber, Klaas Nico; Harmsen, Hermie J M

2017-04-01

The microbiota of the gut has many crucial functions in human health. Dysbiosis of the microbiota has been correlated to a large and still increasing number of diseases. Recent studies have mostly focused on analyzing the associations between disease and an aberrant microbiota composition. Functional studies using (in vitro) gut models are required to investigate the precise interactions that occur between specific bacteria (or bacterial mixtures) and gut epithelial cells. As most gut bacteria are obligate or facultative anaerobes, studying their effect on oxygen-requiring human gut epithelial cells is technically challenging. Still, several (anaerobic) bacterial-epithelial co-culture systems have recently been developed that mimic host-microbe interactions occurring in the human gut, including 1) the Transwell "apical anaerobic model of the intestinal epithelial barrier", 2) the Host-Microbiota Interaction (HMI) module, 3) the "Human oxygen-Bacteria anaerobic" (HoxBan) system, 4) the human gut-on-a-chip and 5) the HuMiX model. This review discusses the role of gut microbiota in health and disease and gives an overview of the characteristics and applications of these novel host-microbe co-culture systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Gut microbiota and immunopathogenesis of diabetes mellitus type 1 and 2.

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Wang, Fei; Zhang, Chunfang; Zeng, Qiang

2016-06-01

Diabetes mellitus (DM) is a major increasing global health burden in the aging population. Understanding the etiology of DM is beneficial for its prevention as well as treatment. In light of the metagenome hypothesis, defined as the overall bacterial genome, gut microbes have attracted increasing attention in the pathogenesis of DM. Many studies have found that gut microbes are involved in the immunopathogenesis of DM. Probiotics strengthen the host's intestinal barrier and modulate the immune system, and have therefore been investigated in DM management. Recent epigenetic findings in context of genes associated with inflammation suggest a possible way in which gut microbiota participate in the immunopathogenesis of DM. In this review, we discuss the role of gut microbiota in the immunopathogenesis of DM.

Effect of sucralfate on gastric permeability in an ex vivo model of stress-related mucosal disease in dogs.

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Hill, Tracy L; Lascelles, B Duncan X; Blikslager, Anthony T

2018-03-01

Sucralfate is a gastroprotectant with no known systemic effects. The efficacy of sucralfate for prevention and treatment of stress-related mucosal diseases (SRMD) in dogs is unknown. To develop a canine ex vivo model of SRMD and to determine the effect of sucralfate on mucosal barrier function in this model. Gastric antral mucosa was collected immediately postmortem from 29 random-source apparently healthy dogs euthanized at a local animal control facility. Randomized experimental trial. Sucralfate (100 mg/mL) was applied to ex vivo canine gastric mucosa concurrent with and after acid injury. Barrier function was assessed by measurement of transepithelial electrical resistance (TER) and radiolabeled mannitol flux. Application of acidified Ringers solution to the mucosal side of gastric antrum caused a reduction in gastric barrier function, and washout of acidified Ringers solution allowed recovery of barrier function (TER: 34.0 ± 2.8% of control at maximum injury, 71.3 ± 5.5% at recovery, P < .001). Sucralfate application at the time of injury or after injury significantly hastened recovery of barrier function (TER: 118.0 ± 15.2% of control at maximum injury, P < .001 and 111.0 ± 15.5% at recovery, P = .35). Sucralfate appeared effective at restoring defects in gastric barrier function induced by acid and accelerating repair of tissues subjected to acid in this model, suggesting that sucralfate could have utility for the treatment and prevention of SRMD in dogs. Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Burn-injury affects gut-associated lymphoid tissues derived CD4+ T cells.

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Fazal, Nadeem; Shelip, Alla; Alzahrani, Alhusain J

2013-01-01

After scald burn-injury, the intestinal immune system responds to maintain immune balance. In this regard CD4+T cells in Gut-Associated Lymphoid Tissues (GALT), like mesenteric lymph nodes (MLN) and Peyer's patches (PP) respond to avoid immune suppression following major injury such as burn. Therefore, we hypothesized that the gut CD4+T cells become dysfunctional and turn the immune homeostasis towards depression of CD4+ T cell-mediated adaptive immune responses. In the current study we show down regulation of mucosal CD4+ T cell proliferation, IL-2 production and cell surface marker expression of mucosal CD4+ T cells moving towards suppressive-type. Acute burn-injury lead to up-regulation of regulatory marker (CD25+), down regulation of adhesion (CD62L, CD11a) and homing receptor (CD49d) expression, and up-regulation of negative co-stimulatory (CTLA-4) molecule. Moreover, CD4+CD25+ T cells of intestinal origin showed resistance to spontaneous as well as induced apoptosis that may contribute to suppression of effector CD4+ T cells. Furthermore, gut CD4+CD25+ T cells obtained from burn-injured animals were able to down-regulate naïve CD4+ T cell proliferation following adoptive transfer of burn-injured CD4+CD25+ T cells into sham control animals, without any significant effect on cell surface activation markers. Together, these data demonstrate that the intestinal CD4+ T cells evolve a strategy to promote suppressive CD4+ T cell effector responses, as evidenced by enhanced CD4+CD25+ T cells, up-regulated CTLA-4 expression, reduced IL-2 production, tendency towards diminished apoptosis of suppressive CD4+ T cells, and thus lose their natural ability to regulate immune homeostasis following acute burn-injury and prevent immune paralysis.

Neutrophil Interactions with Epithelial Expressed ICAM-1 Enhances Intestinal Mucosal Wound Healing

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Sumagin, R; Brazil, JC; Nava, P; Nishio, H; Alam, A; Luissint, AC; Weber, DA; Neish, AS; Nusrat, A; Parkos, CA

2015-01-01

A characteristic feature of gastrointestinal tract inflammatory disorders, such as inflammatory bowel disease, is polymorphonuclear neutrophil (PMN) transepithelial migration (TEM) and accumulation in the gut lumen. PMN accumulation within the intestinal mucosa contributes to tissue injury. While epithelial infiltration by large numbers of PMNs results in mucosal injury, we found that PMN interactions with luminal epithelial membrane receptors may also play a role in wound healing. Intercellular adhesion molecule-1 (ICAM-1) is a PMN ligand that is upregulated on apical surfaces of intestinal epithelial cells under inflammatory conditions. In our study, increased expression of ICAM-1 resulted in enhanced PMN binding to the apical epithelium, which was associated with reduced PMN apoptosis. Following TEM, PMN adhesion to ICAM-1 resulted in activation of Akt and β-catenin signaling, increased epithelial-cell proliferation, and wound healing. Such responses were ICAM-1 dependent as engagement of epithelial ICAM-1 by antibody-mediated cross-linking yielded similar results. Furthermore, using an in-vivo biopsy-based, colonic-mucosal-injury model, we demonstrated epithelial ICAM-1 plays an important role in activation of epithelial Akt and β-catenin signaling and wound healing. These findings suggest that post-migrated PMNs within the intestinal lumen can regulate epithelial homeostasis, thereby identifying ICAM-1 as a potential therapeutic target for promoting mucosal wound healing. PMID:26732677

Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing.

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Sumagin, R; Brazil, J C; Nava, P; Nishio, H; Alam, A; Luissint, A C; Weber, D A; Neish, A S; Nusrat, A; Parkos, C A

2016-09-01

A characteristic feature of gastrointestinal tract inflammatory disorders, such as inflammatory bowel disease, is polymorphonuclear neutrophil (PMN) transepithelial migration (TEM) and accumulation in the gut lumen. PMN accumulation within the intestinal mucosa contributes to tissue injury. Although epithelial infiltration by large numbers of PMNs results in mucosal injury, we found that PMN interactions with luminal epithelial membrane receptors may also play a role in wound healing. Intercellular adhesion molecule-1 (ICAM-1) is a PMN ligand that is upregulated on apical surfaces of intestinal epithelial cells under inflammatory conditions. In our study, increased expression of ICAM-1 resulted in enhanced PMN binding to the apical epithelium, which was associated with reduced PMN apoptosis. Following TEM, PMN adhesion to ICAM-1 resulted in activation of Akt and β-catenin signaling, increased epithelial-cell proliferation, and wound healing. Such responses were ICAM-1 dependent as engagement of epithelial ICAM-1 by antibody-mediated cross-linking yielded similar results. Furthermore, using an in-vivo biopsy-based, colonic-mucosal-injury model, we demonstrated epithelial ICAM-1 has an important role in activation of epithelial Akt and β-catenin signaling and wound healing. These findings suggest that post-migrated PMNs within the intestinal lumen can regulate epithelial homeostasis, thereby identifying ICAM-1 as a potential therapeutic target for promoting mucosal wound healing.

Lactobacillus protects the integrity of intestinal epithelial barrier damaged by pathogenic bacteria

Directory of Open Access Journals (Sweden)

Qinghua eYu

2015-03-01

Full Text Available Pathogens invade intestinal mucosal barrier through phagocytosis of antigen presenting cells (dendritic cell, microfold cells, or through the invasion into the intestinal epithelial directly. Some pathogens could damage the cell junction between epithelial cells and use the paracellular pathway as an entrance to invade. Moreover, some Lactobacillus could inhibit the adhesion of the pathogens and protect the integrity of the cell junction and mucosal barrier. This research focused on the potential therapeutic effect of Lactobacillus fructosus (L. fructosus C2 to attenuate ETEC K88 or S. typhimurium SL1344 induced changes to mucosal barrier. The results demonstrated that treatment of polarized Caco-2 cells with L. fructosus C2 reduced the permeation of dextran, and expression of IL-8, p-ERK and p-JNK when cells were infected with pathogenic bacteria. The findings indicated that L. fructosus C2 exerted a protective effect against the damage to the integrity of Caco-2 cells by ETEC or S. typhimurium infection.

The paneth cell: A guardian of gut health

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The article by Podany et al in the current issue of Cellular and Molecular Gastroenterology and Hepatology makes observations that significantly advance our understanding of Paneth cells and zinc transporters in maintenance of a healthy gut barrier and microbiota of the small intestine. Paneth cells...

Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall.

Science.gov (United States)

Fasano, Alessio

2008-11-01

The anatomical and functional arrangement of the gastrointestinal tract suggests that this organ, beside its digestive and absorptive functions, regulates the trafficking of macromolecules between the environment and the host through a barrier mechanism. Under physiological circumstances, this trafficking is safeguarded by the competency of intercellular tight junctions, structures whose physiological modulation is mediated by, among others, the recently described protein zonulin. To prevent harm and minimize inflammation, the same paracellular pathway, in concert with the gut-associated lymphoid tissue and the neuroendocrine network, controls the equilibrium between tolerance and immunity to nonself antigens. The zonulin pathway has been exploited to deliver drugs, macromolecules, or vaccines that normally would not be absorbed through the gastrointestinal mucosal barrier. However, if the tightly regulated trafficking of macromolecules is jeopardized secondary to prolonged zonulin up-regulation, the excessive flow of nonself antigens in the intestinal submucosa can cause both intestinal and extraintestinal autoimmune disorders in genetically susceptible individuals. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier competency. Understanding the role of zonulin-dependent intestinal barrier dysfunction in the pathogenesis of autoimmune diseases is an area of translational research that encompasses many fields.

Nutritional modulation of the gut microbiota and immune system in preterm neonates susceptible to necrotizing enterocolitis

DEFF Research Database (Denmark)

Siggers, Richard H.; Siggers, Jayda; Thymann, Thomas

2011-01-01

on the nutritional, microbial and immunological interactions during the early feeding-induced mucosal dysfunction and later NEC development. We show that introduction of suboptimal enteral formula diets, coupled with parenteral nutrition, predispose to disease, while advancing amounts of mother's milk from birth...... (particularly colostrum) protects against disease. Hence, the transition from parenteral to enteral nutrition shortly after birth plays a pivotal role to secure gut growth, digestive maturation and an appropriate response to bacterial colonization in the sensitive gut of preterm neonates.......The gastrointestinal inflammatory disorder, necrotizing enterocolitis (NEC), is among the most serious diseases for preterm neonates. Nutritional, microbiological and immunological dysfunctions all play a role in disease progression but the relationship among these determinants is not understood...

Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells.

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Mehrnaz Nouri

Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system with a pathogenesis involving a dysfunctional blood-brain barrier and myelin-specific, autoreactive T cells. Although the commensal microbiota seems to affect its pathogenesis, regulation of the interactions between luminal antigens and mucosal immune elements remains unclear. Herein, we investigated whether the intestinal mucosal barrier is also targeted in this disease. Experimental autoimmune encephalomyelitis (EAE, the prototypic animal model of MS, was induced either by active immunization or by adoptive transfer of autoreactive T cells isolated from these mice. We show increased intestinal permeability, overexpression of the tight junction protein zonulin and alterations in intestinal morphology (increased crypt depth and thickness of the submucosa and muscularis layers. These intestinal manifestations were seen at 7 days (i.e., preceding the onset of neurological symptoms and at 14 days (i.e., at the stage of paralysis after immunization. We also demonstrate an increased infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T cell number in the gut lamina propria, Peyer's patches and mesenteric lymph nodes. Adoptive transfer to healthy mice of encephalitogenic T cells, isolated from EAE-diseased animals, led to intestinal changes similar to those resulting from the immunization procedure. Our findings show that disruption of intestinal homeostasis is an early and immune-mediated event in EAE. We propose that this intestinal dysfunction may act to support disease progression, and thus represent a potential therapeutic target in MS. In particular, an increased understanding of the regulation of tight junctions at the blood-brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.

Intestinal Barrier Dysfunction Develops at the Onset of Experimental Autoimmune Encephalomyelitis, and Can Be Induced by Adoptive Transfer of Auto-Reactive T Cells

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Nouri, Mehrnaz; Bredberg, Anders; Weström, Björn; Lavasani, Shahram

2014-01-01

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a pathogenesis involving a dysfunctional blood-brain barrier and myelin-specific, autoreactive T cells. Although the commensal microbiota seems to affect its pathogenesis, regulation of the interactions between luminal antigens and mucosal immune elements remains unclear. Herein, we investigated whether the intestinal mucosal barrier is also targeted in this disease. Experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS, was induced either by active immunization or by adoptive transfer of autoreactive T cells isolated from these mice. We show increased intestinal permeability, overexpression of the tight junction protein zonulin and alterations in intestinal morphology (increased crypt depth and thickness of the submucosa and muscularis layers). These intestinal manifestations were seen at 7 days (i.e., preceding the onset of neurological symptoms) and at 14 days (i.e., at the stage of paralysis) after immunization. We also demonstrate an increased infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T cell number in the gut lamina propria, Peyer's patches and mesenteric lymph nodes. Adoptive transfer to healthy mice of encephalitogenic T cells, isolated from EAE-diseased animals, led to intestinal changes similar to those resulting from the immunization procedure. Our findings show that disruption of intestinal homeostasis is an early and immune-mediated event in EAE. We propose that this intestinal dysfunction may act to support disease progression, and thus represent a potential therapeutic target in MS. In particular, an increased understanding of the regulation of tight junctions at the blood-brain barrier and in the intestinal wall may be crucial for design of future innovative therapies. PMID:25184418

Modulating bacterial and gut mucosal interactions with engineered biofilm matrix proteins.

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Duraj-Thatte, Anna M; Praveschotinunt, Pichet; Nash, Trevor R; Ward, Frederick R; Joshi, Neel S

2018-02-22

Extracellular appendages play a significant role in mediating communication between bacteria and their host. Curli fibers are a class of bacterial fimbria that is highly amenable to engineering. We demonstrate the use of engineered curli fibers to rationally program interactions between bacteria and components of the mucosal epithelium. Commensal E. coli strains were engineered to produce recombinant curli fibers fused to the trefoil family of human cytokines. Biofilms formed from these strains bound more mucins than those producing wild-type curli fibers, and modulated mucin rheology as well. When treated with bacteria producing the curli-trefoil fusions mammalian cells behaved identically in terms of their migration behavior as when they were treated with the corresponding soluble trefoil factors. Overall, this demonstrates the potential utility of curli fibers as a scaffold for the display of bioactive domains and an untapped approach to rationally modulating host-microbe interactions using bacterial matrix proteins.

Effects of Dietary Bacillus licheniformis on Gut Physical Barrier, Immunity, and Reproductive Hormones of Laying Hens.

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Wang, Yang; Du, Wei; Lei, Kai; Wang, Baikui; Wang, Yuanyuan; Zhou, Yingshan; Li, Weifen

2017-09-01

Previous study showed that dietary Bacillus licheniformis (B. licheniformis) administration contributes to the improvement of laying performance and egg quality in laying hens. In this study, we aimed to further evaluate its underlying mechanisms. Three hundred sixty Hy-Line Variety W-36 hens (28 weeks of age) were randomized into four groups, each group with six replications (n = 15). The control group received the basal diet and the treatment groups received the same basal diets supplemented with 0.01, 0.03, and 0.06% B. licheniformis powder (2 × 10 10  cfu/g) for an 8-week trial. The results demonstrate that B. licheniformis significantly enhance the intestinal barrier functions via decreasing gut permeability, promoting mucin-2 transcription, and regulating inflammatory cytokines. The systemic immunity of layers in B. licheniformis treatment groups is improved through modulating the specific and non-specific immunity. In addition, gene expressions of hormone receptors, including estrogen receptor α, estrogen receptor β, and follicle-stimulating hormone receptor, are also regulated by B. licheniformis. Meanwhile, compared with the control, B. licheniformis significantly increase gonadotropin-releasing hormone level, but markedly reduce ghrelin and inhibin secretions. Overall, our data suggest that dietary inclusion of B. licheniformis can improve the intestinal barrier function and systemic immunity and regulate reproductive hormone secretions, which contribute to better laying performance and egg quality of hens.

Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers.

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Mitragotri, Samir

2013-01-01

Overcoming biological barriers including skin, mucosal membranes, blood brain barrier as well as cell and nuclear membrane constitutes a key hurdle in the field of drug delivery. While these barriers serve the natural protective function in the body, they limit delivery of drugs into the body. A variety of methods have been developed to overcome these barriers including formulations, targeting peptides and device-based technologies. This review focuses on the use of physical methods including acoustic devices, electric devices, high-pressure devices, microneedles and optical devices for disrupting various barriers in the body including skin and other membranes. A summary of the working principles of these devices and their ability to enhance drug delivery is presented. Copyright © 2012. Published by Elsevier B.V.

Association of gut microbiota with post-operative clinical course in Crohn’s disease

Science.gov (United States)

2013-01-01

Background The gut microbiome is altered in Crohn’s disease. Although individual taxa have been correlated with post-operative clinical course, global trends in microbial diversity have not been described in this context. Methods We collected mucosal biopsies from the terminal ileum and ascending colon during surgery and post-operative colonoscopy in 6 Crohn’s patients undergoing ileocolic resection (and 40 additional Crohn’s and healthy control patients undergoing either surgery or colonoscopy). Using next-generation sequencing technology, we profiled the gut microbiota in order to identify changes associated with remission or recurrence of inflammation. Results We performed 16S ribosomal profiling using 101 base-pair single-end sequencing on the Illumina GAIIx platform with deep coverage, at an average depth of 1.3 million high quality reads per sample. At the time of surgery, Crohn’s patients who would remain in remission were more similar to controls and more species-rich than Crohn’s patients with subsequent recurrence. Patients remaining in remission also exhibited greater stability of the microbiota through time. Conclusions These observations permitted an association of gut microbial profiles with probability of recurrence in this limited single-center study. These results suggest that profiling the gut microbiota may be useful in guiding treatment of Crohn’s patients undergoing surgery. PMID:23964800

Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells.

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Arnold, Kelly B; Burgener, Adam; Birse, Kenzie; Romas, Laura; Dunphy, Laura J; Shahabi, Kamnoosh; Abou, Max; Westmacott, Garrett R; McCorrister, Stuart; Kwatampora, Jessie; Nyanga, Billy; Kimani, Joshua; Masson, Lindi; Liebenberg, Lenine J; Abdool Karim, Salim S; Passmore, Jo-Ann S; Lauffenburger, Douglas A; Kaul, Rupert; McKinnon, Lyle R

2016-01-01

Elevated inflammatory cytokines (EMCs) at mucosal surfaces have been associated with HIV susceptibility, but the underlying mechanisms remain unclear. We characterized the soluble mucosal proteome associated with elevated cytokine expression in the female reproductive tract. A scoring system was devised based on the elevation (upper quartile) of at least three of seven inflammatory cytokines in cervicovaginal lavage. Using this score, HIV-uninfected Kenyan women were classified as either having EMC (n=28) or not (n=68). Of 455 proteins quantified in proteomic analyses, 53 were associated with EMC (5% false discovery rate threshold). EMCs were associated with proteases, cell motility, and actin cytoskeletal pathways, whereas protease inhibitor, epidermal cell differentiation, and cornified envelope pathways were decreased. Multivariate analysis identified an optimal signature of 16 proteins that distinguished the EMC group with 88% accuracy. Three proteins in this signature were neutrophil-associated proteases that correlated with many cytokines, especially GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-1β (interleukin-1β), MIP-3α (macrophage inflammatory protein-3α), IL-17, and IL-8. Gene set enrichment analyses implicated activated immune cells; we verified experimentally that EMC women had an increased frequency of endocervical CD4(+) T cells. These data reveal strong linkages between mucosal cytokines, barrier function, proteases, and immune cell movement, and propose these as potential mechanisms that increase risk of HIV acquisition.

Effects of the oral administration of the exopolysaccharide produced by Lactobacillus kefiranofaciens on the gut mucosal immunity.

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Vinderola, Gabriel; Perdigón, Gabriela; Duarte, Jairo; Farnworth, Edward; Matar, Chantal

2006-12-01

IL-10+, IL-6+ and IL-12+ cells, the values found were slightly increased compared to control values, while IFNgamma+ and TNFalpha+ cells did not change compared to control values. The effects observed on immunoglobulins and in all the cytokines assayed in the large intestine after kefiran administration were of greater magnitude than the ones observed in the small intestine lamina propria, which may be due to the saccharolytic action of the colonic microflora. In the intestinal fluid, only IL-4 and IL-12 increased compared to control values. In blood serum, all the cytokines assayed followed a pattern of production quite similar to the one found for them in the small intestine lamina propria. We observed that the exopolysaccharide induced a gut mucosal response and it was able to up and down regulate it for protective immunity, maintaining intestinal homeostasis, enhancing the IgA production at both the small and large intestine level and influencing the systemic immunity through the cytokines released to the circulating blood.

Probiotics promote endocytic allergen degradation in gut epithelial cells

International Nuclear Information System (INIS)

Song, Chun-Hua; Liu, Zhi-Qiang; Huang, Shelly; Zheng, Peng-Yuan; Yang, Ping-Chang

2012-01-01

Highlights: ► Knockdown of A20 compromised the epithelial barrier function. ► The fusion of endosome/lysosome was disturbed in the A20-deficient HT-29 cells. ► Antigens transported across A20-deficient HT-29 monolayers conserved antigenicity. ► Probiotic proteins increased the expression of A20 in HT-29 cells. -- Abstract: Background and aims: Epithelial barrier dysfunction plays a critical role in the pathogenesis of allergic diseases; the mechanism is to be further understood. The ubiquitin E3 ligase A20 (A20) plays a role in the endocytic protein degradation in the cells. This study aims to elucidate the role of A20 in the maintenance of gut epithelial barrier function. Methods: Gut epithelial cell line, HT-29 cell, was cultured into monolayers to evaluate the barrier function in transwells. RNA interference was employed to knock down the A20 gene in HT-29 cells to test the role of A20 in the maintenance of epithelial barrier function. Probiotic derived proteins were extracted from the culture supernatants using to enhance the expression of A20 in HT-29 cells. Results: The results showed that the knockdown of A20 compromised the epithelial barrier function in HT-29 monolayers, mainly increased the intracellular permeability. The fusion of endosome/lysosome was disturbed in the A20-deficient HT-29 cells. Allergens collected from the transwell basal chambers of A20-deficient HT-29 monolayers still conserved functional antigenicity. Treating with probiotic derived proteins increased the expression of A20 in HT-29 cells and promote the barrier function. Conclusion: A20 plays an important role in the maintenance of epithelial barrier function as shown by HT-29 monolayer. Probiotic derived protein increases the expression of A20 and promote the HT-29 monolayer barrier function.

Probiotics promote endocytic allergen degradation in gut epithelial cells

Energy Technology Data Exchange (ETDEWEB)

Song, Chun-Hua [Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou (China); Liu, Zhi-Qiang [Department of Gastroenterology, The Second Hospital, Zhengzhou University, Zhengzhou (China); Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON (Canada); Huang, Shelly [Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON (Canada); Zheng, Peng-Yuan, E-mail: medp7123@126.com [Department of Gastroenterology, The Second Hospital, Zhengzhou University, Zhengzhou (China); Yang, Ping-Chang, E-mail: yangp@mcmaster.ca [Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON (Canada)

2012-09-14

Highlights: Black-Right-Pointing-Pointer Knockdown of A20 compromised the epithelial barrier function. Black-Right-Pointing-Pointer The fusion of endosome/lysosome was disturbed in the A20-deficient HT-29 cells. Black-Right-Pointing-Pointer Antigens transported across A20-deficient HT-29 monolayers conserved antigenicity. Black-Right-Pointing-Pointer Probiotic proteins increased the expression of A20 in HT-29 cells. -- Abstract: Background and aims: Epithelial barrier dysfunction plays a critical role in the pathogenesis of allergic diseases; the mechanism is to be further understood. The ubiquitin E3 ligase A20 (A20) plays a role in the endocytic protein degradation in the cells. This study aims to elucidate the role of A20 in the maintenance of gut epithelial barrier function. Methods: Gut epithelial cell line, HT-29 cell, was cultured into monolayers to evaluate the barrier function in transwells. RNA interference was employed to knock down the A20 gene in HT-29 cells to test the role of A20 in the maintenance of epithelial barrier function. Probiotic derived proteins were extracted from the culture supernatants using to enhance the expression of A20 in HT-29 cells. Results: The results showed that the knockdown of A20 compromised the epithelial barrier function in HT-29 monolayers, mainly increased the intracellular permeability. The fusion of endosome/lysosome was disturbed in the A20-deficient HT-29 cells. Allergens collected from the transwell basal chambers of A20-deficient HT-29 monolayers still conserved functional antigenicity. Treating with probiotic derived proteins increased the expression of A20 in HT-29 cells and promote the barrier function. Conclusion: A20 plays an important role in the maintenance of epithelial barrier function as shown by HT-29 monolayer. Probiotic derived protein increases the expression of A20 and promote the HT-29 monolayer barrier function.

Mucosal vaccines: a paradigm shift in the development of mucosal adjuvants and delivery vehicles.

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Srivastava, Atul; Gowda, Devegowda Vishakante; Madhunapantula, SubbaRao V; Shinde, Chetan G; Iyer, Meenakshi

2015-04-01

Mucosal immune responses are the first-line defensive mechanisms against a variety of infections. Therefore, immunizations of mucosal surfaces from which majority of infectious agents make their entry, helps to protect the body against infections. Hence, vaccinization of mucosal surfaces by using mucosal vaccines provides the basis for generating protective immunity both in the mucosal and systemic immune compartments. Mucosal vaccines offer several advantages over parenteral immunization. For example, (i) ease of administration; (ii) non-invasiveness; (iii) high-patient compliance; and (iv) suitability for mass vaccination. Despite these benefits, to date, only very few mucosal vaccines have been developed using whole microorganisms and approved for use in humans. This is due to various challenges associated with the development of an effective mucosal vaccine that can work against a variety of infections, and various problems concerned with the safe delivery of developed vaccine. For instance, protein antigen alone is not just sufficient enough for the optimal delivery of antigen(s) mucosally. Hence, efforts have been made to develop better prophylactic and therapeutic vaccines for improved mucosal Th1 and Th2 immune responses using an efficient and safe immunostimulatory molecule and novel delivery carriers. Therefore, in this review, we have made an attempt to cover the recent advancements in the development of adjuvants and delivery carriers for safe and effective mucosal vaccine production. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Circadian Disruption Changes Gut Microbiome Taxa and Functional Gene Composition.

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Deaver, Jessica A; Eum, Sung Y; Toborek, Michal

2018-01-01

Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light-dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4-week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques , a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii , a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances.

Gut Microbiota in Cardiovascular Health and Disease

Science.gov (United States)

Tang, W.H. Wilson; Kitai, Takeshi; Hazen, Stanley L

2017-01-01

Significant interest in recent years has focused on gut microbiota-host interaction because accumulating evidence has revealed that intestinal microbiota play an important role in human health and disease, including cardiovascular diseases. Changes in the composition of gut microbiota associated with disease, referred to as dysbiosis, have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity and type 2 diabetes mellitus. In addition to alterations in gut microbiota composition, the metabolic potential of gut microbiota has been identified as a contributing factor in the development of diseases. Recent studies revealed that gut microbiota can elicit a variety of effects on the host. Indeed, the gut microbiome functions like an endocrine organ, generating bioactive metabolites, that can impact host physiology. Microbiota interact with the host through a number of pathways, including the trimethylamine (TMA)/ trimethylamine N-oxide (TMAO) pathway, short-chain fatty acids pathway, and primary and secondary bile acids pathways. In addition to these “metabolism dependent” pathways, metabolism independent processes are suggested to also potentially contribute to CVD pathogenesis. For example, heart failure associated splanchnic circulation congestion, bowel wall edema and impaired intestinal barrier function are thought to result in bacterial translocation, the presence of bacterial products in the systemic circulation and heightened inflammatory state. These are believed to also contribute to further progression of heart failure and atherosclerosis. The purpose of the current review is to highlight the complex interplay between microbiota, their metabolites and the development and progression of cardiovascular diseases. We will also discuss the roles of gut microbiota in normal physiology and the potential of modulating intestinal microbial inhabitants as novel therapeutic targets. PMID:28360349

The role of CD103+ Dendritic cells in the intestinal mucosal immune system.

Directory of Open Access Journals (Sweden)

Darren Thomas Ruane

2011-07-01

Full Text Available While dendritic cells (DC are central to the induction and regulation of adaptive immunity, these cells are very heterogenous and specific subsets can be characterized based on the expression of cell surface markers and functional properties. Intestinal CD103+ DCs are the subject of particular interest due to their role in regulating mucosal immunity. Since the epithelial surfaces are constantly exposed to a high antigenic load, tight regulation of innate and adaptive intestinal immune responses is vital as intestinal inflammation can have detrimental consequences for the host. Strategically positioned within the lamina propria, CD103+ DCs play an important role in maintaining intestinal immune homeostasis. These cells are required for the induction of tolerogenic immune responses and imprinting gut homing phenotypic changes on antigen-specific T cells. Recent insights into their development and regulatory properties have revealed additional immunoregulatory roles and further highlighted their importance for intestinal immunity. In this review we discuss the nature of the intestinal CD103+ DC population and the emerging roles of these cells in the regulation of mucosal immunity.

The Role of IL-33 in Gut Mucosal Inflammation

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Luca Pastorelli

2013-01-01

Full Text Available Interleukin (IL-33 is a recently identified cytokine belonging to the IL-1 family that is widely expressed throughout the body and has the ability to induce Th2 immune responses. In addition, IL-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells. In recent years, a growing body of evidence has shown that the proinflammatory properties displayed by IL-33 are detrimental in several experimental models of inflammation; in others, however, IL-33 appears to have protective functions. In 2010, four different research groups consistently described the upregulation of IL-33 in patients with inflammatory bowel disease (IBD. Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective. Indeed, data generated from these studies suggest that IL-33 may possess dichotomous functions, enhancing inflammatory responses on one hand and promoting epithelial integrity on the other. This review focuses on the available data regarding IL-33/ST2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel IL-1 family member in intestinal inflammation.

Metabolic Interaction of Helicobacter pylori Infection and Gut Microbiota

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Yao-Jong Yang

2016-02-01

Full Text Available As a barrier, gut commensal microbiota can protect against potential pathogenic microbes in the gastrointestinal tract. Crosstalk between gut microbes and immune cells promotes human intestinal homeostasis. Dysbiosis of gut microbiota has been implicated in the development of many human metabolic disorders like obesity, hepatic steatohepatitis, and insulin resistance in type 2 diabetes (T2D. Certain microbes, such as butyrate-producing bacteria, are lower in T2D patients. The transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome, but the exact pathogenesis remains unclear. H. pylori in the human stomach cause chronic gastritis, peptic ulcers, and gastric cancers. H. pylori infection also induces insulin resistance and has been defined as a predisposing factor to T2D development. Gastric and fecal microbiota may have been changed in H. pylori-infected persons and mice to promote gastric inflammation and specific diseases. However, the interaction of H. pylori and gut microbiota in regulating host metabolism also remains unknown. Further studies aim to identify the H. pylori-microbiota-host metabolism axis and to test if H. pylori eradication or modification of gut microbiota can improve the control of human metabolic disorders.

MetaPro-IQ: a universal metaproteomic approach to studying human and mouse gut microbiota.

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Zhang, Xu; Ning, Zhibin; Mayne, Janice; Moore, Jasmine I; Li, Jennifer; Butcher, James; Deeke, Shelley Ann; Chen, Rui; Chiang, Cheng-Kang; Wen, Ming; Mack, David; Stintzi, Alain; Figeys, Daniel

2016-06-24

The gut microbiota has been shown to be closely associated with human health and disease. While next-generation sequencing can be readily used to profile the microbiota taxonomy and metabolic potential, metaproteomics is better suited for deciphering microbial biological activities. However, the application of gut metaproteomics has largely been limited due to the low efficiency of protein identification. Thus, a high-performance and easy-to-implement gut metaproteomic approach is required. In this study, we developed a high-performance and universal workflow for gut metaproteome identification and quantification (named MetaPro-IQ) by using the close-to-complete human or mouse gut microbial gene catalog as database and an iterative database search strategy. An average of 38 and 33 % of the acquired tandem mass spectrometry (MS) spectra was confidently identified for the studied mouse stool and human mucosal-luminal interface samples, respectively. In total, we accurately quantified 30,749 protein groups for the mouse metaproteome and 19,011 protein groups for the human metaproteome. Moreover, the MetaPro-IQ approach enabled comparable identifications with the matched metagenome database search strategy that is widely used but needs prior metagenomic sequencing. The response of gut microbiota to high-fat diet in mice was then assessed, which showed distinct metaproteome patterns for high-fat-fed mice and identified 849 proteins as significant responders to high-fat feeding in comparison to low-fat feeding. We present MetaPro-IQ, a metaproteomic approach for highly efficient intestinal microbial protein identification and quantification, which functions as a universal workflow for metaproteomic studies, and will thus facilitate the application of metaproteomics for better understanding the functions of gut microbiota in health and disease.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress.

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Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-12-02

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress

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Leilei Yu

2016-12-01

Full Text Available Aluminum (Al is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

Influence of plant-originated gastroproteciive and antiulcer substances on gastric mucosal repair.

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Zayachkivska, O S; Konturek, S J; Drozdowicz, D; Brzozowski, T; Gzhegotsky, M R

2004-01-01

Fundamental basis of cellular and molecular mechanisms involved in mucosal injury and repair in gastrointestinal tract helps to develop new therapeutic approaches to various gut mucosal injury- related diseases. The study was aimed to assess the relations between plant-originated substances and their bioactivity measured in terms of antioxidant, cytoprotective and antiulceric activities and to deteminate if these effects are capable of affecting the gastric mucosal lesions induced by absolute ethanol applied intragastrically. The following plant-originated substances were considered: Solon, capsaicin, grapefruit-seed extract and amaranth. The area of gastric mucosa lesions and gastric blood flow were measured in rats with ethanol-induced lesions without (control) and with one of the tested substances without and with capsaicin denervation of afferent nerves or administration of L-nitro-arginine (L-NNA), an inhibitor of nitric oxide synthase (NOS). male Wistar rats, weighing 180-220 g fasted for 24 h before the study, 100% ethanol was applied ig to induced gastric lesions, whose area was determined by planimetry. Gastric blood flow was assessed using electrolytic regional blood flowmeter. All tested plant-originated substances afforded gastroprotection against ethanol-induced damage and this was accompanied by an increase in gastric microcirculation, both changes being reversed by pretreatment with neurotoxic dose of capsaicin or by pretreatment-with L-NNA. Plant-originated substances are highly gastroprotective probably due to enhancement of the expression of NOS I, NO release and an increase in gastric microcirculation.

Impact of a 3-Months Vegetarian Diet on the Gut Microbiota and Immune Repertoire

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Chenchen Zhang

2018-04-01

Full Text Available The dietary pattern can influence the immune system directly, but may also modulate it indirectly by regulating the gut microbiota. Here, we investigated the effect of a 3-months lacto-ovo-vegetarian diet on the diversity of gut microbiota and the immune system in healthy omnivorous volunteers, using high-throughput sequencing technologies. The short-term vegetarian diet did not have any major effect on the diversity of the immune system and the overall composition of the metagenome. The prevalence of bacterial genera/species with known beneficial effects on the intestine, including butyrate-producers and probiotic species and the balance of autoimmune-related variable genes/families were, however, altered in the short-term vegetarians. A number of bacterial species that are associated with the expression level of IgA, a key immunoglobulin class that protects the gastrointestinal mucosal system, were also identified. Furthermore, a lower diversity of T-cell repertoire and expression level of IgE, as well as a reduced abundance of inflammation-related genes in the gut microbiota were potentially associated with a control group with long-term vegetarians. Thus, the composition and duration of the diet may have an impact on the balance of pro-/anti-inflammatory factors in the gut microbiota and immune system.

Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating Disorders

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Yan Y. Lam

2017-06-01

Full Text Available Traditionally recognized as mental illnesses, eating disorders are increasingly appreciated to be biologically-driven. There is a growing body of literature that implicates a role of the gut microbiota in the etiology and progression of these conditions. Gut bacteria may act on the gut–brain axis to alter appetite control and brain function as part of the genesis of eating disorders. As the illnesses progress, extreme feeding patterns and psychological stress potentially feed back to the gut ecosystem that can further compromise physiological, cognitive, and social functioning. Given the established causality between dysbiosis and metabolic diseases, an altered gut microbial profile is likely to play a role in the co-morbidities of eating disorders with altered immune function, short-chain fatty acid production, and the gut barrier being the key mechanistic links. Understanding the role of the gut ecosystem in the pathophysiology of eating disorders will provide critical insights into improving current treatments and developing novel microbiome-based interventions that will benefit patients with eating disorders.

Mechanisms of transepithelial ammonia excretion and luminal alkalinization in the gut of an intestinal air-breathing fish, Misgurnus anguilliacaudatus.

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Wilson, Jonathan M; Moreira-Silva, Joana; Delgado, Inês L S; Ebanks, Sue C; Vijayan, Mathilakath M; Coimbra, João; Grosell, Martin

2013-02-15

The weatherloach, Misgurnus angulliacaudatus, is an intestinal air-breathing, freshwater fish that has the unique ability to excrete ammonia through gut volatilization when branchial and cutaneous routes are compromised during high environmental ammonia or air exposure. We hypothesized that transepithelial gut NH(4)(+) transport is facilitated by an apical Na(+)/H(+) (NH(4)(+)) exchanger (NHE) and a basolateral Na(+)/K(+)(NH(4)(+))-ATPase, and that gut boundary layer alkalinization (NH(4)(+) → NH(3) + H(+)) is facilitated by apical HCO(3)(-) secretion through a Cl(-)/HCO(3)(-) anion exchanger. This was tested using a pharmacological approach with anterior (digestive) and posterior (respiratory) intestine preparations mounted in pH-stat-equipped Ussing chambers. The anterior intestine had a markedly higher conductance, increased short-circuit current, and greater net base (J(base)) and ammonia excretion rates (J(amm)) than the posterior intestine. In the anterior intestine, HCO(3)(-) accounted for 70% of J(base). In the presence of an imposed serosal-mucosal ammonia gradient, inhibitors of both NHE (EIPA, 0.1 mmol l(-1)) and Na(+)/K(+)-ATPase (ouabain, 0.1 mmol l(-1)) significantly inhibited J(amm) in the anterior intestine, although only EIPA had an effect in the posterior intestine. In addition, the anion exchange inhibitor DIDS significantly reduced J(base) in the anterior intestine although only at a high dose (1 mmol l(-1)). Carbonic anhydrase does not appear to be associated with gut alkalinization under these conditions as ethoxzolamide was without effect on J(base). Membrane fluidity of the posterior intestine was low, suggesting low permeability, which was also reflected in a lower mucosal-serosal J(amm) in the presence of an imposed gradient, in contrast to that in the anterior intestine. To conclude, although the posterior intestine is highly modified for gas exchange, it is the anterior intestine that is the likely site of ammonia excretion and

GM-CSF increases mucosal and systemic immunogenicity of an H1N1 influenza DNA vaccine administered into the epidermis of non-human primates.

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Peter T Loudon

2010-06-01

Full Text Available The recent H5N1 avian and H1N1 swine-origin influenza virus outbreaks reaffirm that the threat of a world-wide influenza pandemic is both real and ever-present. Vaccination is still considered the best strategy for protection against influenza virus infection but a significant challenge is to identify new vaccine approaches that offer accelerated production, broader protection against drifted and shifted strains, and the capacity to elicit anti-viral immune responses in the respiratory tract at the site of viral entry. As a safe alternative to live attenuated vaccines, the mucosal and systemic immunogenicity of an H1N1 influenza (A/New Caledonia/20/99 HA DNA vaccine administered by particle-mediated epidermal delivery (PMED or gene gun was analyzed in rhesus macaques.Macaques were immunized at weeks 0, 8, and 16 using a disposable single-shot particle-mediated delivery device designed for clinical use that delivers plasmid DNA directly into cells of the epidermis. Significant levels of hemagglutination inhibiting (HI antibodies and cytokine-secreting HA-specific T cells were observed in the periphery of macaques following 1-3 doses of the PMED HA DNA vaccine. In addition, HA DNA vaccination induced detectable levels of HA-specific mucosal antibodies and T cells in the lung and gut-associated lymphoid tissues of vaccinated macaques. Importantly, co-delivery of a DNA encoding the rhesus macaque GM-CSF gene was found to significantly enhance both the systemic and mucosal immunogenicity of the HA DNA vaccine.These results provide strong support for the development of a particle-mediated epidermal DNA vaccine for protection against respiratory pathogens such as influenza and demonstrate, for the first time, the ability of skin-delivered GM-CSF to serve as an effective mucosal adjuvant for vaccine induction of immune responses in the gut and respiratory tract.

Gut as a target for cadmium toxicity.

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Tinkov, Alexey A; Gritsenko, Viktor A; Skalnaya, Margarita G; Cherkasov, Sergey V; Aaseth, Jan; Skalny, Anatoly V

2018-04-01

The primary objective of the present study was to review the impact of Cd exposure on gut microbiota and intestinal physiology, as well as to estimate whether gut may be considered as the target for Cd toxicity. The review is based on literature search in available databases. The existing data demonstrate that the impact of Cd on gut physiology is two-sided. First, Cd exposure induces a significant alteration of bacterial populations and their relative abundance in gut (increased Bacteroidetes-to-Firmicutes ratio), accompanied by increased lipopolysaccharide (LPS) production, reflecting changed metabolic activity of the intestinal microbiome. Second, in intestinal wall Cd exposure induces inflammatory response and cell damage including disruption of tight junctions, ultimately leading to increased gut permeability. Together with increased LPS production, impaired barrier function causes endotoxinemia and systemic inflammation. Hypothetically, Cd-induced increase gut permeability may also result in increased bacterial translocation. On the one hand, bacteriolysis may be associated with aggravation of endotoxemia. At the same time, together with Cd-induced impairment of macrophage inflammatory response, increased bacterial translocation may result in increased susceptibility to infections. Such a supposition is generally in agreement with the finding of higher susceptibility of Cd-exposed mice to infections. The changed microbiome metabolic activity and LPS-induced systemic inflammation may have a significant impact on target organs. The efficiency of probiotics in at least partial prevention of the local (intestinal) and systemic toxic effects of cadmium confirms the role of altered gut physiology in Cd toxicity. Therefore, probiotic treatment may be considered as the one of the strategies for prevention of Cd toxicity in parallel with chelation, antioxidant, and anti-inflammatory therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Discovery of J chain in African lungfish (Protopterus dolloi, Sarcopterygii using high throughput transcriptome sequencing: implications in mucosal immunity.

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Luca Tacchi

Full Text Available J chain is a small polypeptide responsible for immunoglobulin (Ig polymerization and transport of Igs across mucosal surfaces in higher vertebrates. We identified a J chain in dipnoid fish, the African lungfish (Protopterus dolloi by high throughput sequencing of the transcriptome. P. dolloi J chain is 161 aa long and contains six of the eight Cys residues present in mammalian J chain. Phylogenetic studies place the lungfish J chain closer to tetrapod J chain than to the coelacanth or nurse shark sequences. J chain expression occurs in all P. dolloi immune tissues examined and it increases in the gut and kidney in response to an experimental bacterial infection. Double fluorescent in-situ hybridization shows that 88.5% of IgM⁺ cells in the gut co-express J chain, a significantly higher percentage than in the pre-pyloric spleen. Importantly, J chain expression is not restricted to the B-cell compartment since gut epithelial cells also express J chain. These results improve our current view of J chain from a phylogenetic perspective.

big bang gene modulates gut immune tolerance in Drosophila.

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Bonnay, François; Cohen-Berros, Eva; Hoffmann, Martine; Kim, Sabrina Y; Boulianne, Gabrielle L; Hoffmann, Jules A; Matt, Nicolas; Reichhart, Jean-Marc

2013-02-19

Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases.

Combined enteral infusion of glutamine, carbohydrates, and antioxidants modulates gut protein metabolism in humans.

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Coëffier, Moïse; Claeyssens, Sophie; Lecleire, Stéphane; Leblond, Jonathan; Coquard, Aude; Bôle-Feysot, Christine; Lavoinne, Alain; Ducrotté, Philippe; Déchelotte, Pierre

2008-11-01

Available data suggest that nutrients can affect intestinal protein metabolism, which contributes to the regulation of gut barrier function. We aimed to assess whether an oral nutritional supplement (ONS) containing glutamine (as the dipeptide Ala-Gln), carbohydrates, and antioxidants would modulate duodenal protein metabolism in healthy humans. Thirty healthy control subjects were included and, over a period of 5 h, received by nasogastric tube either saline or ONS providing 11.7 kcal/kg as 0.877 g Ala-Gln/kg, 3.9 g carbohydrates/kg, and antioxidants (29.25 mg vitamin C/kg, 9.75 mg vitamin E/kg, 195 microg beta-carotene/kg, 5.85 mg Se/kg, and 390 microg Zn/kg) or glutamine (0.585 g/kg, 2.34 kcal/kg). Simultaneously, a continuous intravenous infusion of l-[1-(13)C]-leucine was done until endoscopy. Leucine enrichment was assessed by using gas chromatography-mass spectrometric analysis, and mucosal fractional synthesis rate was calculated by using intracellular amino acid enrichment as precursor. Mucosal proteolytic pathways were also evaluated. ONS infusion resulted in a doubling increase (P < 0.01) of duodenal fractional synthesis rate and a significant (P < 0.05) decrease in cathepsin D-mediated proteolysis compared with saline, whereas proteasome and Ca(2+)-dependent activities were unaffected. ONS infusion significantly (P < 0.01) decreased duodenal glutathione but not glutathione disulfide concentrations or the ratio of glutathione to glutathione disulfide. Insulinemia increased after ONS infusion, whereas plasma essential amino acids decreased. Infusion of glutamine alone did not reproduce ONS effects. ONS infusion improves duodenal protein balance in healthy humans. Further investigations are needed to study the origin of these effects and to evaluate ONS supply in stressed persons.

Intestinal Barrier Function and the Gut Microbiome Are Differentially Affected in Mice Fed a Western-Style Diet or Drinking Water Supplemented with Fructose.

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Volynets, Valentina; Louis, Sandrine; Pretz, Dominik; Lang, Lisa; Ostaff, Maureen J; Wehkamp, Jan; Bischoff, Stephan C

2017-05-01

Background: The consumption of a Western-style diet (WSD) and high fructose intake are risk factors for metabolic diseases. The underlying mechanisms are largely unclear. Objective: To unravel the mechanisms by which a WSD and fructose promote metabolic disease, we investigated their effects on the gut microbiome and barrier function. Methods: Adult female C57BL/6J mice were fed a sugar- and fat-rich WSD or control diet (CD) for 12 wk and given access to tap water or fructose-supplemented water. The microbiota was analyzed with the use of 16S rRNA gene sequencing. Barrier function was studied with the use of permeability tests, and endotoxin, mucus thickness, and gene expressions were measured. Results: The WSD increased body weight gain but not endotoxin translocation compared with the CD. In contrast, high fructose intake increased endotoxin translocation 2.6- and 3.8-fold in the groups fed the CD + fructose and WSD + fructose, respectively, compared with the CD group. The WSD + fructose treatment also induced a loss of mucus thickness in the colon (-46%) and reduced defensin expression in the ileum and colon. The lactulose:mannitol ratio in the WSD + fructose mice was 1.8-fold higher than in the CD mice. Microbiota analysis revealed that fructose, but not the WSD, increased the Firmicutes:Bacteroidetes ratio by 88% for CD + fructose and 63% for WSD + fructose compared with the CD group. Bifidobacterium abundance was greater in the WSD mice than in the CD mice (63-fold) and in the WSD + fructose mice than in the CD + fructose mice (330-fold). Conclusions: The consumption of a WSD or high fructose intake differentially affects gut permeability and the microbiome. Whether these differences are related to the distinct clinical outcomes, whereby the WSD primarily promotes weight gain and high fructose intake causes barrier dysfunction, needs to be investigated in future studies. © 2017 American Society for Nutrition.

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases.

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Lin, Lan; Zhang, Jianqiong

2017-01-06

A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health. This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA). In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction. A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

Food-grade TiO2 is trapped by intestinal mucus in vitro but does not impair mucin O-glycosylation and short-chain fatty acid synthesis in vivo: implications for gut barrier protection.

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Talbot, Pauline; Radziwill-Bienkowska, Joanna M; Kamphuis, Jasper B J; Steenkeste, Karine; Bettini, Sarah; Robert, Véronique; Noordine, Marie-Louise; Mayeur, Camille; Gaultier, Eric; Langella, Philippe; Robbe-Masselot, Catherine; Houdeau, Eric; Thomas, Muriel; Mercier-Bonin, Muriel

2018-06-19

Titanium dioxide (TiO 2 ) particles are commonly used as a food additive (E171 in the EU) for its whitening and opacifying properties. However, the risk of gut barrier disruption is an increasing concern because of the presence of a nano-sized fraction. Food-grade E171 may interact with mucus, a gut barrier protagonist still poorly explored in food nanotoxicology. To test this hypothesis, a comprehensive approach was performed to evaluate in vitro and in vivo interactions between TiO 2 and intestinal mucus, by comparing food-grade E171 with NM-105 (Aeroxyde P25) OECD reference nanomaterial. We tested E171-trapping properties of mucus in vitro using HT29-MTX intestinal epithelial cells. Time-lapse confocal laser scanning microscopy was performed without labeling to avoid modification of the particle surface. Near-UV irradiation of E171 TiO 2 particles at 364 nm resulted in fluorescence emission in the visible range, with a maximum at 510 nm. The penetration of E171 TiO 2 into the mucoid area of HT29-MTX cells was visualized in situ. One hour after exposure, TiO 2 particles accumulated inside "patchy" regions 20 µm above the substratum. The structure of mucus produced by HT29-MTX cells was characterized by MUC5AC immunofluorescence staining. The mucus layer was thin and organized into regular "islands" located approximately 20 µm above the substratum. The region-specific trapping of food-grade TiO 2 particles was attributed to this mucus patchy structure. We compared TiO 2 -mediated effects in vivo in rats after acute or sub-chronic oral daily administration of food-grade E171 and NM-105 at relevant exposure levels for humans. Cecal short-chain fatty acid profiles and gut mucin O-glycosylation patterns remained unchanged, irrespective of treatment. Food-grade TiO 2 is trapped by intestinal mucus in vitro but does not affect mucin O-glycosylation and short-chain fatty acid synthesis in vivo, suggesting the absence of a mucus barrier impairment under "healthy gut

Gut-associated Lymphoid Tissue (GALT) Carcinoma in Ulcerative Colitis.

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Rubio, Carlos A; DE Petris, Giovanni; Puppa, Giacomo

2018-02-01

In ulcerative colitis (UC), the majority of colorectal carcinomas (CRC) arise in the vast colorectal mucosal domain built with mucus-producing goblet cells and columnar cells. Conversely, CRC in UC rarely evolve in the tiny, spotty gut-associated lymphoid tissue (GALT) mucosal domain. Here we review the four reported cases of colonic carcinoma developing in GALT mucosa in UC, searching for possible precursor lesions connected with the evolution of these tumours. The clinical history, age, gender, endoscopic descriptions, and the pathology (localization, gross and histological descriptions of the luminal surface) of the four UC-GALT carcinomas reported in the literature were reviewed. The luminal surface in three out of the four carcinomas revealed conventional (tubular/villous) adenomas or high-grade dysplasia. All four UC-GALT-carcinomas were detected at an early stage (T1N0). GALT carcinomas do occur, albeit infrequently, in patients with UC. The finding that three out of the four GALT carcinomas on record were covered by conventional adenomas or by high-grade dysplasia strongly suggests that non-invasive conventional neoplasias might often precede GALT carcinomas in UC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

A new technique for continuous measurement and recording of gastric potential difference in the rat: evaluation of NSAID-induced gastric mucosal damage.

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Scarpignato, C; Corradi, C; Gandolfi, M A; Galmiche, J P

1995-10-01

Disruption of the gastric mucosal barrier by the so-called "barrier breakers" such as ethanol, aspirin, and bile is associated with an increase in gastric potential difference (GPD), that is, a decrease in its negativity. Because a good correlation between the degree of histological damage and changes in GPD has been observed, this parameter has been used increasingly as an index of mucosal integrity. However, the current methodology for measuring GPD is laborious due to the preparation and checking of KCl-agarose bridges prior to each experiment, and calculations--usually handmade--are time-consuming and inaccurate. In this paper, a new method allowing simultaneous measurement and recording of GPD in the rat is described. The method allows a simultaneous recording of intragastric pH and an automatic data analysis. The new technique has been validated by studying mucosal damage induced by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) (namely indomethacin and droxicam) as well as the mucosal protective activity of an antacid and sucralfate. The similarity between the results obtained in this rat model and those derived from human experiments clearly show that the developed methodology yields results that are predictive for human pharmacology.

A gut microbiota-targeted dietary intervention for amelioration of chronic inflammation underlying metabolic syndrome.

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Xiao, Shuiming; Fei, Na; Pang, Xiaoyan; Shen, Jian; Wang, Linghua; Zhang, Baorang; Zhang, Menghui; Zhang, Xiaojun; Zhang, Chenhong; Li, Min; Sun, Lifeng; Xue, Zhengsheng; Wang, Jingjing; Feng, Jie; Yan, Feiyan; Zhao, Naisi; Liu, Jiaqi; Long, Wenmin; Zhao, Liping

2014-02-01

Chronic inflammation induced by endotoxin from a dysbiotic gut microbiota contributes to the development of obesity-related metabolic disorders. Modification of gut microbiota by a diet to balance its composition becomes a promising strategy to help manage obesity. A dietary scheme based on whole grains, traditional Chinese medicinal foods, and prebiotics (WTP diet) was designed to meet human nutritional needs as well as balance the gut microbiota. Ninety-three of 123 central obese volunteers (BMI ≥ 28 kg m(-2) ) completed a self-controlled clinical trial consisting of 9-week intervention on WTP diet followed by a 14-week maintenance period. The average weight loss reached 5.79 ± 4.64 kg (6.62 ± 4.94%), in addition to improvement in insulin sensitivity, lipid profiles, and blood pressure. Pyrosequencing of fecal samples showed that phylotypes related to endotoxin-producing opportunistic pathogens of Enterobacteriaceae and Desulfovibrionaceae were reduced significantly, while those related to gut barrier-protecting bacteria of Bifidobacteriaceae increased. Gut permeability, measured as lactulose/mannitol ratio, was decreased compared with the baseline. Plasma endotoxin load as lipopolysaccharide-binding protein was also significantly reduced, with concomitant decrease in tumor necrosis factor-α, interleukin-6, and an increase in adiponectin. These results suggest that modulation of the gut microbiota via dietary intervention may enhance the intestinal barrier integrity, reduce circulating antigen load, and ultimately ameliorate the inflammation and metabolic phenotypes. © 2013 The Authors. FEMS Microbiology Ecology pubished by John Wiley & Sons Ltd on behalf of the Federation of European Microbiological Societies.

TFH cells accumulate in mucosal tissues of humanized-DRAG mice and are highly permissive to HIV-1

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Allam, Atef; Majji, Sai; Peachman, Kristina; Jagodzinski, Linda; Kim, Jiae; Ratto-Kim, Silvia; Wijayalath, Wathsala; Merbah, Melanie; Kim, Jerome H.; Michael, Nelson L.; Alving, Carl R.; Casares, Sofia; Rao, Mangala

2015-01-01

CD4+ T follicular helper cells (TFH) in germinal centers are required for maturation of B-cells. While the role of TFH-cells has been studied in blood and lymph nodes of HIV-1 infected individuals, its role in the mucosal tissues has not been investigated. We show that the gut and female reproductive tract (FRT) of humanized DRAG mice have a high level of human lymphocytes and a high frequency of TFH (CXCR5+PD-1++) and precursor-TFH (CXCR5+PD-1+) cells. The majority of TFH-cells expressed CCR...

New Pathways for Alimentary Mucositis

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Joanne M. Bowen

2008-01-01

Full Text Available Alimentary mucositis is a major dose-limiting toxicity associated with anticancer treatment. It is responsible for reducing patient quality of life and represents a significant economic burden in oncology. The pathobiology of alimentary mucositis is extremely complex, and an increased understanding of mechanisms and pathway interactions is required to rationally design improved therapies. This review describes the latest advances in defining mechanisms of alimentary mucositis pathobiology in the context of pathway activation. It focuses particularly on the recent genome-wide analyses of regimen-related mucosal injury and the identification of specific regulatory pathways implicated in mucositis development. This review also discusses the currently known alimentary mucositis risk factors and the development of novel treatments. Suggestions for future research directions have been raised.

High salt intake increases plasma trimethylamine N-oxide (TMAO) concentration and produces gut dysbiosis in rats.

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Bielinska, Klaudia; Radkowski, Marek; Grochowska, Marta; Perlejewski, Karol; Huc, Tomasz; Jaworska, Kinga; Motooka, Daisuke; Nakamura, Shota; Ufnal, Marcin

2018-03-22

A high-salt diet is considered a cardiovascular risk factor; however, the mechanisms are not clear. Research suggests that gut bacteria-derived metabolites such as trimethylamine N-oxide (TMAO) are markers of cardiovascular diseases. We evaluated the effect of high salt intake on gut bacteria and their metabolites plasma level. Sprague Dawley rats ages 12-14 wk were maintained on either water (controls) or 0.9% or 2% sodium chloride (NaCl) water solution (isotonic and hypertonic groups, respectively) for 2 wk. Blood plasma, urine, and stool samples were analyzed for concentrations of trimethylamine (TMA; a TMAO precursor), TMAO, and indoxyl sulfate (indole metabolite). The gut-blood barrier permeability to TMA and TMA liver clearance were assessed at baseline and after TMA intracolonic challenge test. Gut bacterial flora was analyzed with a 16S ribosomal ribonucleic acid (rRNA) gene sequence analysis. The isotonic and hypertonic groups showed a significantly higher plasma TMAO and significantly lower 24-hr TMAO urine excretion than the controls. However, the TMA stool level was similar between the groups. There was no significant difference between the groups in gut-blood barrier permeability and TMA liver clearance. Plasma indoxyl concentration and 24-hr urine indoxyl excretion were similar between the groups. There was a significant difference between the groups in gut bacteria composition. High salt intake increases plasma TMAO concentration, which is associated with decreased TMAO urine excretion. Furthermore, high salt intake alters gut bacteria composition. These findings suggest that salt intake affects an interplay between gut bacteria and their host homeostasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Radiation induced oral mucositis

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P S Satheesh Kumar

2009-01-01

Full Text Available Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii who also received concomitant chemotherapy; (iii who received a total dose over 5,000 cGy; and (iv who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene

Effect of caloric restriction on gut permeability, inflammation markers, and fecal microbiota in obese women.

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Ott, Beate; Skurk, Thomas; Hastreiter, Ljiljana; Lagkouvardos, Ilias; Fischer, Sandra; Büttner, Janine; Kellerer, Teresa; Clavel, Thomas; Rychlik, Michael; Haller, Dirk; Hauner, Hans

2017-09-20

Recent findings suggest an association between obesity, loss of gut barrier function and changes in microbiota profiles. Our primary objective was to examine the effect of caloric restriction and subsequent weight reduction on gut permeability in obese women. The impact on inflammatory markers and fecal microbiota was also investigated. The 4-week very-low calorie diet (VLCD, 800 kcal/day) induced a mean weight loss of 6.9 ± 1.9 kg accompanied by a reduction in HOMA-IR (Homeostasis model assessment-insulin resistance), fasting plasma glucose and insulin, plasma leptin, and leptin gene expression in subcutaneous adipose tissue. Plasma high-molecular weight adiponectin (HMW adiponectin) was significantly increased after VLCD. Plasma levels of high-sensitivity C-reactive protein (hsCRP) and lipopolysaccharide-binding protein (LBP) were significantly decreased after 28 days of VLCD. Using three different methods, gut paracellular permeability was decreased after VLCD. These changes in clinical parameters were not associated with major consistent changes in dominant bacterial communities in feces. In summary, a 4-week caloric restriction resulted in significant weight loss, improved gut barrier integrity and reduced systemic inflammation in obese women.

Gut barrier function and systemic endotoxemia after laparotomy or laparoscopic resection for colon cancer: A prospective randomized study

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Mario Schietroma

2016-01-01

Full Text Available Purpose: The gut barrier is altered in certain pathologic conditions (shock, trauma, or surgical stress, resulting in bacterial and/or endotoxin translocation from the gut lumen into the systemic circulation. In this prospective randomized study, we investigated the effect of surgery on intestinal permeability (IP and endotoxemia in patients undergoing elective colectomy for colon cancer by comparing the laparoscopic with the open approach. Patients and Methods: A hundred twenty-three consecutive patients underwent colectomy for colon cancer: 61 cases were open resection (OR and 62 cases were laparoscopic resection (LR. IP was measured preoperatively and at days 1 and 3 after surgery. Serial venous blood sample were taken at 0, 30, 60, 90, 120, and 180 min, and at 12, 24, and 48 h after surgery for endotoxin measurement. Results: IP was significantly increased in the open and closed group at day 1 compared with the preoperative level (P < 0.05, but no difference was found between laparoscopic and open surgery group. The concentration endotoxin systemic increased significantly in the both groups during the course of surgery and returned to baseline levels at the second day. No difference was found between laparoscopic and open surgery. A significant correlation was observed between the maximum systemic endotoxin concentration and IP measured at day 1 in the open group and in the laparoscopic group. Conclusion: An increase in IP, and systemic endotoxemia were observed during the open and laparoscopic resection for colon cancer, without significant statistically difference between the two groups.

New insights into the gut as the driver of critical illness and organ failure.

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Meng, Mei; Klingensmith, Nathan J; Coopersmith, Craig M

2017-04-01

The gut has long been hypothesized to be the 'motor' of multiple organ dysfunction syndrome. This review serves as an update on new data elucidating the role of the gut as the propagator of organ failure in critical illness. Under basal conditions, the gut absorbs nutrients and serves as a barrier that prevents approximately 40 trillion intraluminal microbes and their products from causing host injury. However, in critical illness, gut integrity is disrupted with hyperpermeability and increased epithelial apoptosis, allowing contamination of extraluminal sites that are ordinarily sterile. These alterations in gut integrity are further exacerbated in the setting of preexisting comorbidities. The normally commensal microflora is also altered in critical illness, with increases in microbial virulence and decreases in diversity, which leads to further pathologic responses within the host. All components of the gut are adversely impacted by critical illness. Gut injury can not only propagate local damage, but can also cause distant injury and organ failure. Understanding how the multifaceted components of the gut interact and how these are perturbed in critical illness may play an important role in turning off the 'motor' of multiple organ dysfunction syndrome in the future.

Reshaping the gut microbiota at an early age: functional impact on obesity risk?

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Luoto, R; Collado, M C; Salminen, S; Isolauri, E

2013-01-01

Overweight and obesity can currently be considered a major threat to human health and well-being. Recent scientific advances point to an aberrant compositional development of the gut microbiota and low-grade inflammation as contributing factors, in conjunction with excessive energy intake. A high-fat/energy diet alters the gut microbiota composition, which reciprocally engenders excessive energy harvesting and storage. Further, microbial imbalance increases gut permeability, leading to metabolic endotoxemia, inflammation and insulin resistance. Local intestinal immunologic homeostasis is achieved by tolerogenic immune responses to microbial antigens. In the context of amelioration of insulin sensitivity and decreased adiposity, the potential of gut microbiota modulation with specific probiotics and prebiotics lies in the normalization of aberrant microbiota, improved gut barrier function and creation of an anti-inflammatory milieu. This would suggest a role for probiotic/prebiotic interventions in the search for preventive and therapeutic applications in weight management. © 2013 S. Karger AG, Basel.

Intestinal Microbiota Promotes Psoriasis-Like Skin Inflammation by Enhancing Th17 Response

Czech Academy of Sciences Publication Activity Database

Zákostelská, Z.; Málková, J.; Klimešová, K.; Rossmann, P.; Hornová, M.; Novosádová, I.; Stehlíková, Z.; Kostovčík, M.; Hudcovič, T.; Štěpánková, R.; Jůzlová, K.; Hercogová, J.; Tlaskalová-Hogenová, H.; Kverka, Miloslav

2016-01-01

Roč. 11, č. 7 (2016), e0159539 E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GAP303/12/0535; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:68378041 Keywords : altered gut microbiota * delta t-cells * bacterial overgrowth * mucosal barrier Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 2.806, year: 2016

The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea.

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Kathrin Endt

Full Text Available Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm(att, sseD causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis and sIgA-deficient mice (TCRβ(-/-δ(-/-, J(H (-/-, IgA(-/-, pIgR(-/-. Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using 'L-mice' which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm(att from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota, the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most "classical" immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has

Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4+ memory T cells.

Science.gov (United States)

Szilagyi, B A; Triebus, J; Kressler, C; de Almeida, M; Tierling, S; Durek, P; Mardahl, M; Szilagyi, A; Floess, S; Huehn, J; Syrbe, U; Walter, J; Polansky, J K; Hamann, A

2017-11-01

The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α 4 β 7 was found in CD8 + T cells, questioning the concept. We now demonstrate that α 4 β 7 expression in murine CD4 + memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α 4 β 7 . A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α 4 β 7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α 4 β 7 is imprinted in CD4 + memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.

The Human Neonatal Gut Microbiome: A Brief Review

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Emily C. Gritz

2015-03-01

Full Text Available The field of genomics has expanded into subspecialties such as metagenomics over the course of the last decade and a half. The development of massively parallel sequencing capabilities has allowed for increasingly detailed study of the genome of the human microbiome, the microbial super organ that resides symbiotically within the mucosal tissues and integumentary system of the human host. The gut microbiome, and particularly the study of its origins in neonates, have become subtopics of great interest within the field of genomics. This brief review seeks to summarize recent literature regarding the origins and establishment of the neonatal gut microbiome, beginning in utero, and how it is affected by neonatal nutritional status (breastfed versus formula fed and gestational age (term versus preterm. We also explore the role of dysbiosis, a perturbation within the fragile ecosystem of the microbiome, and its role in the origin of select pathologic states, specifically, obesity and necrotizing enterocolitis in preterm infants. We discuss the evidence supporting enteral pre- and probiotic supplementation of commensal organisms such as Bifidobacterium and Lactobacillus in the neonatal period, and their role in the prevention and amelioration of necrotizing enterocolitis in premature infants. Finally, we review directions to consider for further research to promote human health within this field.

Gut

DEFF Research Database (Denmark)

Muscogiuri, Giovanna; Balercia, Giancarlo; Barrea, Luigi

2017-01-01

The gut regulates glucose and energy homeostasis; thus, the presence of ingested nutrients into the gut activates sensing mechanisms that affect both glucose homeostasis and regulate food intake. Increasing evidence suggest that gut may also play a key role in the pathogenesis of type 2 diabetes...... which may be related to both the intestinal microbiological profile and patterns of gut hormones secretion. Intestinal microbiota includes trillions of microorganisms but its composition and function may be adversely affected in type 2 diabetes. The intestinal microbiota may be responsible...... metabolism. Thus, the aim of this manuscript is to review the current evidence on the role of the gut in the pathogenesis of type 2 diabetes, taking into account both hormonal and microbiological aspects....

Intravenous administration of high-dose Paclitaxel reduces gut-associated lymphoid tissue cell number and respiratory immunoglobulin A concentrations in mice.

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Moriya, Tomoyuki; Fukatsu, Kazuhiko; Noguchi, Midori; Okamoto, Koichi; Murakoshi, Satoshi; Saitoh, Daizoh; Miyazaki, Masaru; Hase, Kazuo; Yamamoto, Junji

2014-02-01

Chemotherapy remains a mainstay of treatment for cancer patients. However, anti-cancer drugs frequently cause a wide range of side effects, including leukopenia and gastrointestinal toxicity. These adverse effects can lead to treatment delays or necessitate temporary dose reductions. Although chemotherapy-related changes in gut morphology have been demonstrated, the influences of chemotherapeutic regimens on gut immunity are understood poorly. This study aimed to examine whether the anti-cancer drug paclitaxel (PTX) impairs gut immunity in mice. Male ICR mice were randomized into three groups: Control, low-dose PTX (low PTX; 2 mg/kg), or high-dose PTX (high PTX; 4 mg/kg). A single intravenous dose was given. On day seven after the injection, lymphocytes from Peyer patches (PP), intraepithelial (IE) spaces, and the lamina propria (LP) were counted and analyzed by flow cytometry (CD4(+), CD8(+), αβTCR(+), γδTCR(+), B220(+)). Immunoglobulin A (IgA) concentrations were measured in small intestinal and respiratory tract washings. Total, CD4(+) and γδTCR(+) lymphocyte numbers in PPs were significantly lower in the high PTX than in the control group. The CD4(+) lymphocyte numbers in the IE spaces were significantly lower in both PTX groups than in the control group. Respiratory tract IgA concentrations were lower in the high PTX than in the control group. The present data suggest high-dose PTX impairs mucosal immunity, possibly rendering patients more vulnerable to infection. Careful dose selection and new therapies may be important for maintaining mucosal immunity during PTX chemotherapy.

Assessment of intestinal permeability and bacterial translocation employing nuclear methods in murine mucositis

International Nuclear Information System (INIS)

Pessoa, Rafaela M.; Takenaka, Isabella K.T.M.; Barros, Patricia A.V.; Moura, Livia P.; Contarini, Sara M.L.; Amorim, Juliana M.; Castilho, Raquel O.; Leite, Camila M.A.; Cardoso, Valbert N.; Diniz, Simone Odilia F.

2017-01-01

Full text: Introduction: Mucositis affects approximately 80% of patients who receive chemotherapy combinations. The lesions are painful, restrict food intake and make patients more susceptible to systemic infections. Some agents and strategies are being studied for controlling mucositis, none of them is used in clinical practice. In Minas Gerais, many studies have addressed the popular use of the plant Arrabidaea chica in the form of tea, to treat intestinal cramps and diarrhea, the main symptoms of mucositis. Objective: To evaluate the potential of Arrabidaea chica extract in the management of the integrity of the intestinal mucosa, using the experimental model of gut mucositis induced by 5-Fluorouracila (5-FU). Methods: The UFMG Ethics Committee for Animal Experimentation (CETEA/UFMG) approved this study (nº 411/2015). Male BALB/c mice between 6-8 weeks of age were randomly divided into four groups (n=9) as follows: 1. Control (CTL) - oral administration of saline solution (10 days); 2. A. chica (AC) - oral administration of A. chica extract (10 days); 3. Mucositis (MUC) - underwent mucositis (5-FU) (10 days); 4. Mucositis + A. chica (MUC+ AC) - underwent mucositis and received oral administration of A. chica extract (10 days). At the 7 th day, mice in the MUC and MUC + AC groups received an intraperitoneal (IP) injection containing 300 mg/kg 5-FU, whereas the animals of the CTL and AC groups received a saline IP injection. After 72 hours (10 th experimental day), intestinal permeability was determined by measuring the radioactivity diffusion in the blood after oral administration of diethylenetriaminepentaacetic acid (DTPA) labelled with technetium-99m ( 99m Tc) and bacterial translocation was determined by measuring the radioactivity diffusion in the blood after oral administration of E. coli labelled with technetium-99m ( 99m Tc). After 4 hours, the mice were euthanized and assessed for intestinal permeability, bacterial translocation and intestinal histology

Assessment of intestinal permeability and bacterial translocation employing nuclear methods in murine mucositis

Energy Technology Data Exchange (ETDEWEB)

Pessoa, Rafaela M.; Takenaka, Isabella K.T.M.; Barros, Patricia A.V.; Moura, Livia P.; Contarini, Sara M.L.; Amorim, Juliana M.; Castilho, Raquel O.; Leite, Camila M.A.; Cardoso, Valbert N.; Diniz, Simone Odilia F. [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Mg (Brazil)

2017-07-01

Full text: Introduction: Mucositis affects approximately 80% of patients who receive chemotherapy combinations. The lesions are painful, restrict food intake and make patients more susceptible to systemic infections. Some agents and strategies are being studied for controlling mucositis, none of them is used in clinical practice. In Minas Gerais, many studies have addressed the popular use of the plant Arrabidaea chica in the form of tea, to treat intestinal cramps and diarrhea, the main symptoms of mucositis. Objective: To evaluate the potential of Arrabidaea chica extract in the management of the integrity of the intestinal mucosa, using the experimental model of gut mucositis induced by 5-Fluorouracila (5-FU). Methods: The UFMG Ethics Committee for Animal Experimentation (CETEA/UFMG) approved this study (nº 411/2015). Male BALB/c mice between 6-8 weeks of age were randomly divided into four groups (n=9) as follows: 1. Control (CTL) - oral administration of saline solution (10 days); 2. A. chica (AC) - oral administration of A. chica extract (10 days); 3. Mucositis (MUC) - underwent mucositis (5-FU) (10 days); 4. Mucositis + A. chica (MUC+ AC) - underwent mucositis and received oral administration of A. chica extract (10 days). At the 7{sup th} day, mice in the MUC and MUC + AC groups received an intraperitoneal (IP) injection containing 300 mg/kg 5-FU, whereas the animals of the CTL and AC groups received a saline IP injection. After 72 hours (10{sup th} experimental day), intestinal permeability was determined by measuring the radioactivity diffusion in the blood after oral administration of diethylenetriaminepentaacetic acid (DTPA) labelled with technetium-99m ({sup 99m}Tc) and bacterial translocation was determined by measuring the radioactivity diffusion in the blood after oral administration of E. coli labelled with technetium-99m ({sup 99m}Tc). After 4 hours, the mice were euthanized and assessed for intestinal permeability, bacterial translocation and

Influence of the gut microbiota on transcriptional regulation of genes involved in early life development of the intestinal mucus layer

DEFF Research Database (Denmark)

Bergström, Anders; Kristensen, Matilde Bylov; Metzdorff, Stine Broeng

2010-01-01

The interplay between the gut microbiota and the intestinal mucus layer is important both in the maintenance of the epithelial barrier as part of the innate immune defense, and in the conservation of gut homeostasis. Little is known about how the microbiota regulates mucin proteins, which protect...

Influence of the gut microbiota on transcriptional regulation of genes involved in early life development of the intestinal mucus layer

DEFF Research Database (Denmark)

Bergström, Anders; Kristensen, Matilde Bylov; Metzdorff, Stine Broeng

The interplay between the gut microbiota and the intestinal mucus layer is important both in the maintenance of the epithelial barrier as part of the innate immune defense, and in the conservation of gut homeostasis. Little is known about how the microbiota regulates mucin proteins, which protect...

New frontiers in mucositis.

Science.gov (United States)

Peterson, Douglas E; Keefe, Dorothy M; Sonis, Stephen T

2012-01-01

Mucositis is among the most debilitating side effects of radiotherapy, chemotherapy, and targeted anticancer therapy. Research continues to escalate regarding key issues such as etiopathology, incidence and severity across different mucosae, relationships between mucosal and nonmucosal toxicities, and risk factors. This approach is being translated into enhanced management strategies. Recent technology advances provide an important foundation for this continuum. For example, evolution of applied genomics is fostering development of new algorithms to rapidly screen genomewide single-nucleotide polymorphisms (SNPs) for patient-associated risk prediction. This modeling will permit individual tailoring of the most effective, least toxic treatment in the future. The evolution of novel cancer therapeutics is changing the mucositis toxicity profile. These agents can be associated with unique mechanisms of mucosal damage. Additional research is needed to optimally manage toxicity caused by agents such as mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors, without reducing antitumor effect. There has similarly been heightened attention across the health professions regarding clinical practice guidelines for mucositis management in the years following the first published guidelines in 2004. New opportunities exist to more effectively interface this collective guideline portfolio by capitalizing upon novel technologies such as an Internet-based Wiki platform. Substantive progress thus continues across many domains associated with mucosal injury in oncology patients. In addition to enhancing oncology patient care, these advances are being integrated into high-impact educational and scientific venues including the National Cancer Institute Physician Data Query (PDQ) portfolio as well as a new Gordon Research Conference on mucosal health and disease scheduled for June 2013.

Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis.

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Chu, Van Trung; Beller, Alexander; Rausch, Sebastian; Strandmark, Julia; Zänker, Michael; Arbach, Olga; Kruglov, Andrey; Berek, Claudia

2014-04-17

Although in normal lamina propria (LP) large numbers of eosinophils are present, little is known about their role in mucosal immunity at steady state. Here we show that eosinophils are needed to maintain immune homeostasis in gut-associated tissues. By using eosinophil-deficient ΔdblGATA-1 and PHIL mice or an eosinophil-specific depletion model, we found a reduction in immunoglobulin A(+) (IgA(+)) plasma cell numbers and in secreted IgA. Eosinophil-deficient mice also showed defects in the intestinal mucous shield and alterations in microbiota composition in the gut lumen. In addition, TGF-β-dependent events including class switching to IgA in Peyer's patches (PP), the formation of CD103(+) T cells including Foxp3(+) regulatory (Treg), and also CD103(+) dendritic cells were disturbed. In vitro cultures showed that eosinophils produce factors that promote T-independent IgA class switching. Our findings show that eosinophils are important players for immune homeostasis in gut-associated tissues and add to data suggesting that eosinophils can promote tissue integrity. Copyright © 2014 Elsevier Inc. All rights reserved.

Mucosal melanosis associated with chemoembolization

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Ali Alkan

2015-06-01

Full Text Available Mucosal lesions due to underlying disease or drug toxicity, are important part of oncology practice. Patient with a diagnosis of hepatocellular carcinoma was treated with chemoembolisation. She presented with new onset of mucosal hyperpigmented lesion all through her oral cavity. Biopsy was consistent with mucosal melanosis, which was associated with the chemotherapeutics used in the chemoembolisation procedure. Lesion progressively improved without any treatment. Here we present an mucosal melanosis experience after chemoembolisation. J Clin Exp Invest 2015; 6 (2: 189-191

Leaky gut and autoimmune diseases.

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Fasano, Alessio

2012-02-01

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.

Role of gut pathogens in development of irritable bowel syndrome

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Madhusudan Grover

2014-01-01

Full Text Available Acute infectious gastroenteritis is one of the most commonly identifiable risk factors for the development of irritable bowel syndrome (IBS. A number of bacterial, viral and parasitic pathogens have been found to be associated with the development of IBS and other functional gastrointestinal (GI disorders. Epidemiological studies have identified demographic and acute enteritis-related risk factors for the development of post-infectious-IBS (PI-IBS. Immune dysregulation, alterations in barrier function, serotonergic and mast cell activation have been identified as potential pathophysiological mechanisms. Additionally, variations in host genes involved in barrier function, antigen presentation and cytokine response have been associated with PI-IBS development. However, it is unknown whether specific pathogens have unique effects on long-term alterations in gut physiology or different pathogens converge to cause common alterations resulting in similar phenotype. The role of microbial virulence and pathogenicity factors in development of PI-IBS is also largely unknown. Additionally, alterations in host gut sensation, motility, secretion, and barrier function in PI-IBS need to be elucidated. Finally, both GI infections and antibiotics used to treat these infections can cause long-term alterations in host commensal microbiota. It is plausible that alteration in the commensal microbiome persists in a subset of patients predisposing them to develop PI-IBS.

The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions.

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Abdollahi-Roodsaz, Shahla; Abramson, Steven B; Scher, Jose U

2016-08-01

The role of the gut microbiome in animal models of inflammatory and autoimmune disease is now well established. The human gut microbiome is currently being studied as a potential modulator of the immune response in rheumatic disorders. However, the vastness and complexity of this host-microorganism interaction is likely to go well beyond taxonomic, correlative observations. In fact, most advances in the field relate to the functional and metabolic capabilities of these microorganisms and their influence on mucosal immunity and systemic inflammation. An intricate relationship between the microbiome and the diet of the host is now fully recognized, with the microbiota having an important role in the degradation of polysaccharides into active metabolites. This Review summarizes the current knowledge on the metabolic role of the microbiota in health and rheumatic disease, including the advances in pharmacomicrobiomics and its potential use in diagnostics, therapeutics and personalized medicine.

Molecular Paths Linking Metabolic Diseases, Gut Microbiota Dysbiosis and Enterobacteria Infections.

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Serino, Matteo

2018-03-02

Alterations of both ecology and functions of gut microbiota are conspicuous traits of several inflammatory pathologies, notably metabolic diseases such as obesity and type 2 diabetes. Moreover, the proliferation of enterobacteria, subdominant members of the intestinal microbial ecosystem, has been shown to be favored by Western diet, the strongest inducer of both metabolic diseases and gut microbiota dysbiosis. The inner interdependence between the host and the gut microbiota is based on a plethora of molecular mechanisms by which host and intestinal microbes modify each other. Among these mechanisms are as follows: (i) the well-known metabolic impact of short chain fatty acids, produced by microbial fermentation of complex carbohydrates from plants; (ii) a mutual modulation of miRNAs expression, both on the eukaryotic (host) and prokaryotic (gut microbes) side; (iii) the production by enterobacteria of virulence factors such as the genotoxin colibactin, shown to alter the integrity of host genome and induce a senescence-like phenotype in vitro; (iv) the microbial excretion of outer-membrane vesicles, which, in addition to other functions, may act as a carrier for multiple molecules such as toxins to be delivered to target cells. In this review, I describe the major molecular mechanisms by which gut microbes exert their metabolic impact at a multi-organ level (the gut barrier being in the front line) and support the emerging triad of metabolic diseases, gut microbiota dysbiosis and enterobacteria infections. Copyright © 2018 Elsevier Ltd. All rights reserved.

Endocytic trafficking from the small intestinal brush border probed with FM dye

DEFF Research Database (Denmark)

Hansen, Gert H; Rasmussen, Karina; Niels-Christiansen, Lise-Lotte

2009-01-01

-linking galectins/intelectin, but little is known about the dynamic properties of this highly specialized membrane. Here, we probed the endocytic membrane trafficking from the brush border of organ cultured pig intestinal mucosal explants by use of a fixable, lipophilic FM dye. The fluorescent dye readily......, contributes to the overall permeability barrier of the gut. Key words: FM dye, small intestine, brush border, endocytosis....

The Gut Microbiome Feelings of the Brain: A Perspective for Non-Microbiologists

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Aaron Lerner

2017-10-01

Full Text Available Objectives: To comprehensively review the scientific knowledge on the gut–brain axis. Methods: Various publications on the gut–brain axis, until 31 July 2017, were screened using the Medline, Google, and Cochrane Library databases. The search was performed using the following keywords: “gut-brain axis”, “gut-microbiota-brain axis”, “nutrition microbiome/microbiota”, “enteric nervous system”, “enteric glial cells/network”, “gut-brain pathways”, “microbiome immune system”, “microbiome neuroendocrine system” and “intestinal/gut/enteric neuropeptides”. Relevant articles were selected and reviewed. Results: Tremendous progress has been made in exploring the interactions between nutrients, the microbiome, and the intestinal, epithelium–enteric nervous, endocrine and immune systems and the brain. The basis of the gut–brain axis comprises of an array of multichannel sensing and trafficking pathways that are suggested to convey the enteric signals to the brain. These are mediated by neuroanatomy (represented by the vagal and spinal afferent neurons, the neuroendocrine–hypothalamic–pituitary–adrenal (HPA axis (represented by the gut hormones, immune routes (represented by multiple cytokines, microbially-derived neurotransmitters, and finally the gate keepers of the intestinal and brain barriers. Their mutual and harmonious but intricate interaction is essential for human life and brain performance. However, a failure in the interaction leads to a number of inflammatory-, autoimmune-, neurodegenerative-, metabolic-, mood-, behavioral-, cognitive-, autism-spectrum-, stress- and pain-related disorders. The limited availability of information on the mechanisms, pathways and cause-and-effect relationships hinders us from translating and implementing the knowledge from the bench to the clinic. Implications: Further understanding of this intricate field might potentially shed light on novel preventive and

Assessment and protection of esophageal mucosal integrity in patients with heartburn without esophagitis.

Science.gov (United States)

Woodland, Philip; Lee, Chung; Duraisamy, Yasotha; Duraysami, Yasotha; Farré, Ricard; Dettmar, Peter; Sifrim, Daniel

2013-04-01

Intact esophageal mucosal integrity is essential to prevent symptoms during gastroesophageal reflux events. Approximately 70% of patients with heartburn have macroscopically normal esophageal mucosa. In patients with heartburn, persistent functional impairment of esophageal mucosal barrier integrity may underlie remaining symptoms. Topical protection of a functionally vulnerable mucosa may be an attractive therapeutic strategy. We aimed to evaluate esophageal mucosal functional integrity in patients with heartburn without esophagitis, and test the feasibility of an alginate-based topical mucosal protection. Three distal esophageal biopsies were obtained from 22 patients with heartburn symptoms, and 22 control subjects. In mini-Ussing chambers, the change in transepithelial electrical resistance (TER) of biopsies when exposed to neutral, weakly acidic, and acidic solutions was measured. The experiment was repeated in a further 10 patients after pretreatment of biopsies with sodium alginate, viscous control, or liquid control "protectant" solutions. Biopsy exposure to neutral solution caused no change in TER. Exposure to weakly acidic and acidic solutions caused a greater reduction in TER in patients than in controls (weakly acid -7.2% (95% confidence interval (CI) -9.9 to -4.5) vs. 3.2% (-2.2 to 8.6), Pheartburn without esophagitis shows distinct vulnerability to acid and weakly acidic exposures. Experiments in vitro suggest that such vulnerable mucosa may be protected by application of an alginate-containing topical solution.

Mucus: An Underestimated Gut Target for Environmental Pollutants and Food Additives.

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Gillois, Kévin; Lévêque, Mathilde; Théodorou, Vassilia; Robert, Hervé; Mercier-Bonin, Muriel

2018-06-15

Synthetic chemicals (environmental pollutants, food additives) are widely used for many industrial purposes and consumer-related applications, which implies, through manufactured products, diet, and environment, a repeated exposure of the general population with growing concern regarding health disorders. The gastrointestinal tract is the first physical and biological barrier against these compounds, and thus their first target. Mounting evidence indicates that the gut microbiota represents a major player in the toxicity of environmental pollutants and food additives; however, little is known on the toxicological relevance of the mucus/pollutant interplay, even though mucus is increasingly recognized as essential in gut homeostasis. Here, we aimed at describing how environmental pollutants (heavy metals, pesticides, and other persistent organic pollutants) and food additives (emulsifiers, nanomaterials) might interact with mucus and mucus-related microbial species; that is, “mucophilic” bacteria such as mucus degraders. This review highlights that intestinal mucus, either directly or through its crosstalk with the gut microbiota, is a key, yet underestimated gut player that must be considered for better risk assessment and management of environmental pollution.

The cereal type in feed influences gut wall morphology and intestinal immune cell infiltration in broiler chickens

DEFF Research Database (Denmark)

Teirlynck, Emma; Friis-Holm, Lotte Bjerrum; Eeckhaut, Venessa

2009-01-01

In broiler chickens a diet where the major cereal types are wheat, rye and/or barley has a lower digestibility compared with a diet in which maize is the major cereal type In the present study, the effects of two different dietary cereal types, maize v. wheat/rye on host factors (inflammation...... and gut integrity) and gut microbiota composition were studied In addition, the effects of low-dose Zn-bacitracin supplementation were examined Broilers given a wheat/rye-based diet showed more villus fusion, a thinner tunica muscularis, more T-lymphocyte infiltration, higher amount of immune cell...... showing changes in the microbiota compostion was larger than that of Zn-bacitracin supplementation In conclusion, a wheat/rye-based diet evoked mucosal damage, an alteration in the composition of the microbiota and an inflammatory bowel type of condition....

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

DEFF Research Database (Denmark)

Feng, Yongjia; Demehri, Farok R; Xiao, Weidong

2017-01-01

BACKGROUND & AIMS: Total parenteral nutrition (TPN), a crucial treatment for patients who cannot receive enteral nutrition, is associated with mucosal atrophy, barrier dysfunction, and infectious complications. Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) improve intestinal...... deprived of enteral nutrition. METHODS: Adult C57BL/6J, IEC-Egfr(knock out (KO)) and IEC-pik3r1(KO) mice receiving TPN or enteral nutrition were treated with EGF or GLP-2 alone or in combination with reciprocal receptor inhibitors, GLP-2(3-33) or gefitinib. Jejunum was collected and mucosal atrophy and IEC...

TLR-dependent human mucosal epithelial cell responses to microbial pathogens.

Directory of Open Access Journals (Sweden)

Paola eMassari

2014-08-01

Full Text Available AbstractToll-Like Receptor (TLR signaling represents one of the best studied pathways to implement defense mechanisms against invading microbes in humans as well as in animals. TLRs respond to specific microbial ligands and to danger signals produced by the host during infection, and initiate downstream cascades that activate both innate and adaptive immunity. TLRs are expressed by professional immune cells and by the large majority of non-hematopoietic cells, including epithelial cells. In epithelial tissues, TLR functions are particularly important because these sites are constantly exposed to microorganisms, due to their location at the host interface with the environment. While at these sites, specific defense mechanisms and inflammatory responses are initiated via TLR signaling against pathogens, suppression or lack of TLR activation is also observed in response to the commensal microbiota. The mechanisms by which TLR signaling is regulated in mucosal epithelial cells include differential expression and levels of TLRs (and their signaling partners, their cellular localization and positioning within the tissue in a fashion that favors responses to pathogens while dampening responses to commensals and maintaining tissue homeostasis in physiologic conditions. In this review, the expression and activation of TLRs in mucosal epithelial cells of several sites of the human body are examined. Specifically, the oral cavity, the ear canal and eye, the airways, the gut and the reproductive tract are discussed, along with how site-specific host defense mechanisms are implemented via TLR signaling.

Just a Gut Feeling: Central Nervous Effects of Peripheral Gastrointestinal Hormones.

Science.gov (United States)

Roth, Christian L; Doyle, Robert Patrick

2017-01-01

Despite greater health education, obesity remains one of the greatest health challenges currently facing the world. The prevalence of obesity among children and adolescents and the rising rates of prediabetes and diabetes are of particular concern. A deep understanding of regulatory pathways and development of new anti-obesity drugs with increased efficacy and safety are of utmost necessity. The 2 major biological players in the regulation of food intake are the gut and the brain as peptides released from the gut in response to meals convey information about the energy needs to brain centers of energy homeostasis. There is evidence that gut hormones not only pass the blood-brain barrier and bind to receptors located in different brain areas relevant for body weight regulation, but some are also expressed in the brain as part of hedonic and homeostatic pathways. Regarding obesity interventions, the only truly effective treatment for obesity is bariatric surgery, the long-term benefits of which may actually involve increased activity of gut hormones including peptide YY3-36 and glucagon-like peptide 1. This review discusses critical gut-hormones involved in the regulation of food intake and energy homeostasis and their effects on peripheral tissues versus central nervous system actions. © 2017 S. Karger AG, Basel.

Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options.

Science.gov (United States)

Konturek, Peter C; Brzozowski, T; Konturek, S J

2011-12-01

Stress, which is defined as an acute threat to homeostasis, shows both short- and long-term effects on the functions of the gastrointestinal tract. Exposure to stress results in alterations of the brain-gut interactions ("brain-gut axis") ultimately leading to the development of a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases, food antigen-related adverse responses, peptic ulcer and gastroesophageal reflux disease (GERD). The major effects of stress on gut physiology include: 1) alterations in gastrointestinal motility; 2) increase in visceral perception; 3) changes in gastrointestinal secretion; 4) increase in intestinal permeability; 5) negative effects on regenerative capacity of gastrointestinal mucosa and mucosal blood flow; and 6) negative effects on intestinal microbiota. Mast cells (MC) are important effectors of brain-gut axis that translate the stress signals into the release of a wide range of neurotransmitters and proinflammatory cytokines, which may profoundly affect the gastrointestinal physiology. IBS represents the most important gastrointestinal disorder in humans, and is characterized by chronic or recurrent pain associated with altered bowel motility. The diagnostic testing for IBS patients include routine blood tests, stool tests, celiac disease serology, abdominal sonography, breath testing to rule out carbohydrate (lactose, fructose, etc.) intolerance and small intestinal bacterial overgrowth. Colonoscopy is recommended if alarming symptoms are present or to obtain colonic biopsies especially in patients with diarrhoea predominant IBS. The management of IBS is based on a multifactorial approach and includes pharmacotherapy targeted against the predominant symptom, behavioural and psychological treatment, dietary alterations, education, reassurance and effective patient-physician relationship. When evaluating for the stress

Pathogenesis, Experimental Models and Contemporary Pharmacotherapy of Irritable Bowel Syndrome: Story About the Brain-Gut Axis

Science.gov (United States)

Tsang, S.W.; Auyeung, K.K.W.; Bian, Z.X.; Ko, J.K.S.

2016-01-01

Background Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease. Methods Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed. Results When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation. Conclusion Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients. PMID:27009115

High-protein diet differently modifies intestinal goblet cell characteristics and mucosal cytokine expression in ileum and colon.

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Lan, Annaïg; Andriamihaja, Mireille; Blouin, Jean-Marc; Liu, Xinxin; Descatoire, Véronique; Desclée de Maredsous, Caroline; Davila, Anne-Marie; Walker, Francine; Tomé, Daniel; Blachier, François

2015-01-01

We have previously shown that high-protein (HP) diet ingestion causes marked changes in the luminal environment of the colonic epithelium. This study aimed to evaluate the impact of such modifications on small intestinal and colonic mucosa, two segments with different transit time and physiological functions. Rats were fed with either normal protein (NP; 14% protein) or HP (53% protein) isocaloric diet for 2 weeks, and parameters related to intestinal mucous-secreting cells and to several innate/adaptive immune characteristics (myeloperoxidase activity, cytokine and epithelial TLR expression, proportion of immune cells in gut-associated lymphoid tissues) were measured in the ileum and colon. In ileum from HP animals, we observed hyperplasia of mucus-producing cells concomitant with an increased expression of Muc2 at both gene and protein levels, reduction of mucosal myeloperoxidase activity, down-regulation of Tlr4 gene expression in enterocytes and down-regulation of mucosal Th cytokines associated with CD4+ lymphocyte reduction in mesenteric lymph nodes. These changes coincided with an increased amount of acetate in the ileal luminal content. In colon, HP diet ingestion resulted in a lower number of goblet cells at the epithelial surface but increased goblet cell number in colonic crypts together with an increased Muc3 and a slight reduction of Il-6 gene expression. Our data suggest that HP diet modifies the goblet cell distribution in colon and, in ileum, increases goblet cell activity and decreases parameters related to basal gut inflammatory status. The impact of HP diet on intestinal mucosa in terms of beneficial or deleterious effects is discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Gastroduodenal mucosal defence mechanisms and the action of non-steroidal anti-inflammatory agents.

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Garner, A; Allen, A; Rowe, P H

1987-01-01

This review summarises gastroduodenal protective mechanisms, the actions of non-steroidal anti-inflammatory (NSAI) agents on mucus and HCO3 secretions, and the basis of gastric mucosal injury induced by acetylsalicylic and salicylic acids (ASA and SA). Resistance to autodigestion by acid and pepsin present in gastric juice is multifactorial involving pre-epithelial (mucus-bicarbonate barrier) and post-epithelial (blood flow, acid-base balance) factors in addition to properties of the surface cell layer per se. The latter includes mucosal re-epithelialisation, a property which appears particularly important with respect to recovery from acute injury. A range of NSAI agents (ASA, fenclofenac, ibuprofen and indomethacin) inhibit gastric HCO3 transport in isolated mucosal preparations. Inhibition of duodenal HCO3 transport has been demonstrated in response to indomethacin in vitro and in vivo. These effects on secretion can be antagonised by exogenous prostaglandins of the E series. The layer of secreted mucus gel overlying the epithelial surface is not affected by NSAI drugs in the short term. However a number of these agents have been shown to inhibit glycoprotein biosynthesis by the epithelial cells. Thus loss of this protective coat could be anticipated during chronic drug exposure since erosion of adherent mucus by luminal shear and proteolysis would not be compensated by continued secretion. Detailed analysis of the gastric mucosal injury induced by salicylates both in vitro and in vivo reveals that much of the damage previously attributed to ASA is in fact due to the metabolic product SA. In this respect it is concluded that mucosal injury caused by ASA is due to a combination of two factors.(ABSTRACT TRUNCATED AT 250 WORDS)

PGRP-LB homolog acts as a negative modulator of immunity in maintaining the gut-microbe symbiosis of red palm weevil, Rhynchophorus ferrugineus Olivier.

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Dawadi, Bishnu; Wang, Xinghong; Xiao, Rong; Muhammad, Abrar; Hou, Youming; Shi, Zhanghong

2018-09-01

Many notorious insect pests live in the symbiotic associations with gut microbiota. However, the mechanisms underlying how they host their gut microbiota are unknown. Most gut bacteria can release peptidoglycan (PGN) which is an important antigen to activate the immune response. Therefore, how to keep the appropriate gut immune intensity to host commensals while to efficiently remove enteropathogens is vital for insect health. This study is aimed at elucidating the roles of an amidase PGRP, Rf PGRP-LB, in maintaining the gut-microbe symbiosis of Red palm weevil (RPW), Rhynchophorus ferrugineus Olivier. RfPGRP-LB is a secreted protein containing a typical PGRP domain. The existence of five conservative amino acid residues, being required for amidase activity, showed that RfPGRP-LB is a catalytic protein. Expression analysis revealed abundance of RfPGRP-LB transcripts in gut was dramatically higher than those in other tissues. RfPGRP-LB could be significantly induced against the infection of Escherichia coli. In vitro assays revealed that rRfPGRP-LB impaired the growth of E. coli and agglutinated bacteria cells obviously, suggesting RfPGRP-LB is a pathogen recognition receptor and bactericidal molecule. RfPGRP-LB knockdown reduced the persistence of E. coli in gut and load of indigenous gut microbiota significantly. Furthermore, the community structure of indigenous gut microbiota was also intensively altered by RfPGRP-LB silence. Higher levels of the antimicrobial peptide, attacin, were detected in guts of RfPGRP-LB silenced larvae than controls. Collectively, RfPGRP-LB plays multiple roles in modulating the homeostasis of RPW gut microbiota not only by acting as a negative regulator of mucosal immunity through PGN degradation but also as a bactericidal effector to prevent overgrowth of commensals and persistence of noncommensals. Copyright © 2018 Elsevier Ltd. All rights reserved.

Salmonella Typhimurium and multidirectional communication in the gut

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Elena V. Gart

2016-11-01

Full Text Available The mammalian digestive tract is home to trillions of microbes, including bacteria, archaea, protozoa, fungi and viruses. In monogastric mammals the stomach and small intestine harbor diverse bacterial populations but are typically less populated than the colon. The gut bacterial community (microbiota hereafter varies widely among different host species and individuals within a species. It is influenced by season of the year, age of the host, stress and disease. Ideally, the host and microbiota benefit each other. The host provides nutrients to the microbiota and the microbiota assists the host with digestion and nutrient metabolism. The resident microbiota competes with pathogens for space and nutrients and, through this competition, protects the host in a phenomenon called colonization resistance. The microbiota participates in development of the host immune system, particularly regulation of autoimmunity and mucosal immune response. The microbiota also shapes gut-brain communication and host responses to stress; and, indeed, the microbiota is a newly recognized endocrine organ within mammalian hosts.Salmonella enterica serovar Typhimurium (S. Typhimurium hereafter is a food-borne pathogen which adapts to and alters the gastrointestinal (GI environment. In the GI tract, S. Typhimurium competes with the microbiota for nutrients and overcomes colonization resistance to establish infection. To do this, S. Typhimurium uses multiple defense mechanisms to resist environmental stressors, like the acidic pH of the stomach, and virulence mechanisms which allow it to invade the intestinal epithelium and disseminate throughout the host. To coordinate gene expression and disrupt signaling within the microbiota and between host and microbiota, S. Typhimurium employs its own chemical signaling and may regulate host hormone metabolism.This review will discuss the multidirectional interaction between S. Typhimurium, host and microbiota as well as mechanisms

Changes in intestinal fluid and mucosal immune responses to cholera toxin in Giardia muris infection and binding of cholera toxin to Giardia muris trophozoites.

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Ljungström, I; Holmgren, J; Svennerholm, A M; Ferrante, A

1985-10-01

The effect of Giardia muris infection on the diarrheal response and gut mucosal antibody response to cholera toxin was examined in mice. The results obtained showed that the fluid accumulation in intestinal loops exposed to cholera toxin was increased in mice infected with a low number (5 X 10(4) ) of G. muris cysts compared with the response in noninfected mice. This effect was associated with a marked reduction in absorption of oral rehydration fluid from the intestine. In contrast, mice infected with a high dose (2 X 10(5) ) of cysts showed a marked decrease in fluid accumulation in response to the toxin. This decrease might be related to the finding that both G. muris and Giardia lamblia trophozoites can bind significant amounts of cholera toxin. Evidence is presented which suggests that the gut mucosal antibody response, mainly immunoglobulin A but also immunoglobulin G, to an immunization course with perorally administered cholera toxin was depressed in mice infected with G. muris. The reduction in antibody levels was particularly evident when the primary immunization was made very early after infection. The serum antitoxin antibodies to the oral immunization with cholera toxin were, however, not affected. Likewise, the delayed-type hypersensitivity response against sheep erythrocytes in animals primed subcutaneously with sheep erythrocytes was not modified during the course of G. muris infection.

Mechanisms of Expression and Internalisation of FIBCD1; a novel Pattern Recognition Receptor in the Gut Mucosa

DEFF Research Database (Denmark)

Hammond, Mark; Schlosser, Anders; Dubey, Lalit Kumar

2012-01-01

is a carbohydrate recognition domain also expressed by the ficolins, which are pattern recognition molecules that activate the complement system via the lectin pathway. Chitin is a highly ace¬tylated homopolymer of β-1,4-N-acetyl-glucosamine carbohydrate found abundantly in nature in organisms such as fungi...... pattern recognition receptor that binds chitin and directs acetylated structures for de¬gradation in the endosome via clathrin-mediated endocytosis. The localisation of FIBCD1 in the intestinal mucosal epithelia points towards a functional role in innate immunity and/or gut homeostasis....

Hericium erinaceus polysaccharide facilitates restoration of injured intestinal mucosal immunity in Muscovy duck reovirus-infected Muscovy ducklings.

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Wu, Yijian; Jiang, Huihui; Zhu, Erpeng; Li, Jian; Wang, Quanxi; Zhou, Wuduo; Qin, Tao; Wu, Xiaoping; Wu, Baocheng; Huang, Yifan

2018-02-01

To elucidate the effect of Hericium erinaceus polysaccharide (HEP) on the intestinal mucosal immunity in normal and Muscovy duck reovirus (MDRV)-infected Muscovy ducklings, 1-day-old healthy Muscovy ducklings were pretreated with 0.2g/L HEP and/or following by MDRV infection in this study, duodenal samples were respectively collected at 1, 3, 6, 10, 15 and 21day post-infection, tissue sections were prepared for observation of morphological structure and determination of intestinal parameters (villus height/crypt depth ratio, villus surface area) as well as counts of intraepithelial lymphocytes (IELs), goblet cells, mast cells. Additionally, dynamics of secretory immunoglobin A (sIgA), interferon-γ (IFN-γ) and interleukin-4 (IL-4) productions in intestinal mucosa were measured with radioimmunoassay. Results showed that HEP significantly improved intestinal morphological structure and related indexes, and significantly inhibited the reduction of intestinal mucosal IELs, goblet cells and mast cells caused by MDRV infection. Furthermore, HEP significantly increased the secretion of sIgA, IFN-γ and IL-4 to enhance intestinal mucosal immune functions. Our findings indicate that HEP treatment can effectively repair MDRV-caused injures of small intestinal mucosal immune barrier, and improve mucosal immune function in sick Muscovy ducklings, which will provide valuable help for further application of HEP in prevention and treatment of MDRV infection. Copyright © 2017. Published by Elsevier B.V.

The human gut microbiota: metabolism and perspective in obesity.

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Gomes, Aline Corado; Hoffmann, Christian; Mota, João Felipe

2018-04-18

The gut microbiota has been recognized as an important factor in the development of metabolic diseases such as obesity and is considered an endocrine organ involved in the maintenance of energy homeostasis and host immunity. Dysbiosis can change the functioning of the intestinal barrier and the gut-associated lymphoid tissues (GALT) by allowing the passage of structural components of bacteria, such as lipopolysaccharides (LPS), which activate inflammatory pathways that may contribute to the development of insulin resistance. Furthermore, intestinal dysbiosis can alter the production of gastrointestinal peptides related to satiety, resulting in an increased food intake. In obese people, this dysbiosis seems be related to increases of the phylum Firmicutes, the genus Clostridium, and the species Eubacterium rectale, Clostridium coccoides, Lactobacillus reuteri, Akkermansia muciniphila, Clostridium histolyticum, and Staphylococcus aureus.

Effect of glutamine-enriched nutritional support on intestinal mucosal barrier function, MMP-2, MMP-9 and immune function in patients with advanced gastric cancer during perioperative chemotherapy.

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Wang, Juan; Li, Yanfen; Qi, Yuanling

2017-09-01

We studied the effects of glutamine-enriched nutritional support on intestinal mucosal barrier, matrix metalloproteinase (MMP)-2, MMP-9 and immune function during perioperative chemotherapy in patients with advanced gastric cancer. The study was conducted on 94 patients with advanced gastric cancer admitted from April 2015 to March 2016. They were randomly divided into observation and control groups, n=47. Control group was given basic nutritional support whereas glutamine-enriched nutritional support was given to patients in observation group. High-performance liquid chromatography was used to measure lactulose and mannitol ratio in urine (L/M) and ELISA was used to measure D-lactate levels before chemotherapy and in the 1st, 2nd and 3rd cycle of chemotherapy. Immunoglobulin level was detected by immune turbidimetry assay, T lymphocyte subsets were determined by flow cytometry after 3 cycles of chemotherapy, MMP-2 and MMP-9 of patients were compared between the two groups. The serious adverse reactions incidence (grade and IV) of patients were observed. To evaluate the life quality of patients, QLQ-C30 was used after 6 months. The levels of L/M and D-lactate in both groups after the first cycle of chemotherapy were significantly higher than that before chemotherapy; they began to decline after the second or third cycle, but were still significantly higher than the levels before chemotherapy (pgroups after 1st, 2nd, 3rd cycle after chemotherapy, L/M and D-lactate levels of patients in the observation group were significantly lower than in the control group (pgroup was significantly lower than control group (pgroup were significantly higher than control group (pnutritional support can effectively protect the intestinal mucosal barrier function in patients with advanced gastric cancer in their perioperative chemotherapy, improve the level of MMP-2 and MMP-9 in patients with advanced gastric cancer, enhance their immune function, reduce the incidence of adverse

Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats.

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Feng, Wenhuan; Wang, Hongdong; Zhang, Pengzi; Gao, Caixia; Tao, Junxian; Ge, Zhijuan; Zhu, Dalong; Bi, Yan

2017-07-01

Structural disruption of gut microbiota contributes to the development of non-alcoholic fatty liver disease (NAFLD) and modulating the gut microbiota represents a novel strategy for NAFLD prevention. Although previous studies have demonstrated that curcumin alleviates hepatic steatosis, its effect on the gut microbiota modulation has not been investigated. Next generation sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota in a NAFLD rat model induced by high fat-diet (HFD) feeding. We found that curcumin attenuated hepatic ectopic fat deposition, improved intestinal barrier integrity, and alleviated metabolic endotoxemia in HFD-fed rats. More importantly, curcumin dramatically shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean rats fed a normal diet and altered the gut microbial composition. The abundances of 110 operational taxonomic units (OTUs) were altered by curcumin. Seventy-six altered OTUs were significantly correlated with one or more hepatic steatosis associated parameters and designated 'functionally relevant phylotypes'. Thirty-six of the 47 functionally relevant OTUs that were positively correlated with hepatic steatosis associated parameters were reduced by curcumin. These results indicate that curcumin alleviates hepatic steatosis in part through stain-specific impacts on hepatic steatosis associated phylotypes of gut microbiota in rats. Compounds with antimicrobial activities should be further investigated as novel adjunctive therapies for NAFLD. Copyright © 2017 Elsevier B.V. All rights reserved.

Genome-resolved metaproteomic characterization of preterm infant gut microbiota development reveals species-specific metabolic shifts and variabilities during early life.

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Xiong, Weili; Brown, Christopher T; Morowitz, Michael J; Banfield, Jillian F; Hettich, Robert L

2017-07-10

Establishment of the human gut microbiota begins at birth. This early-life microbiota development can impact host physiology during infancy and even across an entire life span. However, the functional stability and population structure of the gut microbiota during initial colonization remain poorly understood. Metaproteomics is an emerging technology for the large-scale characterization of metabolic functions in complex microbial communities (gut microbiota). We applied a metagenome-informed metaproteomic approach to study the temporal and inter-individual differences of metabolic functions during microbial colonization of preterm human infants' gut. By analyzing 30 individual fecal samples, we identified up to 12,568 protein groups for each of four infants, including both human and microbial proteins. With genome-resolved matched metagenomics, proteins were confidently identified at the species/strain level. The maximum percentage of the proteome detected for the abundant organisms was ~45%. A time-dependent increase in the relative abundance of microbial versus human proteins suggested increasing microbial colonization during the first few weeks of early life. We observed remarkable variations and temporal shifts in the relative protein abundances of each organism in these preterm gut communities. Given the dissimilarity of the communities, only 81 microbial EggNOG orthologous groups and 57 human proteins were observed across all samples. These conserved microbial proteins were involved in carbohydrate, energy, amino acid and nucleotide metabolism while conserved human proteins were related to immune response and mucosal maturation. We identified seven proteome clusters for the communities and showed infant gut proteome profiles were unstable across time and not individual-specific. Applying a gut-specific metabolic module (GMM) analysis, we found that gut communities varied primarily in the contribution of nutrient (carbohydrates, lipids, and amino acids

Prior mucosal exposure to heterologous cells alters the pathogenesis of cell-associated mucosal feline immunodeficiency virus challenge

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Leavell Sarah

2010-05-01

Full Text Available Abstract Background Several lines of research suggest that exposure to cellular material can alter the susceptibility to infection by HIV-1. Because sexual contact often includes exposure to cellular material, we hypothesized that repeated mucosal exposure to heterologous cells would induce an immune response that would alter the susceptibility to mucosal infection. Using the feline immunodeficiency virus (FIV model of HIV-1 mucosal transmission, the cervicovaginal mucosa was exposed once weekly for 12 weeks to 5,000 heterologous cells or media (control and then cats were vaginally challenged with cell-associated or cell-free FIV. Results Exposure to heterologous cells decreased the percentage of lymphocytes in the mucosal and systemic lymph nodes (LN expressing L-selectin as well as the percentage of CD4+ CD25+ T cells. These shifts were associated with enhanced ex-vivo proliferative responses to heterologous cells. Following mucosal challenge with cell-associated, but not cell-free, FIV, proviral burden was reduced by 64% in cats previously exposed to heterologous cells as compared to media exposed controls. Conclusions The pathogenesis and/or the threshold for mucosal infection by infected cells (but not cell-free virus can be modulated by mucosal exposure to uninfected heterologous cells.

Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis.

Science.gov (United States)

Carvalho, Rodrigo D; Breyner, Natalia; Menezes-Garcia, Zelia; Rodrigues, Nubia M; Lemos, Luisa; Maioli, Tatiane U; da Gloria Souza, Danielle; Carmona, Denise; de Faria, Ana M C; Langella, Philippe; Chatel, Jean-Marc; Bermúdez-Humarán, Luis G; Figueiredo, Henrique C P; Azevedo, Vasco; de Azevedo, Marcela S

2017-02-13

Mucositis is one of the most relevant gastrointestinal inflammatory conditions in humans, generated by the use of chemotherapy drugs, such as 5-fluoracil (5-FU). 5-FU-induced mucositis affects 80% of patients undergoing oncological treatment causing mucosal gut dysfunctions and great discomfort. As current therapy drugs presents limitations in alleviating mucositis symptoms, alternative strategies are being pursued. Recent studies have shown that the antimicrobial pancreatitis-associated protein (PAP) has a protective role in intestinal inflammatory processes. Indeed, it was demonstrated that a recombinant strain of Lactococcus lactis expressing human PAP (LL-PAP) could prevent and improve murine DNBS-induced colitis, an inflammatory bowel disease (IBD) that causes severe inflammation of the colon. Hence, in this study we sought to evaluate the protective effects of LL-PAP on 5-FU-induced experimental mucositis in BALB/c mice as a novel approach to treat the disease. Our results show that non-recombinant L. lactis NZ9000 have antagonistic activity, in vitro, against the enteroinvasive gastrointestinal pathogen L. monocytogenes and confirmed PAP inhibitory effect against Opportunistic E. faecalis. Moreover, L. lactis was able to prevent histological damage, reduce neutrophil and eosinophil infiltration and secretory Immunoglobulin-A in mice injected with 5-FU. Recombinant lactococci carrying antimicrobial PAP did not improve those markers of inflammation, although its expression was associated with villous architecture preservation and increased secretory granules density inside Paneth cells in response to 5-FU inflammation. We have demonstrated for the first time that L. lactis NZ9000 by itself, is able to prevent 5-FU-induced intestinal inflammation in BALB/c mice. Moreover, PAP delivered by recombinant L. lactis strain showed additional protective effects in mice epithelium, revealing to be a promising strategy to treat intestinal mucositis.

The crosstalk of gut microbiota and chronic kidney disease: role of inflammation, proteinuria, hypertension, and diabetes mellitus.

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Kanbay, Mehmet; Onal, Emine M; Afsar, Baris; Dagel, Tuncay; Yerlikaya, Aslihan; Covic, Adrian; Vaziri, Nosratola D

2018-05-04

Chronic kidney disease (CKD) has been shown to result in profound changes in the composition and functions of the gut microbial flora which by disrupting intestinal epithelial barrier and generating toxic by-products contributes to systemic inflammation and the associated complications. On the other hand, emerging evidence points to the role of the gut microbiota in the development and progression of CKD by provoking inflammation, proteinuria, hypertension, and diabetes. These observations demonstrate the causal interconnection between the gut microbial dysbiosis and CKD. The gut microbiota closely interacts with the inflammatory, renal, cardiovascular, and endocrine systems via metabolic, humoral, and neural signaling pathways, events which can lead to chronic systemic inflammation, proteinuria, hypertension, diabetes, and kidney disease. Given the established role of the gut microbiota in the development and progression of CKD and its complications, favorable modification of the composition and function of the gut microbiome represents an appealing therapeutic target for prevention and treatment of CKD. This review provides an overview of the role of the gut microbial dysbiosis in the pathogenesis of the common causes of CKD including hypertension, diabetes, and proteinuria as well as progression of CKD.

Dietary Considerations in Autism Spectrum Disorders: The Potential Role of Protein Digestion and Microbial Putrefaction in the Gut-Brain Axis.

Science.gov (United States)

Sanctuary, Megan R; Kain, Jennifer N; Angkustsiri, Kathleen; German, J Bruce

2018-01-01

Children with autism spectrum disorders (ASD), characterized by a range of behavioral abnormalities and social deficits, display high incidence of gastrointestinal (GI) co-morbidities including chronic constipation and diarrhea. Research is now increasingly able to characterize the "fragile gut" in these children and understand the role that impairment of specific GI functions plays in the GI symptoms associated with ASD. This mechanistic understanding is extending to the interactions between diet and ASD, including food structure and protein digestive capacity in exacerbating autistic symptoms. Children with ASD and gut co-morbidities exhibit low digestive enzyme activity, impaired gut barrier integrity and the presence of antibodies specific for dietary proteins in the peripheral circulation. These findings support the hypothesis that entry of dietary peptides from the gut lumen into the vasculature are associated with an aberrant immune response. Furthermore, a subset of children with ASD exhibit high concentrations of metabolites originating from microbial activity on proteinaceous substrates. Taken together, the combination of specific protein intakes poor digestion, gut barrier integrity, microbiota composition and function all on a background of ASD represents a phenotypic pattern. A potential consequence of this pattern of conditions is that the fragile gut of some children with ASD is at risk for GI symptoms that may be amenable to improvement with specific dietary changes. There is growing evidence that shows an association between gut dysfunction and dysbiosis and ASD symptoms. It is therefore urgent to perform more experimental and clinical research on the "fragile gut" in children with ASD in order to move toward advancements in clinical practice. Identifying those factors that are of clinical value will provide an evidence-based path to individual management and targeted solutions; from real time sensing to the design of diets with personalized

Effect of Dietary Exogenous Enzyme Supplementation on Enteric Mucosal Morphological Development and Adherent Mucin Thickness in Turkeys

Directory of Open Access Journals (Sweden)

Ayuub A. Ayoola

2015-10-01

Full Text Available Anti-nutritional factors in feed ingredients (ANF can challenge gut health and reduce nutrient utilization. Birds typically activate their innate immune system as a protective response against the adverse effects of ANF, which often involves the secretion of mucin. Although dietary supplementation of exogenous enzymes are commonly used to alleviate the adverse effects of ANF on apparent nutrient digestibility, little is known about how they affect gut health, particularly in relation to the morphological development and mucin secretion of enteric mucosa. We carried out two trials to examine the effect of dietary supplementation of different types of exogenous enzymes on gut health of by accessing the effect of jejunum morphological development and ileal enteric adherent mucin thickness layer in turkeys. Dietary β-mannanase supplementation reduced ileal adherent mucin thickness layer (804 µg/g vs 823 µg/g; p<0.05, while a commercial blend of Xylanase, Amylase and Protease (XAP reduced ileal adherent mucin layer thickness (589 µg/g vs 740 µg/g; p<0.05; thus reducing the apparent endogenous loss of nutrients. Both enzyme supplements also affected gut morphological characteristics. In comparison to the control treatment, dietary β-mannanase supplementation improved the jejunum tip width (219 vs 161; p<0.05, base width (367 vs 300; p<0.05, surface area (509,870 vs 380, 157; p<0.05 and villi height/crypt depth ratio (7.49 vs 5.70; p<0.05, and XAP improved the crypt depth (p<0.05. In conclusion dietary supplementation of exogenous enzymes may help alleviate the adverse effects of ANF on nutrient utilization by directly or indirectly removing the mucosal irritation that stimulates enteric mucin secretion.

GUTs and supersymmetric GUTs in the very early universe

International Nuclear Information System (INIS)

Ellis, J.

1983-01-01

This talk is intended as background material for many of the other talks treating the possible applications of GUTs to the very early universe. It starts with a review of the present theoretical and phenomenological status of GUTs and then goes on to raise some new issues for their prospective cosmological applications which arise in supersymmetric (susy) GUTs. (author)

Mucosal healing in ulcerative colitis

DEFF Research Database (Denmark)

Seidelin, Jakob Benedict; Coskun, Mehmet; Nielsen, Ole Haagen

2013-01-01

. With the introduction of the tumor necrosis factor-alpha inhibitors for the treatment of UC, it has become increasingly evident that the disease course is influenced by whether or not the patient achieves mucosal healing. Thus, patients with mucosal healing have fewer flare-ups, a decreased risk of colectomy......, and a lower probability of developing colorectal cancer. Understanding the mechanisms of mucosal wound formation and wound healing in UC, and how they are affected therapeutically is therefore of importance for obtaining efficient treatment strategies holding the potential of changing the disease course of UC....... This review is focused on the pathophysiological mechanism of mucosal wound formation in UC as well as the known mechanisms of intestinal wound healing. Regarding the latter topic, pathways of both wound healing intrinsic to epithelial cells and the wound-healing mechanisms involving interaction between...

Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases

Czech Academy of Sciences Publication Activity Database

Tlaskalová, Helena; Štěpánková, Renata; Hudcovic, Tomáš; Tučková, Ludmila; Cukrowska, B.; Lodinová-Žádníková, R.; Kozáková, Hana; Rossmann, Pavel; Bártová, J.; Sokol, Dan

2004-01-01

Roč. 93, - (2004), s. 97-108 ISSN 0165-2478 R&D Projects: GA ČR GA310/01/0933; GA ČR GA310/02/1470; GA AV ČR IAA5020101; GA AV ČR IAA5020205; GA AV ČR IAA5020210; GA AV ČR IBS5020203; GA MZd NK6742; GA MZd NI7525 Institutional research plan: CEZ:AV0Z5020903 Keywords : mucosal microbiota * intestina barrier * germ-free animal Subject RIV: EE - Microbiology, Virology Impact factor: 2.136, year: 2004

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis.

Science.gov (United States)

Glover, Louise E; Bowers, Brittelle E; Saeedi, Bejan; Ehrentraut, Stefan F; Campbell, Eric L; Bayless, Amanda J; Dobrinskikh, Evgenia; Kendrick, Agnieszka A; Kelly, Caleb J; Burgess, Adrianne; Miller, Lauren; Kominsky, Douglas J; Jedlicka, Paul; Colgan, Sean P

2013-12-03

Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine-creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2-dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.

Budesonide and fluticasone propionate differentially affect the airway epithelial barrier

NARCIS (Netherlands)

Heijink, I. H.; Jonker, M.R.; Vries, de Maaike; van Oosterhout, A. J. M.; Telenga, E.; ten Hacken, N. H. T.; Postma, D. S.; van den Berge, M.

2016-01-01

Background: COPD patients have a higher risk of pneumonia when treated with fluticasone propionate (FP) than with placebo, and a lower risk with budesonide (BUD). We hypothesized that BUD and FP differentially affect the mucosal barrier in response to viral infection and/or cigarette smoke. Methods:

Vasoactive drugs and the gut: is there anything new?

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Woolsey, Cheryl A; Coopersmith, Craig M

2006-04-01

Systemic changes in blood pressure and cardiac output induced by pressors and inotropes do not always correlate to improvements in regional perfusion. Since the gut is often referred to as the 'motor' of the systemic inflammatory response syndrome, the impact of vasoactive agents on splanchnic perfusion has theoretical importance. This review will highlight recent studies examining secondary effects of vasoactive agents on intestinal perfusion, metabolism, and barrier function. Norepinephrine has minimal impact on mesenteric blood flow although the combination of norepinephrine and dobutamine increases splanchnic blood flow in sepsis. Dopamine also increases mesenteric blood flow although this may be associated with negative hepatic energy balance at high does. Vasopressin and epinephrine both have negative effects on splanchnic blood flow. Newer inodilators levosimendan and olprinone preferentially improve mesenteric perfusion in animal models. Secondary effects of norepinephrine and dopamine on splanchnic perfusion are minor compared with their systemic effects. While vasopressin usage is increasing in the intensive care unit, caution should be used because of its adverse effects on gut perfusion. Experimental agents for the treatment of heart failure have beneficial gut-specific effects although the clinical significance of this is currently limited by their availability.

Characterization of the Probiotic Yeast Saccharomyces boulardii in the Healthy Mucosal Immune System.

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Lauren E Hudson

Full Text Available The probiotic yeast Saccharomyces boulardii has been shown to ameliorate disease severity in the context of many infectious and inflammatory conditions. However, use of S. boulardii as a prophylactic agent or therapeutic delivery vector would require delivery of S. boulardii to a healthy, uninflamed intestine. In contrast to inflamed mucosal tissue, the diverse microbiota, intact epithelial barrier, and fewer inflammatory immune cells within the healthy intestine may all limit the degree to which S. boulardii contacts and influences the host mucosal immune system. Understanding the nature of these interactions is crucial for application of S. boulardii as a prophylactic agent or therapeutic delivery vehicle. In this study, we explore both intrinsic and immunomodulatory properties of S. boulardii in the healthy mucosal immune system. Genomic sequencing and morphological analysis of S. boulardii reveals changes in cell wall components compared to non-probiotic S. cerevisiae that may partially account for probiotic functions of S. boulardii. Flow cytometry and immunohistochemistry demonstrate limited S. boulardii association with murine Peyer's patches. We also show that although S. boulardii induces a systemic humoral immune response, this response is small in magnitude and not directed against S. boulardii itself. RNA-seq of the draining mesenteric lymph nodes indicates that even repeated administration of S. boulardii induces few transcriptional changes in the healthy intestine. Together these data strongly suggest that interaction between S. boulardii and the mucosal immune system in the healthy intestine is limited, with important implications for future work examining S. boulardii as a prophylactic agent and therapeutic delivery vehicle.

Characterization of the Probiotic Yeast Saccharomyces boulardii in the Healthy Mucosal Immune System.

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Hudson, Lauren E; McDermott, Courtney D; Stewart, Taryn P; Hudson, William H; Rios, Daniel; Fasken, Milo B; Corbett, Anita H; Lamb, Tracey J

2016-01-01

The probiotic yeast Saccharomyces boulardii has been shown to ameliorate disease severity in the context of many infectious and inflammatory conditions. However, use of S. boulardii as a prophylactic agent or therapeutic delivery vector would require delivery of S. boulardii to a healthy, uninflamed intestine. In contrast to inflamed mucosal tissue, the diverse microbiota, intact epithelial barrier, and fewer inflammatory immune cells within the healthy intestine may all limit the degree to which S. boulardii contacts and influences the host mucosal immune system. Understanding the nature of these interactions is crucial for application of S. boulardii as a prophylactic agent or therapeutic delivery vehicle. In this study, we explore both intrinsic and immunomodulatory properties of S. boulardii in the healthy mucosal immune system. Genomic sequencing and morphological analysis of S. boulardii reveals changes in cell wall components compared to non-probiotic S. cerevisiae that may partially account for probiotic functions of S. boulardii. Flow cytometry and immunohistochemistry demonstrate limited S. boulardii association with murine Peyer's patches. We also show that although S. boulardii induces a systemic humoral immune response, this response is small in magnitude and not directed against S. boulardii itself. RNA-seq of the draining mesenteric lymph nodes indicates that even repeated administration of S. boulardii induces few transcriptional changes in the healthy intestine. Together these data strongly suggest that interaction between S. boulardii and the mucosal immune system in the healthy intestine is limited, with important implications for future work examining S. boulardii as a prophylactic agent and therapeutic delivery vehicle.

Mucosal immunization using proteoliposome and cochleate structures from Neisseria meningitidis serogroup B induce mucosal and systemic responses.

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Campo, Judith Del; Zayas, Caridad; Romeu, Belkis; Acevedo, Reinaldo; González, Elizabeth; Bracho, Gustavo; Cuello, Maribel; Cabrera, Osmir; Balboa, Julio; Lastre, Miriam

2009-12-01

Most pathogens either invade the body or establish infection in mucosal tissues and represent an enormous challenge for vaccine development by the absence of good mucosal adjuvants. A proteoliposome-derived adjuvant from Neisseria meningitidis serogroup B (AFPL1, Adjuvant Finlay Proteoliposome 1) and its derived cochleate form (Co, AFCo1) contain multiple pathogen-associated molecular patterns as immunopotentiators, and can also serve as delivery systems to elicit a Th1-type immune response. The present studies demonstrate the ability of AFPL1and AFCo1 to induce mucosal and systemic immune responses by different mucosal immunizations routes and significant adjuvant activity for antibody responses of both structures: a microparticle and a nanoparticle with a heterologous antigen. Therefore, we used female mice immunized by intragastric, intravaginal, intranasal or intramuscular routes with both structures alone or incorporated with ovalbumin (OVA). High levels of specific IgG antibody were detected in all sera and in vaginal washes, but specific IgA antibody in external secretions was only detected in mucosally immunized mice. Furthermore, antigen specific IgG1 and IgG2a isotypes were all induced. AFPL1 and AFCo1 are capable of inducing IFN-gamma responses, and chemokine secretions, like MIP-1alpha and MIP-1beta. However, AFCo1 is a better alternative to induce immune responses at mucosal level. Even when we use a heterologous antigen, the AFCo1 response was better than with AFPL1 in inducing mucosal and systemic immune responses. These results support the use of AFCo1 as a potent Th1 inducing adjuvant particularly suitable for mucosal immunization.

The learning curve, interobserver, and intraobserver agreement of endoscopic confocal laser endomicroscopy in the assessment of mucosal barrier defects.

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Chang, Jeff; Ip, Matthew; Yang, Michael; Wong, Brendon; Power, Theresa; Lin, Lisa; Xuan, Wei; Phan, Tri Giang; Leong, Rupert W

2016-04-01

Confocal laser endomicroscopy can dynamically assess intestinal mucosal barrier defects and increased intestinal permeability (IP). These are functional features that do not have corresponding appearance on histopathology. As such, previous pathology training may not be beneficial in learning these dynamic features. This study aims to evaluate the diagnostic accuracy, learning curve, inter- and intraobserver agreement for identifying features of increased IP in experienced and inexperienced analysts and pathologists. A total of 180 endoscopic confocal laser endomicroscopy (Pentax EC-3870FK; Pentax, Tokyo, Japan) images of the terminal ileum, subdivided into 6 sets of 30 were evaluated by 6 experienced analysts, 13 inexperienced analysts, and 2 pathologists, after a 30-minute teaching session. Cell-junction enhancement, fluorescein leak, and cell dropout were used to represent increased IP and were either present or absent in each image. For each image, the diagnostic accuracy, confidence, and quality were assessed. Diagnostic accuracy was significantly higher for experienced analysts compared with inexperienced analysts from the first set (96.7% vs 83.1%, P 0.86 for experienced observers. Features representative of increased IP can be rapidly learned with high inter- and intraobserver agreement. Confidence and image quality were significant predictors of accurate interpretation. Previous pathology training did not have an effect on learning. Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon.

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Baldauf, K J; Royal, J M; Kouokam, J C; Haribabu, B; Jala, V R; Yaddanapudi, K; Hamorsky, K T; Dryden, G W; Matoba, N

2017-07-01

Cholera toxin B subunit (CTB) is a component of a licensed oral cholera vaccine. However, CTB has pleiotropic immunomodulatory effects whose impacts on the gut are not fully understood. Here, we found that oral administration in mice of a plant-made recombinant CTB (CTBp) significantly increased several immune cell populations in the colon lamina propria. Global gene expression analysis revealed that CTBp had more pronounced impacts on the colon than the small intestine, with significant activation of TGFβ-mediated pathways in the colon epithelium. The clinical relevance of CTBp-induced impacts on colonic mucosa was examined. In a human colon epithelial model using Caco2 cells, CTBp, but not the non-GM1-binding mutant G33D-CTBp, induced TGFβ-mediated wound healing. In a dextran sodium sulfate (DSS) acute colitis mouse model, oral administration of CTBp protected against colon mucosal damage as manifested by mitigated body weight loss, decreased histopathological scores, and blunted escalation of inflammatory cytokine levels while inducing wound healing-related genes. Furthermore, biweekly oral administration of CTBp significantly reduced disease severity and tumorigenesis in the azoxymethane/DSS model of ulcerative colitis and colon cancer. Altogether, these results demonstrate CTBp's ability to enhance mucosal healing in the colon, highlighting its potential application in ulcerative colitis therapy besides cholera vaccination.

Effects of pig antibacterial peptides on growth performance and intestine mucosal immune of broiler chickens.

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Bao, H; She, R; Liu, T; Zhang, Y; Peng, K S; Luo, D; Yue, Z; Ding, Y; Hu, Y; Liu, W; Zhai, L

2009-02-01

Currently, substitutions for antibiotic growth promoters in animals are attracting interest. This study investigated the effects of pig antibacterial peptides (PABP) on growth performance and small intestine mucosal immune responses in broilers. Three hundred 1-d-old Arbor Acre male broiler chickens were randomly allocated to 5 groups with 60 birds per group. The groups were control group; PABP administered in drinking water at 20 and 30 mg/L of water; or PABP supplemented in feed at 150 and 200 mg/kg of diet. The birds were fed a corn-soybean based diet for 6 wk. Chickens were weighed weekly and killed after 42 d of feeding, and growth performance was measured. Samples of the duodenum and jejunum were collected. The villus height, mucosa thickness, alkaline phosphatase activity, and numbers of secreting IgA and goblet cells were evaluated. The PABP-treated groups had greater BW and average daily gain, greater height of villus and thickness of gut mucosa, greater activity of alkaline phosphatase, higher ratio of secreting IgA, and a greater number of goblet cells compared with the control group (P<0.05). In conclusion, PABP can improve the growth performance, increase the intestinal ability to absorb nutrients, and improve the mucosal immunity of the intestine.

GUTs and supersymmetric GUTs in the very early universe

International Nuclear Information System (INIS)

Ellis, J.

1982-10-01

This talk is intended as background material for many of the other talks treating the possible applications of GUTs to the very early universe. I start with a review of the present theoretical and phenomenological status of GUTs before going on to raise some new issues for their prospective cosmological applications which arise in supersymmetric (susy) GUTs. The first section is an update on conventional GUTs, which is followed by a reminder of some of the motivations for going supersymmetric. There then follows a simple primer on susy and a discussion of the structure and phenomenology of simple sysy GUTs. Finally we come to the cosmological issues, including problems arising from the degeneracy of susy minima, baryosynthesis and supersymmetric inflation, the possibility that gravity is an essential complication in constructing susy GUTs and discussing their cosmology, and the related question of what mass range is allowed for the gravitino. Several parts of this write-up contain new material which has emerged either during the Workshop or subsequently. They are included here for completeness and the convenience of the prospective reader. Wherever possible, these anachronisms will be flagged so as to keep straight the historical record

The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment.

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de Vallière, Cheryl; Vidal, Solange; Clay, Ieuan; Jurisic, Giorgia; Tcymbarevich, Irina; Lang, Silvia; Ludwig, Marie-Gabrielle; Okoniewski, Michal; Eloranta, Jyrki J; Kullak-Ublick, Gerd A; Wagner, Carsten A; Rogler, Gerhard; Seuwen, Klaus

2015-09-15

The pH-sensing receptor ovarian cancer G protein-coupled receptor 1 (OGR1; GPR68) is expressed in the gut. Inflammatory bowel disease is typically associated with a decrease in local pH, which may lead to altered epithelial barrier function and subsequent gastrointestinal repair involving epithelial cell adhesion and migration. As the mechanisms underlying the response to pH changes are not well understood, we have investigated OGR1-mediated, pH-dependent signaling pathways in intestinal epithelial cells. Caco-2 cells stably overexpressing OGR1 were created and validated as tools to study OGR1 signaling. Barrier function, migration, and proliferation were measured using electric cell-substrate impedance-sensing technology. Localization of the tight junction proteins zonula occludens protein 1 and occludin and the rearrangement of cytoskeletal actin were examined by confocal microscopy. Paracellular permeability and protein and gene expression analysis using DNA microarrays were performed on filter-grown Caco-2 monolayers. We report that an acidic pH shift from pH 7.8 to 6.6 improved barrier function and stimulated reorganization of filamentous actin with prominent basal stress fiber formation. Cell migration and proliferation during in vitro wound healing were inhibited. Gene expression analysis revealed significant upregulation of genes related to cytoskeleton remodeling, cell adhesion, and growth factor signaling. We conclude that acidic extracellular pH can have a signaling function and impact the physiology of intestinal epithelial cells. The deconstruction of OGR1-dependent signaling may aid our understanding of mucosal inflammation mechanisms. Copyright © 2015 the American Physiological Society.

Irradiation mucositis and oral flora

International Nuclear Information System (INIS)

Spijkervet, F.K.L.

1989-01-01

This study, which is motivated by the substantial morbidity of local signs of mucositis and generalized symptoms that result from mucositis induced by therapeutic irradiation, has the following objectives: To investigate if it is possible to prevent irradiation mucositis via oral flora elimination, and, if it is true that flora plays a role in irradiation mucositis, what fraction of the oral flora may be involved; to evaluate oral Gram-negative bacillary carriage; to investigate the possibility to eradicate Gram-negative bacilli from the oral cavity; to evaluate oral yeast carriage; to investigate the possibility to eradicate yeasts stomatitis and the 'selectivity' of elimination of flora. Two methods are described for monitoring alterations of mucositis of the oral cavity and changes in oral flora. Chlorhexidine has been tested as the commonly used prophylaxis. The effect of chlorhexidine 0.1% rinses on oral flora and mucositis has been studied in a prospective placebo controlled double blind randomized programme. The results of the influence of saliva on the antimicrobial activity of chlorhexidine and the results of selective elimination of oral flora in irradiated patients who have head and neck cancer are reported. Salivary inactivation of the topical antimicrobials used for selective elimination of oral flora has been studied and the results are reported. Finally, the objectives that have been achieved (or not) are delineated. The significance of the results of the study are discussed in terms of published information and further lines of research are suggested. (author). 559 refs.; 29 figs.; 20 tabs

Electron tomography of HIV-1 infection in gut-associated lymphoid tissue.

Science.gov (United States)

Ladinsky, Mark S; Kieffer, Collin; Olson, Gregory; Deruaz, Maud; Vrbanac, Vladimir; Tager, Andrew M; Kwon, Douglas S; Bjorkman, Pamela J

2014-01-01

Critical aspects of HIV-1 infection occur in mucosal tissues, particularly in the gut, which contains large numbers of HIV-1 target cells that are depleted early in infection. We used electron tomography (ET) to image HIV-1 in gut-associated lymphoid tissue (GALT) of HIV-1-infected humanized mice, the first three-dimensional ultrastructural examination of HIV-1 infection in vivo. Human immune cells were successfully engrafted in the mice, and following infection with HIV-1, human T cells were reduced in GALT. Virions were found by ET at all stages of egress, including budding immature virions and free mature and immature viruses. Immuno-electron microscopy verified the virions were HIV-1 and showed CD4 sequestration in the endoplasmic reticulum of infected cells. Observation of HIV-1 in infected GALT tissue revealed that most HIV-1-infected cells, identified by immunolabeling and/or the presence of budding virions, were localized to intestinal crypts with pools of free virions concentrated in spaces between cells. Fewer infected cells were found in mucosal regions and the lamina propria. The preservation quality of reconstructed tissue volumes allowed details of budding virions, including structures interpreted as host-encoded scission machinery, to be resolved. Although HIV-1 virions released from infected cultured cells have been described as exclusively mature, we found pools of both immature and mature free virions within infected tissue. The pools could be classified as containing either mostly mature or mostly immature particles, and analyses of their proximities to the cell of origin supported a model of semi-synchronous waves of virion release. In addition to HIV-1 transmission by pools of free virus, we found evidence of transmission via virological synapses. Three-dimensional EM imaging of an active infection within tissue revealed important differences between cultured cell and tissue infection models and furthered the ultrastructural understanding of

Electron tomography of HIV-1 infection in gut-associated lymphoid tissue.

Directory of Open Access Journals (Sweden)

Mark S Ladinsky

2014-01-01

Full Text Available Critical aspects of HIV-1 infection occur in mucosal tissues, particularly in the gut, which contains large numbers of HIV-1 target cells that are depleted early in infection. We used electron tomography (ET to image HIV-1 in gut-associated lymphoid tissue (GALT of HIV-1-infected humanized mice, the first three-dimensional ultrastructural examination of HIV-1 infection in vivo. Human immune cells were successfully engrafted in the mice, and following infection with HIV-1, human T cells were reduced in GALT. Virions were found by ET at all stages of egress, including budding immature virions and free mature and immature viruses. Immuno-electron microscopy verified the virions were HIV-1 and showed CD4 sequestration in the endoplasmic reticulum of infected cells. Observation of HIV-1 in infected GALT tissue revealed that most HIV-1-infected cells, identified by immunolabeling and/or the presence of budding virions, were localized to intestinal crypts with pools of free virions concentrated in spaces between cells. Fewer infected cells were found in mucosal regions and the lamina propria. The preservation quality of reconstructed tissue volumes allowed details of budding virions, including structures interpreted as host-encoded scission machinery, to be resolved. Although HIV-1 virions released from infected cultured cells have been described as exclusively mature, we found pools of both immature and mature free virions within infected tissue. The pools could be classified as containing either mostly mature or mostly immature particles, and analyses of their proximities to the cell of origin supported a model of semi-synchronous waves of virion release. In addition to HIV-1 transmission by pools of free virus, we found evidence of transmission via virological synapses. Three-dimensional EM imaging of an active infection within tissue revealed important differences between cultured cell and tissue infection models and furthered the ultrastructural

Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg.

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Arab, Juan P; Martin-Mateos, Rosa M; Shah, Vijay H

2018-02-01

The term gut-liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized epithelial membrane which regulates transport across the mucosa. Due to dysbiosis, impairment of the intestinal barrier and altered immunity status, bacterial products can reach the liver through the portal vein, where they are recognized by specific receptors, activate the immune system and lead to a proinflammatory response. Gut microbiota and bacterial translocation play an important role in the pathogenesis of chronic liver diseases, including alcoholic and non-alcoholic fatty liver disease, cirrhosis, and its complications, such as portal hypertension, spontaneous bacterial peritonitis and hepatic encephalopaty. The gut microbiota also plays a critical role as a modulator of bile acid metabolism which can also influence intestinal permeability and portal hypertension through the farnesoid-X receptor. On the other hand, cirrhosis and portal hypertension affect the microbiota and increase translocation, leading to a "chicken and egg" situation, where translocation increases portal pressure, and vice versa. A myriad of therapies targeting gut microbiota have been evaluated specifically in patients with chronic liver disease. Further studies targeting intestinal microbiota and its possible hemodynamic and metabolic effects are needed. This review summarizes the current knowledge about the role of gut microbiota in the pathogenesis of chronic liver diseases and portal hypertension.

GUTs without guts

Energy Technology Data Exchange (ETDEWEB)

Gato-Rivera, B. [NIKHEF Theory Group, Science Park 105, 1098 XG Amsterdam (Netherlands); Instituto de Física Fundamental, IFF-CSIC, Serrano 123, Madrid 28006 (Spain); Schellekens, A.N., E-mail: t58@nikhef.nl [NIKHEF Theory Group, Science Park 105, 1098 XG Amsterdam (Netherlands); Instituto de Física Fundamental, IFF-CSIC, Serrano 123, Madrid 28006 (Spain); IMAPP, Radboud Universiteit, Nijmegen (Netherlands)

2014-06-15

The structure of a Standard Model family is derived in a class of brane models with a U(M)×U(N) factor, from two mildly anthropic requirements: a massless photon and a universe that does not turn into a plasma of massless charged particles. If we choose M=3 and N=2, the only option is shown to be the Standard Model with an undetermined number of families. We do not assume the U(1) embedding, charge quantization, family repetition, nor the fermion representations; all of these features are derived, assuming a doublet Higgs. With a slightly stronger assumption even the Higgs representation is determined. We also consider a more general class, requiring an asymptotically free strong SU(M) (with M⩾3) interaction from the first factor and an electromagnetic U(1) embedded in both factors. We allow Higgs symmetry breaking of the U(N)×U(1) flavor group by at most one Higgs boson in any representation, combined with any allowed chiral symmetry breaking by SU(M). For M=3 there is a large number of solutions with an unbroken U(1). In all of these, “quarks” have third-integral charges and color singlets have integer charges in comparison to leptons. Hence Standard Model charge quantization holds for any N. Only for N=2 these models allow an SU(5) GUT extension, but this extension offers no advantages whatsoever for understanding the Standard Model; it only causes complications, such as the doublet–triplet splitting problem. Although all these models have a massless photon, all except the Standard Model are ruled out by the second anthropic requirement. In this class of brane models the Standard Model is realized as a GUT with its intestines removed, to keep only the good parts: a GUT without guts.

GUTs without guts

International Nuclear Information System (INIS)

Gato-Rivera, B.; Schellekens, A.N.

2014-01-01

The structure of a Standard Model family is derived in a class of brane models with a U(M)×U(N) factor, from two mildly anthropic requirements: a massless photon and a universe that does not turn into a plasma of massless charged particles. If we choose M=3 and N=2, the only option is shown to be the Standard Model with an undetermined number of families. We do not assume the U(1) embedding, charge quantization, family repetition, nor the fermion representations; all of these features are derived, assuming a doublet Higgs. With a slightly stronger assumption even the Higgs representation is determined. We also consider a more general class, requiring an asymptotically free strong SU(M) (with M⩾3) interaction from the first factor and an electromagnetic U(1) embedded in both factors. We allow Higgs symmetry breaking of the U(N)×U(1) flavor group by at most one Higgs boson in any representation, combined with any allowed chiral symmetry breaking by SU(M). For M=3 there is a large number of solutions with an unbroken U(1). In all of these, “quarks” have third-integral charges and color singlets have integer charges in comparison to leptons. Hence Standard Model charge quantization holds for any N. Only for N=2 these models allow an SU(5) GUT extension, but this extension offers no advantages whatsoever for understanding the Standard Model; it only causes complications, such as the doublet–triplet splitting problem. Although all these models have a massless photon, all except the Standard Model are ruled out by the second anthropic requirement. In this class of brane models the Standard Model is realized as a GUT with its intestines removed, to keep only the good parts: a GUT without guts

Intraluminal Flagellin Differentially Contributes to Gut Dysbiosis and Systemic Inflammation following Burn Injury.

Directory of Open Access Journals (Sweden)

Logan Grimes

Full Text Available Burn injury is associated with a loss of gut barrier function, resulting in systemic dissemination of gut-derived bacteria and their products. The bacterial protein and TLR5 agonist, flagellin, induces non-specific innate immune responses. Because we detected flagellin in the serum of burn patients, we investigated whether gut-derived flagellin was a primary or secondary contributor to intestinal dysfunction and systemic inflammation following burn injury. The apical surface of polarized human intestinal epithelial cells (IECs, Caco-2BBe, were exposed to 50 or 500 ng of purified flagellin and 1 x 105 of an intestinal E. coli (EC isolate as follows: 1 flagellin added 30 min prior to EC, 2 flagellin and EC added simultaneously, or 3 EC added 30 min prior to flagellin. Our results showed that luminal flagellin and EC modulated each other's biological actions, which influenced their ability to induce basolateral secretion of inflammatory cytokines and subsequent translocation of bacteria and their products. A low dose of flagellin accompanied by an enteric EC in the lumen, tempered inflammation in a dose- and time-dependent manner. However, higher doses of flagellin acted synergistically with EC to induce both intestinal and systemic inflammation that compromised barrier integrity, increasing systemic inflammation following burn injury, a process we have termed flagellemia. In a murine model of burn injury we found that oral gavage of flagellin (1 μg/mouse significantly affected the gut microbiome after burn injury. In these mice, flagellin disseminated out of the intestine into the serum and to distal organs (mesenteric lymph nodes and lungs where it induced secretion of monocyte chemoattractant protein (MCP-1 and CXCL1/KC (mouse equivalent of human IL-8 at 24 and 48h post-burn. Our results illustrated that gut-derived flagellin alone or accompanied by a non-pathogenic enteric EC strain can function as an initiator of luminal and systemic

Mind-altering with the gut: Modulation of the gut-brain axis with probiotics.

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Kim, Namhee; Yun, Misun; Oh, Young Joon; Choi, Hak-Jong

2018-03-01

It is increasingly evident that bidirectional interactions exist among the gastrointestinal tract, the enteric nervous system, and the central nervous system. Recent preclinical and clinical trials have shown that gut microbiota plays an important role in these gut-brain interactions. Furthermore, alterations in gut microbiota composition may be associated with pathogenesis of various neurological disorders, including stress, autism, depression, Parkinson's disease, and Alzheimer's disease. Therefore, the concepts of the microbiota-gut-brain axis is emerging. Here, we review the role of gut microbiota in bidirectional interactions between the gut and the brain, including neural, immune-mediated, and metabolic mechanisms. We highlight recent advances in the understanding of probiotic modulation of neurological and neuropsychiatric disorders via the gut-brain axis.

Gut Microbiota in HIV Infection: Implication for Disease Progression and Management

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Felix Chinweije Nwosu

2014-01-01

Full Text Available Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression.

The human gut resistome.

Science.gov (United States)

van Schaik, Willem

2015-06-05

In recent decades, the emergence and spread of antibiotic resistance among bacterial pathogens has become a major threat to public health. Bacteria can acquire antibiotic resistance genes by the mobilization and transfer of resistance genes from a donor strain. The human gut contains a densely populated microbial ecosystem, termed the gut microbiota, which offers ample opportunities for the horizontal transfer of genetic material, including antibiotic resistance genes. Recent technological advances allow microbiota-wide studies into the diversity and dynamics of the antibiotic resistance genes that are harboured by the gut microbiota ('the gut resistome'). Genes conferring resistance to antibiotics are ubiquitously present among the gut microbiota of humans and most resistance genes are harboured by strictly anaerobic gut commensals. The horizontal transfer of genetic material, including antibiotic resistance genes, through conjugation and transduction is a frequent event in the gut microbiota, but mostly involves non-pathogenic gut commensals as these dominate the microbiota of healthy individuals. Resistance gene transfer from commensals to gut-dwelling opportunistic pathogens appears to be a relatively rare event but may contribute to the emergence of multi-drug resistant strains, as is illustrated by the vancomycin resistance determinants that are shared by anaerobic gut commensals and the nosocomial pathogen Enterococcus faecium.

Dose-response studies of depletion and repopulation of rat intestinal mucosal mast cells after irradiation

International Nuclear Information System (INIS)

Sedgwick, D.M.; Ferguson, A.

1994-01-01

The effects of radiation on gut mucosal mast cells (MMC) and tissue eosinophils were examined. Groups of rats were given single doses of whole-body irradiation from 0.5 to 5 Gy. Serum rat mast cell protease II (RMCPII) concentration showed a significant dose-dependent fall after 1 Gy on day 3 and 1.5 Gy on day 7. MMC counts and tissue RMCPII values on day 7 decreased significantly by 70% after 1 Gy and were undetectable with larger doses. Rats with normal and expanded MMC populations were irradiated or given anaphylaxis. Serum RMCPII concentrations did not change after irradiation, but there was a 10-fold increase in RMCPII after anaphylaxis. Tissue eosinophils in jejunum were 50% of control at 7 days after 2 Gy, and this effect was progressively more marked with higher doses. Similar effects on MMC and eosinophils were demonstrated in ileum, ascending colon and rectum. After 4.5 Gy, repopulation of the gut with MMC did not occur until week 3-4 postirradiation and MMC counts were still 50% below those of controls at 5 weeks postirradiation. Counts of tisse eosinophils 5 weeks after 4.5 Gy irradiation had returned to control levels in jejunum but were still significantly depleted in colon. (Author)

Gut microbiota’s effect on mental health: The gut-brain axis

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Megan Clapp

2017-09-01

Full Text Available The bidirectional communication between the central nervous system and gut microbiota, referred to as the gut-brain-axis, has been of significant interest in recent years. Increasing evidence has associated gut microbiota to both gastrointestinal and extragastrointestinal diseases. Dysbiosis and inflammation of the gut have been linked to causing several mental illnesses including anxiety and depression, which are prevalent in society today. Probiotics have the ability to restore normal microbial balance, and therefore have a potential role in the treatment and prevention of anxiety and depression. This review aims to discuss the development of the gut microbiota, the linkage of dysbiosis to anxiety and depression, and possible applications of probiotics to reduce symptoms.

Radiation-induced mucositis pain in laryngeal cancer

International Nuclear Information System (INIS)

Takahashi, Atsuhito; Shoji, Kazuhiko; Iki, Takehiro; Mizuta, Masanobu; Matsubara, Mami

2009-01-01

Radiation therapy in those with head and neck malignancies often triggers painful mucositis poorly controlled by nonsteroidal antiinflammatory drugs (NSAIDs). To better understand how radiation-induced pain develops over time, we studied the numerical rating scale (NRS 0-5) pain scores from 32 persons undergoing radiation therapy of 60-72 Gy for newly diagnosed laryngeal cancer. The degree of mucositis was evaluated using Common Terminology Criteria for Adverse Events version3.0 (CTCAE v3.0). We divided the 32 into a conventional fractionation (CF) group of 14 and a hyperfractionation (HF) group of 18, and further divided laryngeal cancer into a small-field group of 23 and a large-field group of 9. The mucositis pain course was similar in CF and HF, but mucositis pain was severer in the HF group, which also required more NSAIDs. Those in the large-field group had severer pain and mucositis and required more NSAIDs than those in the small-field group. We therefore concluded that small/large-field radiation therapy, rather fractionation type, was related to the incidence of radiation-induced mucositis pain. (author)

Stress, Nutrition, and Intestinal Immune Responses in Pigs — A Review

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In Kyu Lee

2016-08-01

Full Text Available Modern livestock production became highly intensive and large scaled to increase production efficiency. This production environment could add stressors affecting the health and growth of animals. Major stressors can include environment (air quality and temperature, nutrition, and infection. These stressors can reduce growth performance and alter immune systems at systemic and local levels including the gastrointestinal tract. Heat stress increases the permeability, oxidative stress, and inflammatory responses in the gut. Nutritional stress from fasting, antinutritional compounds, and toxins induces the leakage and destruction of the tight junction proteins in the gut. Fasting is shown to suppress pro-inflammatory cytokines, whereas deoxynivalenol increases the recruitment of intestinal pro-inflammatory cytokines and the level of lymphocytes in the gut. Pathogenic and viral infections such as Enterotoxigenic E. coli (ETEC and porcine epidemic diarrhea virus can lead to loosening the intestinal epithelial barrier. On the other hand, supplementation of Lactobacillus or Saccharaomyces reduced infectious stress by ETEC. It was noted that major stressors altered the permeability of intestinal barriers and profiles of genes and proteins of pro-inflammatory cytokines and chemokines in mucosal system in pigs. However, it is not sufficient to fully explain the mechanism of the gut immune system in pigs under stress conditions. Correlation and interaction of gut and systemic immune system under major stressors should be better defined to overcome aforementioned obstacles.

Gut Microbiota, Obesity and Metabolic Dysfunction

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Anna Meiliana

2011-12-01

Full Text Available BACKGROUND: The prevalence of obesity and related disorders such as metabolic syndrome and diabetes has vastly increased throughout the world. Recent insights have generated an entirely new perspective suggesting that our microbiota might be involved in the development of these disorders. This represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems. CONTENT: Our bowels have two major roles: the digestion and absorption of nutrients and the maintenance of a barrier against the external environment. They fulfill these functions in the context of, and with the help from, tens of trillions of resident microbes, known as the gut microbiota. Studies have demonstrated that obesity and metabolic syndrome may be associated with profound microbiotal changes, and the induction of a metabolic syndrome phenotype through fecal transplants corroborates the important role of the microbiota in this disease. Dietary composition and caloric intake appear to swiftly regulate intestinal microbial composition and function. SUMMARY: The interaction of the intestinal microbial world with its host, and its mutual regulation, will become one of the important topics of biomedical research and will provide us with further insights at the interface of microbiota, metabolism, metabolic syndrome, and obesity. A better understanding of the interaction between certain diets and the human gut microbiome should help to develop new guidelines for feeding humans at various time points in their life, help to improve global human health, and establish ways to prevent or treat various food-related diseases. KEYWORDS: gut microbiota, obesity, metabolic syndrome, type 2 diabetes.

Comparison of subcutaneous versus intranasal immunization of male koalas (Phascolarctos cinereus) for induction of mucosal and systemic immunity against Chlamydia pecorum.

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Waugh, Courtney A; Timms, Peter; Andrew, Dean; Rawlinson, Galit; Brumm, Jacqui; Nilsson, Karen; Beagley, Kenneth W

2015-02-11

Chlamydia pecorum infections are debilitating in the koala, contributing significantly to morbidity and mortality, with current antibiotic treatments having minimal success and adversely affecting gut microflora. This, combined with the sometimes-asymptomatic nature of the infection, suggests that an efficacious anti-chlamydial vaccine is required to control chlamydial infections in the koala. To date vaccination studies have focused primarily on female koalas, however, given the physiological differences between male and female reproductive tracts, we tested the efficacy of a vaccine in 12 captive male koalas. We evaluated the potential of both subcutaneous and intranasal vaccine delivery to elicit mucosal immunity in male koalas. Our results showed that both intranasal and subcutaneous delivery of a vaccine consisting of C. pecorum major outer membrane protein (MOMP) and the adjuvant immunostimulating complex (ISC) induced significant immune responses in male koalas. Subcutaneous immunization elicited stronger cell-mediated responses in peripheral blood lymphocytes (PBL), and greater plasma antibody levels whereas the intranasal immunization elicited stronger humoral responses in urogenital tract (UGT) secretions. This is the first time a Chlamydia vaccine has been tested in the male koala and the first assessment of a mucosal vaccination route in this species. Our results suggest that vaccination of male koalas can elicit mucosal immunity and could contribute to the long-term survivability of wild populations of the koala. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tail gut cyst.

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Rao, G Mallikarjuna; Haricharan, P; Ramanujacharyulu, S; Reddy, K Lakshmi

2002-01-01

The tail gut is a blind extension of the hindgut into the tail fold just distal to the cloacal membrane. Remnants of this structure may form tail gut cyst. We report a 14-year-old girl with tail gut cyst that presented as acute abdomen. The patient recovered after cyst excision.

Beyond gut feelings: how the gut microbiota regulates blood pressure.

Science.gov (United States)

Marques, Francine Z; Mackay, Charles R; Kaye, David M

2018-01-01

Hypertension is the leading risk factor for heart disease and stroke, and is estimated to cause 9.4 million deaths globally every year. The pathogenesis of hypertension is complex, but lifestyle factors such as diet are important contributors to the disease. High dietary intake of fruit and vegetables is associated with reduced blood pressure and lower cardiovascular mortality. A critical relationship between dietary intake and the composition of the gut microbiota has been described in the literature, and a growing body of evidence supports the role of the gut microbiota in the regulation of blood pressure. In this Review, we describe the mechanisms by which the gut microbiota and its metabolites, including short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides, act on downstream cellular targets to prevent or contribute to the pathogenesis of hypertension. These effects have a direct influence on tissues such as the kidney, the endothelium, and the heart. Finally, we consider the role of the gut microbiota in resistant hypertension, the possible intergenerational effect of the gut microbiota on blood pressure regulation, and the promising therapeutic potential of gut microbiota modification to improve health and prevent disease.

Building GUTs from strings

International Nuclear Information System (INIS)

Aldazabal, G.; Ibanez, L.E.; Uranga, A.M.

1996-01-01

We study in detail the structure of Grand Unified Theories derived as the low-energy limit of orbifold four-dimensional strings. To this aim, new techniques for building level-two symmetric orbifold theories are presented. New classes of GUTs in the context of symmetric orbifolds are then constructed. The method of permutation modding is further explored and SO(10) GUTs with both 45- or 54-plets are obtained. SU(5) models are also found through this method. It is shown that, in the context of symmetric orbifold SO(10) GUTs, only a single GUT Higgs, either a 54 or a 45, can be present and it always resides in an order-two untwisted sector. Very restrictive results also hold in the case of SU(5). General properties and selection rules for string GUTs are described. Some of these selection rules forbid the presence of some particular GUT-Higgs couplings which are sometimes used in SUSY-GUT model building. Some semi-realistic string GUT examples are presented and their properties briefly discussed. (orig.)

Sex hormones selectively impact the endocervical mucosal microenvironment: implications for HIV transmission.

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Diana Goode

Full Text Available Several studies suggest that progesterone and estrogens may affect HIV transmission in different, possibly opposing ways. Nonetheless, a direct comparison of their effects on the mucosal immune system has never been done. We hypothesize that sex hormones might impact the availability of cells and immune factors important in early stages of mucosal transmission, and, in doing so influence the risk of HIV acquisition. To test this hypothesis, we employed 15 ovarectomized rhesus macaques: 5 were treated with Depot Medroxy Progesterone Acetate (DMPA, 6 with 17-β estradiol (E2 and 4 were left untreated. All animals were euthanized 5 weeks after the initiation of hormone treatment, a time post-DMPA injection associated with high susceptibility to SIV infection. We found that DMPA-treated macaques exhibited higher expression of integrin α4β7 (α4β7 on CD4+ T cells, the gut homing receptor and a marker of cells highly susceptible to HIV, in the endocervix than did the E2-treated animals. In contrast, the frequency of CCR5+ CD4+ T cells in DMPA-treated macaques was higher than in the E2-treated group in vaginal tissue, but lower in endocervix. α4β7 expression on dendritic cells (DCs was higher in the DMPA-treated group in the endocervical tissue, but lower in vaginal tissue and on blood DCs compared with the E2-treated animals. Soluble MAdCAM-1, the α4β7 ligand, was present in the vaginal fluids of the control and E2-treated groups, but absent in the fluids from DMPA-treated animals. Both hormones modulated the expression and release of inflammatory factors and modified the distribution of sialomucins in the endocervix. In summary, we found that sex hormones profoundly impact mucosal immune factors that are directly implicated in HIV transmission. The effect is particularly significant in the endocervix. This may increase our understanding of the potential hormone-driven modulation of HIV susceptibility and potentially guide contraceptive

Arabinoxylans, inulin and Lactobacillus reuteri 1063 repress the adherent-invasive Escherichia coli from mucus in a mucosa-comprising gut model.

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Van den Abbeele, Pieter; Marzorati, Massimo; Derde, Melanie; De Weirdt, Rosemarie; Joan, Vermeiren; Possemiers, Sam; Van de Wiele, Tom

2016-01-01

The microbiota that colonises the intestinal mucus may particularly affect human health given its proximity to the epithelium. For instance, the presence of the adherent-invasive Escherichia coli (AIEC) in this mucosal microbiota has been correlated with Crohn's disease. Using short-term screening assays and a novel long-term dynamic gut model, which comprises a simulated mucosal environment (M-SHIME), we investigated how (potential) pro- and prebiotics may repress colonisation of AIEC from mucus. Despite that during the short-term screening assays, some of the investigated Lactobacillus strains adhered strongly to mucins, none of them competed with AIEC for mucin-adhesion. In contrast, AIEC survival and growth during co-culture batch incubations was decreased by Lactobacillus rhamnosus GG and L. reuteri 1063, which correlated with (undissociated) lactic acid and reuterin levels. Regarding the prebiotics, long-chain arabinoxylans (LC-AX) lowered the initial mucin-adhesion of AIEC, while both inulin (IN) and galacto-oligosaccharides (GOS) limited AIEC survival and growth during batch incubations. L. reuteri 1063, LC-AX and IN were thus retained for a long-term study with the M-SHIME. All treatments repressed AIEC from mucus without affecting AIEC numbers in the luminal content. As a possible explanation, L. reuteri 1063 treatment increased lactobacilli levels in mucus, while LC-AX and IN additionally increased mucosal bifidobacteria levels, thus leading to antimicrobial effects against AIEC in mucus. Overall, this study shows that pro- and prebiotics can beneficially modulate the in vitro mucosal microbiota, thus limiting occurrence of opportunistic pathogens among those mucosal microbes which may directly interact with the host given their proximity to the epithelium.

Effect of dark sweet cherry powder consumption on the gut microbiota, short-chain fatty acids, and biomarkers of gut health in obese db/db mice

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Jose F. Garcia-Mazcorro

2018-01-01

Full Text Available Cherries are fruits containing fiber and bioactive compounds (e.g., polyphenolics with the potential of helping patients with diabetes and weight disorders, a phenomenon likely related to changes in the complex host-microbiota milieu. The objective of this study was to investigate the effect of cherry supplementation on the gut bacterial composition, concentrations of caecal short-chain fatty acids (SCFAs and biomarkers of gut health using an in vivo model of obesity. Obese diabetic (db/db mice received a supplemented diet with 10% cherry powder (supplemented mice, n = 12 for 12 weeks; obese (n = 10 and lean (n = 10 mice served as controls and received a standard diet without cherry. High-throughput sequencing of the 16S rRNA gene and quantitative real-time PCR (qPCR were used to analyze the gut microbiota; SCFAs and biomarkers of gut health were also measured using standard techniques. According to 16S sequencing, supplemented mice harbored a distinct colonic microbiota characterized by a higher abundance of mucin-degraders (i.e., Akkermansia and fiber-degraders (the S24-7 family as well as lower abundances of Lactobacillus and Enterobacteriaceae. Overall this particular cherry-associated colonic microbiota did not resemble the microbiota in obese or lean controls based on the analysis of weighted and unweighted UniFrac distance metrics. qPCR confirmed some of the results observed in sequencing, thus supporting the notion that cherry supplementation can change the colonic microbiota. Moreover, the SCFAs detected in supplemented mice (caproate, methyl butyrate, propionate, acetate and valerate exceeded those concentrations detected in obese and lean controls except for butyrate. Despite the changes in microbial composition and SCFAs, most of the assessed biomarkers of inflammation, oxidative stress, and intestinal health in colon tissues and mucosal cells were similar in all obese mice with and without supplementation. This paper shows

Gut metabolome meets microbiome

DEFF Research Database (Denmark)

Lamichhane, Santosh; Sen, Partho; Dickens, Alex M

2018-01-01

It is well established that gut microbes and their metabolic products regulate host metabolism. The interactions between the host and its gut microbiota are highly dynamic and complex. In this review we present and discuss the metabolomic strategies to study the gut microbial ecosystem. We...... highlight the metabolic profiling approaches to study faecal samples aimed at deciphering the metabolic product derived from gut microbiota. We also discuss how metabolomics data can be integrated with metagenomics data derived from gut microbiota and how such approaches may lead to better understanding...

Surgical revirgination: Four vaginal mucosal flaps for reconstruction of a hymen

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Hemant A Saraiya

2015-01-01

Full Text Available Introduction: Over centuries, virginity has been given social, religious and moral importance. It is widely believed as a state of a female who has never engaged in sexual intercourse, and her hymen is intact. Hymenoplasty for torn hymen is carried out not only for the sake of cultural and religious traditions but also for the social status and interpersonal relationships. Materials and Methods: 2.5 cm long and 1 cm wide four vaginal mucosal flaps were raised from the anterior vaginal wall just behind labia minora. Two flaps were based proximally, and their two opposing flaps were based distally. These flaps were overlapped in a crisscross fashion and were sutured with 5/0 Polyglactin (Vicryl® sutures leaving no area raw. The donor area was closed primarily. When some remains of a torn hymen were found, one to three vaginal mucosal flaps were added to its remains as per the need for reconstruction. Results: We operated upon 11 patients. In nine cases, the hymen was reconstructed with four flaps. In remaining two, it was reconstructed from the remains using vaginal mucosal flaps. All flaps healed without any infection or disruption. Sutures got absorbed in 25-35 days. In all cases, this newly constructed barrier broke with only moderate pressure at the time of penetrative sex serving the purpose of the surgery completely. Conclusion: Erasing evidence of the sexual history simply by ′Surgical Revirgination′ is extremely important to women contemplating marriage in cultures where a high value is placed on virginity.

Bacteria, phages and pigs: the effects of in-feed antibiotics on the microbiome at different gut locations.

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Looft, Torey; Allen, Heather K; Cantarel, Brandi L; Levine, Uri Y; Bayles, Darrell O; Alt, David P; Henrissat, Bernard; Stanton, Thaddeus B

2014-08-01

Disturbance of the beneficial gut microbial community is a potential collateral effect of antibiotics, which have many uses in animal agriculture (disease treatment or prevention and feed efficiency improvement). Understanding antibiotic effects on bacterial communities at different intestinal locations is essential to realize the full benefits and consequences of in-feed antibiotics. In this study, we defined the lumenal and mucosal bacterial communities from the small intestine (ileum) and large intestine (cecum and colon) plus feces, and characterized the effects of in-feed antibiotics (chlortetracycline, sulfamethazine and penicillin (ASP250)) on these communities. 16S rRNA gene sequence and metagenomic analyses of bacterial membership and functions revealed dramatic differences between small and large intestinal locations, including enrichment of Firmicutes and phage-encoding genes in the ileum. The large intestinal microbiota encoded numerous genes to degrade plant cell wall components, and these genes were lacking in the ileum. The mucosa-associated ileal microbiota harbored greater bacterial diversity than the lumen but similar membership to the mucosa of the large intestine, suggesting that most gut microbes can associate with the mucosa and might serve as an inoculum for the lumen. The collateral effects on the microbiota of antibiotic-fed animals caused divergence from that of control animals, with notable changes being increases in Escherichia coli populations in the ileum, Lachnobacterium spp. in all gut locations, and resistance genes to antibiotics not administered. Characterizing the differential metabolic capacities and response to perturbation at distinct intestinal locations will inform strategies to improve gut health and food safety.

Can the oral microflora affect oral ulcerative mucositis?

NARCIS (Netherlands)

Laheij, A.M.G.A.; de Soet, J.J.

2014-01-01

Purpose of review: Oral mucositis is one of the most prevalent toxicities after hematopoietic stem cell transplantation. Mucositis is initiated by the chemotherapy or radiotherapy preceding the transplantation. It is commonly accepted that microorganisms play a role in the process of oral mucositis.

Proteins and Carbohydrates from Red Seaweeds: Evidence for Beneficial Effects on Gut Function and Microbiota

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Raúl E. Cian

2015-08-01

Full Text Available Based on their composition, marine algae, and namely red seaweeds, are good potential functional foods. Intestinal mucosal barrier function refers to the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules. Here, we will first outline the component of seaweeds and will summarize the effects of these on the regulation of mucosal barrier function. Special attention will be paid to unique components of red seaweeds: proteins and derived peptides (e.g., phycobiliproteins, glycoproteins that contain “cellulose binding domains”, phycolectins and the related mycosporine-like amino acids together with polysaccharides (e.g., floridean starch and sulfated galactans, such as carrageenans, agarans and “dl-hybrid” and minerals. These compounds have been shown to exert prebiotic effects, to regulate intestinal epithelial cell, macrophage and lymphocyte proliferation and differentiation and to modulate the immune response. Molecular mechanisms of action of peptides and polysaccharides are starting to be elucidated, and evidence indicating the involvement of epidermal growth factor receptor (EGFR, insulin-like growth factor receptor (IGFR, Toll-like receptors (TLR and signal transduction pathways mediated by protein kinase B (PKB or AKT, nuclear factor-κB (NF-κB and mitogen activated protein kinases (MAPK will also be summarized. The need for further research is clear, but in vivo experiments point to an overall antiinflammatory effect of these algae, indicating that they can reinforce membrane barrier function.

Review article: the gut microbiome in inflammatory bowel disease-avenues for microbial management.

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McIlroy, J; Ianiro, G; Mukhopadhya, I; Hansen, R; Hold, G L

2018-01-01

The concept of an altered collective gut microbiota rather than identification of a single culprit is possibly the most significant development in inflammatory bowel disease research. We have entered the "omics" era, which now allows us to undertake large-scale/high-throughput microbiota analysis which may well define how we approach diagnosis and treatment of inflammatory bowel disease (IBD) in the future, with a strong steer towards personalised therapeutics. To assess current epidemiological, experimental and clinical evidence of the current status of knowledge relating to the gut microbiome, and its role in IBD, with emphasis on reviewing the evidence relating to microbial therapeutics and future microbiome modulating therapeutics. A Medline search including items 'intestinal microbiota/microbiome', 'inflammatory bowel disease', 'ulcerative colitis', 'Crohn's disease', 'faecal microbial transplantation', 'dietary manipulation' was performed. Disease remission and relapse are associated with microbial changes in both mucosal and luminal samples. In particular, a loss of species richness in Crohn's disease has been widely observed. Existing therapeutic approaches broadly fall into 3 categories, namely: accession, reduction or indirect modulation of the microbiome. In terms of microbial therapeutics, faecal microbial transplantation appears to hold the most promise; however, differences in study design/methodology mean it is currently challenging to elegantly translate results into clinical practice. Existing approaches to modulate the gut microbiome are relatively unrefined. Looking forward, the future of microbiome-modulating therapeutics looks bright with several novel strategies/technologies on the horizon. Taken collectively, it is clear that ignoring the microbiome in IBD is not an option. © 2017 John Wiley & Sons Ltd.

The analysis of bacterial culture in radiation mucositis

International Nuclear Information System (INIS)

Wen Zunbei; Su Deqing; Liang Yuxue

2006-01-01

Objective: To investigate pathogen dose existing or not in patients with radiation mucositis. Methods: From Juanary 2004 to August 2005, from 46 patients with radiation mucositis some pharynx secretion were taken for culture. Then they were treated with antibiotics selected by the cultured results and gargle. Results: 5 patients with grade 0 of radiation mucositis were with no cultured pathogen, and the results of some other patients with radiation mucositis include 8 cases of epiphyte, 1 cases of p. vulgaris and 3 cases of Staphylococcus. the positive rate is 29.2% (12/41); Conclusion: Some patients with radiation mucositis do exist pathogen, and we must slect antibiotics by the bacterial cultured results. (authors)

A human gut phage catalog correlates the gut phageome with type 2 diabetes.

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Ma, Yingfei; You, Xiaoyan; Mai, Guoqin; Tokuyasu, Taku; Liu, Chenli

2018-02-01

Substantial efforts have been made to link the gut bacterial community to many complex human diseases. Nevertheless, the gut phages are often neglected. In this study, we used multiple bioinformatic methods to catalog gut phages from whole-community metagenomic sequencing data of fecal samples collected from both type II diabetes (T2D) patients (n = 71) and normal Chinese adults (n = 74). The definition of phage operational taxonomic units (pOTUs) and identification of large phage scaffolds (n = 2567, ≥ 10 k) revealed a comprehensive human gut phageome with a substantial number of novel sequences encoding genes that were unrelated to those in known phages. Interestingly, we observed a significant increase in the number of gut phages in the T2D group and, in particular, identified 7 pOTUs specific to T2D. This finding was further validated in an independent dataset of 116 T2D and 109 control samples. Co-occurrence/exclusion analysis of the bacterial genera and pOTUs identified a complex core interaction between bacteria and phages in the human gut ecosystem, suggesting that the significant alterations of the gut phageome cannot be explained simply by co-variation with the altered bacterial hosts. Alterations in the gut bacterial community have been linked to the chronic disease T2D, but the role of gut phages therein is not well understood. This is the first study to identify a T2D-specific gut phageome, indicating the existence of other mechanisms that might govern the gut phageome in T2D patients. These findings suggest the importance of the phageome in T2D risk, which warrants further investigation.

Diet, gut microbiota and cognition.

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Proctor, Cicely; Thiennimitr, Parameth; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-02-01

The consumption of a diet high in fat and sugar can lead to the development of obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease and cognitive decline. In the human gut, the trillions of harmless microorganisms harboured in the host's gastrointestinal tract are called the 'gut microbiota'. Consumption of a diet high in fat and sugar changes the healthy microbiota composition which leads to an imbalanced microbial population in the gut, a phenomenon known as "gut dysbiosis". It has been shown that certain types of gut microbiota are linked to the pathogenesis of obesity. In addition, long-term consumption of a high fat diet is associated with cognitive decline. It has recently been proposed that the gut microbiota is part of a mechanistic link between the consumption of a high fat diet and the impaired cognition of an individual, termed "microbiota-gut-brain axis". In this complex relationship between the gut, the brain and the gut microbiota, there are several types of gut microbiota and host mechanisms involved. Most of these mechanisms are still poorly understood. Therefore, this review comprehensively summarizes the current evidence from mainly in vivo (rodent and human) studies of the relationship between diet, gut microbiota and cognition. The possible mechanisms that the diet and the gut microbiota have on cognition are also presented and discussed.

Crosslinking of a Peritrophic Matrix Protein Protects Gut Epithelia from Bacterial Exotoxins

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Shibata, Toshio; Maki, Kouki; Hadano, Jinki; Fujikawa, Takumi; Kitazaki, Kazuki; Koshiba, Takumi; Kawabata, Shun-ichiro

2015-01-01

Transglutaminase (TG) catalyzes protein-protein crosslinking, which has important and diverse roles in vertebrates and invertebrates. Here we demonstrate that Drosophila TG crosslinks drosocrystallin, a peritrophic matrix protein, to form a stable fiber structure on the gut peritrophic matrix. RNA interference (RNAi) of the TG gene was highly lethal in flies and induced apoptosis of gut epithelial cells after oral infection with Pseudomonas entomophila. Moreover, AprA, a metalloprotease secreted by P. entomophila, digested non-crosslinked drosocrystallin fibers, but not drosocrystallin fibers crosslinked by TG. In vitro experiments using recombinant drosocrystallin and monalysin proteins demonstrated that monalysin, a pore-forming exotoxin of P. entomophila, was adsorbed on the crosslinked drosocrystallin fibers in the presence of P. entomophila culture supernatant. In addition, gut-specific TG-RNAi flies had a shorter lifespan than control flies after ingesting P. entomophila, whereas the lifespan after ingesting AprA-knockout P. entomophila was at control levels. We conclude that drosocrystallin fibers crosslinked by TG, but not non-crosslinked drosocrystallin fibers, form an important physical barrier against exotoxins of invading pathogenic microbes. PMID:26506243

Crosslinking of a Peritrophic Matrix Protein Protects Gut Epithelia from Bacterial Exotoxins.

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Toshio Shibata

2015-10-01

Full Text Available Transglutaminase (TG catalyzes protein-protein crosslinking, which has important and diverse roles in vertebrates and invertebrates. Here we demonstrate that Drosophila TG crosslinks drosocrystallin, a peritrophic matrix protein, to form a stable fiber structure on the gut peritrophic matrix. RNA interference (RNAi of the TG gene was highly lethal in flies and induced apoptosis of gut epithelial cells after oral infection with Pseudomonas entomophila. Moreover, AprA, a metalloprotease secreted by P. entomophila, digested non-crosslinked drosocrystallin fibers, but not drosocrystallin fibers crosslinked by TG. In vitro experiments using recombinant drosocrystallin and monalysin proteins demonstrated that monalysin, a pore-forming exotoxin of P. entomophila, was adsorbed on the crosslinked drosocrystallin fibers in the presence of P. entomophila culture supernatant. In addition, gut-specific TG-RNAi flies had a shorter lifespan than control flies after ingesting P. entomophila, whereas the lifespan after ingesting AprA-knockout P. entomophila was at control levels. We conclude that drosocrystallin fibers crosslinked by TG, but not non-crosslinked drosocrystallin fibers, form an important physical barrier against exotoxins of invading pathogenic microbes.

Scoring irradiation mucositis in head and neck cancer patients

International Nuclear Information System (INIS)

Spijkervet, F.K.L.; Panders, A.K.; Saene, H.K.F. van; Vermey, A.; Mehta, D.M.

1989-01-01

Irradiation mucositis is defined as an inflammatory-like process of the oropharyngeal mucosa following therapeutic irradiation of patients who have head and neck cancer. Clinically, it is a serious side effect because severe mucositis can cause generalized problems (weight loss, nasogastic tube feedings) and interferes with the well-being of the patient seriously. Grading mucositis is important for the evaluation of preventive and therapeutic measures. The object of this study was to develop a scoring method based on local mucositis signs only. Four clinical local signs of mucositis were used in this score: white discoloration, erythema, pseudomembranes and ulceration. Mucositis of the oral cavity was calcualted during conventional irradiation protocol for 8 distinguishable areas using the 4 signs and their extent. A prospective evaluation of this method in 15 irradiated head and neck cancer patients displayed an S-curve reflecting a symptomless first irradiation week, followed by a rapid and steady increase of white discoloration, erythema and pseudomembranes during the second and third week. Oral candidiasis, generalized symptoms such as weight loss and the highest mucositis scores were seen after 3 weeks irradiation. The novel mucositis scoring method may be of value in studying the effect of hygiene programs, topical application of disinfectans or antibiotics on oral mucositis. (author)

Scoring irradiation mucositis in head and neck cancer patients

Energy Technology Data Exchange (ETDEWEB)

Spijkervet, F.K.L.; Panders, A.K. (Departments of Oral and Maxillofacial Surgery, University Hospital Groningen (Netherlands)); Saene, H.K.F. van (Medical Microbiology, University of Liverpool (UK)); Vermey, A. (Department of Surgery Oncology Division, University Hospital Groningen (Netherlands)); Mehta, D.M. (Department of Radiotherapy, University Hospital Groningen (Netherlands))

1989-01-01

Irradiation mucositis is defined as an inflammatory-like process of the oropharyngeal mucosa following therapeutic irradiation of patients who have head and neck cancer. Clinically, it is a serious side effect because severe mucositis can cause generalized problems (weight loss, nasogastic tube feedings) and interferes with the well-being of the patient seriously. Grading mucositis is important for the evaluation of preventive and therapeutic measures. The object of this study was to develop a scoring method based on local mucositis signs only. Four clinical local signs of mucositis were used in this score: white discoloration, erythema, pseudomembranes and ulceration. Mucositis of the oral cavity was calcualted during conventional irradiation protocol for 8 distinguishable areas using the 4 signs and their extent. A prospective evaluation of this method in 15 irradiated head and neck cancer patients displayed an S-curve reflecting a symptomless first irradiation week, followed by a rapid and steady increase of white discoloration, erythema and pseudomembranes during the second and third week. Oral candidiasis, generalized symptoms such as weight loss and the highest mucositis scores were seen after 3 weeks irradiation. The novel mucositis scoring method may be of value in studying the effect of hygiene programs, topical application of disinfectans or antibiotics on oral mucositis. (author).

The Overarching Influence of the Gut Microbiome on End-Organ Function: The Role of Live Probiotic Cultures

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Luis Vitetta

2014-09-01

Full Text Available At the time of birth, humans experience an induced pro-inflammatory beneficial event. The mediators of this encouraged activity, is a fleet of bacteria that assault all mucosal surfaces as well as the skin. Thus initiating effects that eventually provide the infant with immune tissue maturation. These effects occur beneath an emergent immune system surveillance and antigenic tolerance capability radar. Over time, continuous and regulated interactions with environmental as well as commensal microbial, viral, and other antigens lead to an adapted and maintained symbiotic state of tolerance, especially in the gastrointestinal tract (GIT the organ site of the largest microbial biomass. However, the perplexing and much debated surprise has been that all microbes need not be targeted for destruction. The advent of sophisticated genomic techniques has led to microbiome studies that have begun to clarify the critical and important biochemical activities that commensal bacteria provide to ensure continued GIT homeostasis. Until recently, the GIT and its associated micro-biometabolome was a neglected factor in chronic disease development and end organ function. A systematic underestimation has been to undervalue the contribution of a persistent GIT dysbiotic (a gut barrier associated abnormality state. Dysbiosis provides a plausible clue as to the origin of systemic metabolic disorders encountered in clinical practice that may explain the epidemic of chronic diseases. Here we further build a hypothesis that posits the role that subtle adverse responses by the GIT microbiome may have in chronic diseases. Environmentally/nutritionally/and gut derived triggers can maintain microbiome perturbations that drive an abnormal overload of dysbiosis. Live probiotic cultures with specific metabolic properties may assist the GIT microbiota and reduce the local metabolic dysfunctions. As such the effect may translate to a useful clinical treatment approach for patients

BISPHOSPHONATE - RELATED MUCOSITIS (BRM: A CASE REPORT

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Pavel Stanimirov

2017-03-01

Full Text Available Bisphosphonates (BPs are the most widely used and effective antiresorptive agents for the treatment of diseases in which there is an increase in osteoclastic resorption, including post-menopausal osteoporosis, Paget’s disease, and tumor-associated osteolysis. Oral and maxillofacial surgeons are well aware of the side effects of bisphosphonates and mainly with bisphosphonate-related osteonecrosis of the jaws (BRONJ. Less known are the mucosal lesions associated with the use of these agents. In the scientific literature, there are only few reports of mucosal lesions due to the direct contact of the oral form of BPs with the mucosa (bisphosphonate-related mucositis. They are mostly related to improper use of bisphosphonate tablets that are chewed, sucked or allowed to melt in the mouth before swallowing. Lesions are atypical and need to be differentiated from other mucosal erosions. We present a case of bisphosphonate-related mucositis due to the improper use of alendronate.

Gut microbiota in chronic kidney disease.

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Cigarran Guldris, Secundino; González Parra, Emilio; Cases Amenós, Aleix

The intestinal microflora maintains a symbiotic relationship with the host under normal conditions, but its imbalance has recently been associated with several diseases. In chronic kidney disease (CKD), dysbiotic intestinal microflora has been reported with an increase in pathogenic flora compared to symbiotic flora. An enhanced permeability of the intestinal barrier, allowing the passage of endotoxins and other bacterial products to the blood, has also been shown in CKD. By fermenting undigested products that reach the colon, the intestinal microflora produce indoles, phenols and amines, among others, that are absorbed by the host, accumulate in CKD and have harmful effects on the body. These gut-derived uraemic toxins and the increased permeability of the intestinal barrier in CKD have been associated with increased inflammation and oxidative stress and have been involved in various CKD-related complications, including cardiovascular disease, anaemia, mineral metabolism disorders or the progression of CKD. The use of prebiotics, probiotics or synbiotics, among other approaches, could improve the dysbiosis and/or the increased permeability of the intestinal barrier in CKD. This article describes the situation of the intestinal microflora in CKD, the alteration of the intestinal barrier and its clinical consequences, the harmful effects of intestinal flora-derived uraemic toxins, and possible therapeutic options to improve this dysbiosis and reduce CKD-related complications. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Molecular players involved in the interaction between beneficial bacteria and the immune system

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Arancha eHevia

2015-11-01

Full Text Available The human gastrointestinal tract is a very complex ecosystem, in which there is a continuous interaction between nutrients, host cells, and microorganisms. The gut microbiota comprises trillions of microbes that have been selected during evolution on the basis of their functionality and capacity to survive in, and adapt to, the intestinal environment. Host bacteria and our immune system constantly sense and react to one another. In this regard, commensal microbes contribute to gut homeostasis, whereas the necessary responses are triggered against enteropathogens. Some representatives of our gut microbiota have beneficial effects on human health. Some of the most important roles of these microbes are to help to maintain the integrity of the mucosal barrier, to provide nutrients such as vitamins, or to protect against pathogens. In addition, the interaction between commensal microbiota and the mucosal immune system is crucial for proper immune function. This process is mainly performed via the pattern recognition receptors of epithelial cells, such as Toll-like or Nod-like receptors, which are able to recognize the molecular effectors that are produced by intestinal microbes. These effectors mediate processes that can ameliorate certain inflammatory gut disorders, discriminate between beneficial and pathogenic bacteria, or increase the number of immune cells or their pattern recognition receptors. This review intends to summarize the molecular players produced by probiotic bacteria, notably Lactobacillus and Bifidobacterium strains, but also other very promising potential probiotics, which affect the human immune system.

A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

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Oosterom, N; Dirks, N F; Heil, S G; de Jonge, R; Tissing, W J E; Pieters, R; van den Heuvel-Eibrink, M M; Heijboer, A C; Pluijm, S M F

2018-06-19

Children with acute lymphoblastic leukemia (ALL) are at increased risk of vitamin D deficiency, which might make them more susceptible to developing adverse events. Previous studies showed that low vitamin D levels were associated with an increased inflammatory mucosal state and impaired mucosal tissue barriers. We examined the prevalence of vitamin D deficiency and studied the association between vitamin D levels and methotrexate (MTX)-induced oral mucositis in pediatric ALL. We assessed 25-hydroxyvitamin D (25(OH)D 3 ) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D 3 ) levels in 99 children with ALL before the start of 4 × 5 g/m 2 high-dose methotrexate (HD-MTX) (T0) and in 81/99 children after discontinuation of HD-MTX (T1). Two cutoff values for vitamin D deficiency exist: 25(OH)D 3 levels D deficiency occurred in respectively 8% ( 4 years of age as compared to children between 1 and 4 years of age. A decrease in 25(OH)D 3 levels during HD-MTX therapy was associated with developing severe oral mucositis (OR 1.6; 95% CI [1.1-2.4]). 25(OH)D 3 and 24,25(OH) 2 D 3 levels at T0 and the change in 24,25(OH) 2 D 3 levels during therapy were not associated with the development of severe oral mucositis. This study showed that vitamin D deficiency occurs frequently in pediatric ALL patients above the age of 4 years. A decrease in 25(OH)D 3 levels during MTX therapy was observed in children with ALL that developed severe oral mucositis.

Enteric glia.

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Rühl, A; Nasser, Y; Sharkey, K A

2004-04-01

The enteric nervous system is composed of both enteric neurones and enteric glia. Enteric glial cells were first described by Dogiel and are now known to outnumber neurones approximately 4 : 1. In the past, these cells were assumed to subserve a largely supportive role; however, recent evidence indicates that enteric glial cells may play a more active role in the control of gut function. In transgenic mouse models, where enteric glial cells are selectively ablated, the loss of glia results in intestinal inflammation and disruption of the epithelial barrier. Enteric glia are activated specifically by inflammatory insults and may contribute actively to inflammatory pathology via antigen presentation and cytokine synthesis. Enteric glia also express receptors for neurotransmitters and so may serve as intermediaries in enteric neurotransmission. Thus, enteric glia may serve as a link between the nervous and immune systems of the gut and may also have an important role in maintaining the integrity of the mucosal barrier and in other aspects of intestinal homeostasis.

Gut Protozoa: Friends or Foes of the Human Gut Microbiota?

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Chabé, Magali; Lokmer, Ana; Ségurel, Laure

2017-12-01

The importance of the gut microbiota for human health has sparked a strong interest in the study of the factors that shape its composition and diversity. Despite the growing evidence suggesting that helminths and protozoa significantly interact with gut bacteria, gut microbiome studies remain mostly focused on prokaryotes and on populations living in industrialized countries that typically have a low parasite burden. We argue that protozoa, like helminths, represent an important factor to take into account when studying the gut microbiome, and that their presence - especially considering their long coevolutionary history with humans - may be beneficial. From this perspective, we examine the relationship between the protozoa and their hosts, as well as their relevance for public health. Copyright © 2017 Elsevier Ltd. All rights reserved.

Commensal Lactobacillus Controls Immune Tolerance during Acute Liver Injury in Mice

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Nobuhiro Nakamoto

2017-10-01

Full Text Available Summary: Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-β through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance. : Nakamoto et.al. find that Lactobacillus accumulates in the gut and activates IL-22 production by innate lymphoid cells during acute liver injury. Gut-derived IL-22 contributes to liver tolerance via induction of regulatory DCs. Keywords: immune tolerance, dendritic cell, innate lymphoid cell, acute liver injury, interleukin-10, interleukin-22, microbiota, dysbiosis

Manipulating the Gut Microbiota: Methods and Challenges.

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Ericsson, Aaron C; Franklin, Craig L

2015-01-01

Eukaryotic organisms are colonized by rich and dynamic communities of microbes, both internally (e.g., in the gastrointestinal and respiratory tracts) and externally (e.g., on skin and external mucosal surfaces). The vast majority of bacterial microbes reside in the lower gastrointestinal (GI) tract, and it is estimated that the gut of a healthy human is home to some 100 trillion bacteria, roughly an order of magnitude greater than the number of host somatic cells. The development of culture-independent methods to characterize the gut microbiota (GM) has spurred a renewed interest in its role in host health and disease. Indeed, associations have been identified between various changes in the composition of the GM and an extensive list of diseases, both enteric and systemic. Animal models provide a means whereby causal relationships between characteristic differences in the GM and diseases or conditions can be formally tested using genetically identical animals in highly controlled environments. Clearly, the GM and its interactions with the host and myriad environmental factors are exceedingly complex, and it is rare that a single microbial taxon associates with, much less causes, a phenotype with perfect sensitivity and specificity. Moreover, while the exact numbers are the subject of debate, it is well recognized that only a minority of gut bacteria can be successfully cultured ex vivo. Thus, to perform studies investigating causal roles of the GM in animal model phenotypes, researchers need clever techniques to experimentally manipulate the GM of animals, and several ingenious methods of doing so have been developed, each providing its own type of information and with its own set of advantages and drawbacks. The current review will focus on the various means of experimentally manipulating the GM of research animals, drawing attention to the factors that would aid a researcher in selecting an experimental approach, and with an emphasis on mice and rats, the

Gut microbiota and obesity.

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Gérard, Philippe

2016-01-01

The human intestine harbors a complex bacterial community called the gut microbiota. This microbiota is specific to each individual despite the existence of several bacterial species shared by the majority of adults. The influence of the gut microbiota in human health and disease has been revealed in the recent years. Particularly, the use of germ-free animals and microbiota transplant showed that the gut microbiota may play a causal role in the development of obesity and associated metabolic disorders, and lead to identification of several mechanisms. In humans, differences in microbiota composition, functional genes and metabolic activities are observed between obese and lean individuals suggesting a contribution of the gut microbiota to these phenotypes. Finally, the evidence linking gut bacteria to host metabolism could allow the development of new therapeutic strategies based on gut microbiota modulation to treat or prevent obesity.

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

NARCIS (Netherlands)

Ijssennagger, Noortje; Belzer, Clara; Hooiveld, Guido J; Dekker, Jan; van Mil, Saskia W C; Müller, Michael; Kleerebezem, Michiel; van der Meer, Roelof; van Mil, SWC

2015-01-01

Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in

SO(10) GUT baryogenesis

International Nuclear Information System (INIS)

Gu Peihong; Sarkar, Utpal

2008-01-01

Baryogenesis, through the decays of heavy bosons, was considered to be one of the major successes of the grand unified theories (GUTs). It was then realized that the sphaleron processes erased any baryon asymmetry from the GUT-baryogenesis at a later stage. In this Letter, we discuss the idea of resurrecting GUT-baryogenesis [M. Fukugita, T. Yanagida, Phys. Rev. Lett. 89 (2002) 131602] in a large class of SO(10) GUTs. Our analysis shows that fast lepton number violating but baryon number conserving processes can partially wash out the GUT-baryogenesis produced lepton and/or baryon asymmetry associated with or without the sphaleron and/or Yukawa interactions

Inside the mucosal immune system.

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Jerry R McGhee

Full Text Available An intricate network of innate and immune cells and their derived mediators function in unison to protect us from toxic elements and infectious microbial diseases that are encountered in our environment. This vast network operates efficiently by use of a single cell epithelium in, for example, the gastrointestinal (GI and upper respiratory (UR tracts, fortified by adjoining cells and lymphoid tissues that protect its integrity. Perturbations certainly occur, sometimes resulting in inflammatory diseases or infections that can be debilitating and life threatening. For example, allergies in the eyes, skin, nose, and the UR or digestive tracts are common. Likewise, genetic background and environmental microbial encounters can lead to inflammatory bowel diseases (IBDs. This mucosal immune system (MIS in both health and disease is currently under intense investigation worldwide by scientists with diverse expertise and interests. Despite this activity, there are numerous questions remaining that will require detailed answers in order to use the MIS to our advantage. In this issue of PLOS Biology, a research article describes a multi-scale in vivo systems approach to determine precisely how the gut epithelium responds to an inflammatory cytokine, tumor necrosis factor-alpha (TNF-α, given by the intravenous route. This article reveals a previously unknown pathway in which several cell types and their secreted mediators work in unison to prevent epithelial cell death in the mouse small intestine. The results of this interesting study illustrate how in vivo systems biology approaches can be used to unravel the complex mechanisms used to protect the host from its environment.

Novel approach to gastric mucosal defect repair using fresh amniotic membrane allograft in dogs (experimental study).

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Farghali, Haithem A; AbdElKader, Naglaa A; Khattab, Marwa S; AbuBakr, Huda O

2017-10-18

-epithelial, epithelial, and post-epithelial normal gastric mucosal barriers.

Surgical outcome in headache due to mucosal contact

International Nuclear Information System (INIS)

Goto, Fumiyuki; Yabe, Haruna; Ogawa, Kaoru

2010-01-01

Headaches is classified as primary and secondary, with secondary originating in head and neck conditions, the most important etiology being acute sinusitis. Headache due to mucosal contact, rarely encountered by otorhinolaryngologists, is an important secondary headache, whose criteria are defined by the International Classification of Headache Disorders to include intermittent pain localized in the periorbital and medial canthal or temporozygomatic regions, evidence that pain is attributable to mucosal contact and the presence of mucosal contact in the absence of acute rhinosinusitis, obtained using clinical examinations, nasal endoscopy, and/or computed tomography (CT). After mucosal contact is surgically corrected pain usually disappears permanently within 7 days. We reviewed mucosal contact headaches in 63 subjects undergoing nasal or paranasal surgery from April 2007 to March 2008. Of those 7 were diagnosed with headaches due to contact points in nasal mucosa, ranging from canthal to the temporozygomatic. The most common contact, between the middle turbinate and nasal septum, was seen in 6 of the 7. Surgery eliminated symptoms in 4 and ameliorated them in 3 indicating effective headache management. Subjects with severe headaches or localized periorbital and medial canthal pain regions, mucosal contact involvement is ruled out when CT allows no lesions. When mucosal contact headache is suspected, however surgery should be considered as a last resort. (author)

Infectious bursal disease virus infection leads to changes in the gut associated-lymphoid tissue and the microbiota composition.

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Li, Li; Kubasová, Tereza; Rychlik, Ivan; Hoerr, Frederic J; Rautenschlein, Silke

2018-01-01

Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive poultry disease. IBD virus (IBDV) is the causative agent, which may lead to high morbidity and mortality rates in susceptible birds. IBDV-pathogenesis studies have focused mainly on primary lymphoid organs. It is not known if IBDV infection may modify the development of the gut associated lymphoid tissues (GALT) as well as the microbiota composition. The aim of the present study was to investigate the effects of IBDV-infection on the bursa of Fabricius (BF), caecal tonsils (CT) and caecum, and to determine the effects on the gut microbiota composition in the caecum. Commercial broiler chickens were inoculated with a very virulent (vv) strain of IBDV at 14 (Experiment 2) or 15 (Experiment 1) days post hatch (dph). Virus replication, lesion development, immune parameters including numbers of T and B lymphocytes, macrophages, as well as the gut microbiota composition were compared between groups. Rapid IBDV-replication was detected in the BF, CT and caecum. It was accompanied by histological lesions including an infiltration of heterophils. In addition a significant reduction in the total mucosal thickness of the caecum was observed in vvIBDV-infected birds compared to virus-free controls (P < 0.05). vvIBDV infection also led to an increase in T lymphocyte numbers and macrophages, as well as a decrease in the number of B lymphocytes in the lamina propria of the caecum, and in the caecal tonsils. Illumina sequencing analysis indicated that vvIBDV infection also induced changes in the abundance of Clostridium XIVa and Faecalibacterium over time. Overall, our results suggested that vvIBDV infection had a significant impact on the GALT and led to a modulation of gut microbiota composition, which may lead to a higher susceptibility of affected birds for pathogens invading through the gut.

Infectious bursal disease virus infection leads to changes in the gut associated-lymphoid tissue and the microbiota composition.

Directory of Open Access Journals (Sweden)

Li Li

Full Text Available Infectious bursal disease (IBD is an acute, highly contagious and immunosuppressive poultry disease. IBD virus (IBDV is the causative agent, which may lead to high morbidity and mortality rates in susceptible birds. IBDV-pathogenesis studies have focused mainly on primary lymphoid organs. It is not known if IBDV infection may modify the development of the gut associated lymphoid tissues (GALT as well as the microbiota composition. The aim of the present study was to investigate the effects of IBDV-infection on the bursa of Fabricius (BF, caecal tonsils (CT and caecum, and to determine the effects on the gut microbiota composition in the caecum. Commercial broiler chickens were inoculated with a very virulent (vv strain of IBDV at 14 (Experiment 2 or 15 (Experiment 1 days post hatch (dph. Virus replication, lesion development, immune parameters including numbers of T and B lymphocytes, macrophages, as well as the gut microbiota composition were compared between groups. Rapid IBDV-replication was detected in the BF, CT and caecum. It was accompanied by histological lesions including an infiltration of heterophils. In addition a significant reduction in the total mucosal thickness of the caecum was observed in vvIBDV-infected birds compared to virus-free controls (P < 0.05. vvIBDV infection also led to an increase in T lymphocyte numbers and macrophages, as well as a decrease in the number of B lymphocytes in the lamina propria of the caecum, and in the caecal tonsils. Illumina sequencing analysis indicated that vvIBDV infection also induced changes in the abundance of Clostridium XIVa and Faecalibacterium over time. Overall, our results suggested that vvIBDV infection had a significant impact on the GALT and led to a modulation of gut microbiota composition, which may lead to a higher susceptibility of affected birds for pathogens invading through the gut.

[Protective effect of Saccharomyces boulardii against intestinal mucosal barrier injury in rats with nonalcoholic fatty liver disease].

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Liu, Y T; Li, Y Q; Wang, Y Z

2016-12-20

Objective: To investigate the protective effect of Saccharomyces boulardii against intestinal mucosal barrier injury in rats with nonalcoholic fatty liver disease (NAFLD). Methods: A total of 36 healthy male Sprague-Dawley rats with a mean body weight of 180±20 g were randomly divided into control group, model group, and treatment group, with 12 rats in each group, after adaptive feeding for 1 week. The rats in the control group were given basic feed, and those in the model group and treatment group were given high-fat feed. After 12 weeks of feeding, the treatment group was given Saccharomyces boulardii (75×10 8 CFU/kg/d) by gavage, and those in the control group and model group were given isotonic saline by gavage. At the 20th week, blood samples were taken from the abdominal aorta to measure the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), intestinal fatty acid binding protein (IFABP), tumor necrosis factor-α (TNF-α), and endotoxins. The liver pathological changes, intestinal histopathological changes, and expression of occludin in the intestinal mucosa were observed. Fecal samples were collected to measure the changes in Escherichia coli and Bacteroides. A one-way analysis of variance and the SNK test were used for comparison between multiple groups, and the rank sum test was used as the non-parametric test. Results: Compared with the control group, the model group had significantly higher body weight, liver mass, and liver index ( P 0.05). Compared with the control group, the model group had significant increases in the levels of endotoxin, TNF-α, and IFABP ( P Saccharomyces boulardii can reduce body weight and improve hepatocyte steatosis. Saccharomyces boulardii can reduce endotoxemia in NAFLD rats and thus alleviate inflammatory response. Saccharomyces boulardii can also adjust the proportion of Escherichia coli and Bacteroides in the intestine of NAFLD rats.

Melatonin plays a protective role in postburn rodent gut pathophysiology.

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Al-Ghoul, Walid M; Abu-Shaqra, Steven; Park, Byeong Gyu; Fazal, Nadeem

2010-05-17

supplementation on postburn gut mucosa barrier inflammatory profiles. Here, our results revealed that daily postburn intraperitoneal melatonin administration at a dose of 1.86 mg/kg (8 micromole/kg) significantly suppressed both neutrophil infiltration and tyrosine nitrosylation as revealed by Gr-1 and nitrotyrosine immunohistochemistry, respectively. In conclusion, our results provide support for high mesenteric melatonin levels and dynamic de novo gut melatonin production, both of which increase endogenously in response to major thermal injury, but appear to fall short of abrogating the excessive postburn hyper-inflammation. Moreover, supplementation by exogenous melatonin significantly suppresses gut inflammation, thus confirming that melatonin is protective against postburn inflammation.

Probiotics in critically ill children [version 1; referees: 2 approved

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Sunit C. Singhi

2016-03-01

Full Text Available Gut microflora contribute greatly to immune and nutritive functions and act as a physical barrier against pathogenic organisms across the gut mucosa. Critical illness disrupts the balance between host and gut microflora, facilitating colonization, overgrowth, and translocation of pathogens and microbial products across intestinal mucosal barrier and causing systemic inflammatory response syndrome and sepsis. Commonly used probiotics, which have been developed from organisms that form gut microbiota, singly or in combination, can restore gut microflora and offer the benefits similar to those offered by normal gut flora, namely immune enhancement, improved barrier function of the gastrointestinal tract (GIT, and prevention of bacterial translocation. Enteral supplementation of probiotic strains containing either Lactobacillus alone or in combination with Bifidobacterium reduced the incidence and severity of necrotizing enterocolitis and all-cause mortality in preterm infants. Orally administered Lactobacillus casei subspecies rhamnosus, Lactobacillus reuteri, and Lactobacillus rhamnosus were effective in the prevention of late-onset sepsis and GIT colonization by Candida in preterm very low birth weight infants. In critically ill children, probiotics are effective in the prevention and treatment of antibiotic-associated diarrhea. Oral administration of a mix of probiotics for 1 week to children on broad-spectrum antibiotics in a pediatric intensive care unit decreased GIT colonization by Candida, led to a 50% reduction in candiduria, and showed a trend toward decreased incidence of candidemia. However, routine use of probiotics cannot be supported on the basis of current scientific evidence. Safety of probiotics is also a concern; rarely, probiotics may cause bacteremia, fungemia, and sepsis in immunocompromised critically ill children. More studies are needed to answer questions on the effectiveness of a mix versus single-strain probiotics

SUSY GUT Model Building

International Nuclear Information System (INIS)

Raby, Stuart

2008-01-01

In this talk I discuss the evolution of SUSY GUT model building as I see it. Starting with 4 dimensional model building, I then consider orbifold GUTs in 5 dimensions and finally orbifold GUTs embedded into the E 8 xE 8 heterotic string.

The postnatal development of the mucosal immune system and mucosal tolerance in domestic animals

OpenAIRE

Bailey , Mick; Haverson , Karin

2006-01-01

International audience; The mucosal immune system is exposed to a range of antigens associated with pathogens, to which it must mount active immune responses. However, it is also exposed to a large number of harmless antigens associated with food and with commensal microbial flora, to which expression of active, inflammatory immune responses to these antigens is undesirable. The mucosal immune system must contain machinery capable of evaluating the antigens to which it is exposed and mounting...

Human Circulating Antibody-Producing B Cell as a Predictive Measure of Mucosal Immunity to Poliovirus.

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Dey, Ayan; Molodecky, Natalie A; Verma, Harish; Sharma, Prashant; Yang, Jae Seung; Saletti, Giulietta; Ahmad, Mohammad; Bahl, Sunil K; Wierzba, Thomas F; Nandy, Ranjan K; Deshpande, Jagadish M; Sutter, Roland W; Czerkinsky, Cecil

2016-01-01

The "gold standard" for assessing mucosal immunity after vaccination with poliovirus vaccines consists in measuring virus excretion in stool after challenge with oral poliovirus vaccine (OPV). This testing is time and resource intensive, and development of alternative methods is a priority for accelerating polio eradication. We therefore evaluated circulating antibody-secreting cells (ASCs) as a potential means to evaluate mucosal immunity to poliovirus vaccine. 199 subjects, aged 10 years, and previously immunized repeatedly with OPV, were selected. Subjects were assigned to receive either a booster dose of inactivated poliovirus vaccine (IPV), bivalent OPV (bOPV), or no vaccine. Using a micro-modified whole blood-based ELISPOT assay designed for field setting, circulating poliovirus type-specific IgA- and IgG-ASCs, including gut homing α4β7+ ASCs, were enumerated on days 0 and 7 after booster immunization. In addition, serum samples collected on days 0, 28 and 56 were tested for neutralizing antibody titers against poliovirus types 1, 2, and 3. Stool specimens were collected on day 28 (day of bOPV challenge), and on days 31, 35 and 42 and processed for poliovirus isolation. An IPV dose elicited blood IgA- and IgG-ASC responses in 84.8 to 94.9% of subjects, respectively. In comparison, a bOPV dose evoked corresponding blood ASC responses in 20.0 to 48.6% of subjects. A significant association was found between IgA- and IgG-ASC responses and serum neutralizing antibody titers for poliovirus type 1, 2, 3 (ppoliovirus types 1, 2 and 3 was 62.7%, 89.8% and 45.8%, respectively. A significant association was observed between virus excretion and α4β7+ IgA- and/or IgG-ASC responses to poliovirus type 3 among immunized children; however, only a weak association was found for type 1 poliovirus. Our results suggest that virus-specific blood ASCs, especially for type 3 poliovirus, can serve as surrogate of mucosal immunity after vaccination. Further studies are needed to

Investigation of Effect of Nutritional Drink on Chemotherapy-Induced Mucosal Injury and Tumor Growth in an Established Animal Model

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Eduardo Schiffrin

2013-09-01

Full Text Available Chemotherapy-induced mucositis represents a significant burden to quality of life and healthcare costs, and may be improved through enhanced nutritional status. We first determined the safety of two nutritional drinks (plus placebo, and then potential gut protection in tumor-bearing rats in a model of methotrexate-induced mucositis. In study 1, animals were fed one of two test diets (or placebo or control chow pellets for a total of 60 days and were monitored daily. All diets were found to be safe to administer. In study 2, after seven days of receiving diets, a Dark Agouti Mammary Adenocarcinoma (DAMA was transplanted subcutaneously. Ten days after starting diets, animals had 2 mg/kg intramuscular methotrexate administered on two consecutive days; after this time, all animals were given soaked chow. Animals were monitored daily for changes in bodyweight, tumor burden and general health. Animals were killed 10, 12 and 16 days after initially starting diets, and tissues were collected at necropsy. In study 1, animals receiving diets had gained 0.8% and 10.8% of their starting bodyweight after 60 days, placebo animals 4.4%, and animals fed on standard chow had gained 15.1%. In study 2, there was no significant influence of test diet on bodyweight, organ weight, tumor burden or biochemical parameters. Only animals treated with MTX exhibited diarrhea, although animals receiving Diet A and Diet C showed a non-significant increase in incidence of diarrhea. Administration of these nutritional drinks did not improve symptoms of mucositis.

Gut transport characteristics in herbivorous and carnivorous serrasalmid fish from ion-poor Rio Negro water.

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Pelster, Bernd; Wood, Chris M; Speers-Roesch, Ben; Driedzic, William R; Almeida-Val, Vera; Val, Adalberto

2015-02-01

Three closely related characids, Tambaqui (omnivore), black Piranha (carnivore), and Pacu (herbivore), all Serrasalmidae, inhabit the ion-poor, acidic Rio Negro. We compared O2-consumption and N excretion rates in vivo, and sodium, chloride, glucose, and ammonia transport characteristics of gut sac preparations in vitro. The Pacu had a significantly higher weight-specific oxygen consumption, and a lower N/Q ratio than the omnivorous Tambaqui, and a significantly lower urea-N excretion rate than the carnivorous black Piranha, suggesting N-limitation in the herbivorous Pacu. With a value of 2.62 ± 0.15, gut to fork length ratio in the Pacu was about 2.5 times higher than in the black Piranha, and 2.0 times higher than in the Tambaqui. Anterior intestinal activities of three enzymes involved in N-fixation for amino acid synthesis (glutamate dehydrogenase, glutamate-oxaloacetate transferase, and glutamate-pyruvate transferase) were generally greatest in the carnivore and lowest in the herbivore species. In all three species, sodium, chloride, glucose, and ammonia were taken up at high rates from the intestine, resulting in an isosmotic fluid flux. Comparing the area-specific fluid flux of the anterior, mid, and posterior gut sections, no difference was detected between the three sections of the Pacu, while in the Tambaqui, it was highest in the anterior section, and in the black Piranha highest in the middle section. Overall, the area-specific uptake rates for sodium, chloride, glucose, and ammonia of anterior, mid, and posterior sections were similar in all three species, indicating that there is no difference in the area-specific transport rates associated with trophic position. The net ammonia uptake flux from gut interior was not significantly different from the net ammonia efflux to the serosal fluid, so that the ammonia removed from the intestine by the mucosal epithelium was quantitatively transferred through the tissue to the serosal side in all three

Faecalibacterium prausnitzii subspecies-level dysbiosis in the human gut microbiome underlying atopic dermatitis.

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Song, Han; Yoo, Young; Hwang, Junghyun; Na, Yun-Cheol; Kim, Heenam Stanley

2016-03-01

Atopic dermatitis (AD) is a serious global epidemic associated with a modern lifestyle. Although aberrant interactions between gut microbes and the intestinal immune system have been implicated in this skin disease, the nature of the microbiome dysfunction underlying the disease remains unclear. The gut microbiome from 132 subjects, including 90 patients with AD, was analyzed by using 16S rRNA gene and metagenome sequence analyses. Reference genomes from the Human Microbiome Project and the KEGG Orthology database were used for metagenome analyses. Short-chain fatty acids in fecal samples were compared by using gas chromatographic-mass spectrometric analyses. We show that enrichment of a subspecies of the major gut species Faecalibacterium prausnitzii is strongly associated with AD. In addition, the AD microbiome was enriched in genes encoding the use of various nutrients that could be released from damaged gut epithelium, reflecting a bloom of auxotrophic bacteria. Fecal samples from patients with AD showed decreased levels of butyrate and propionate, which have anti-inflammatory effects. This is likely a consequence of an intraspecies compositional change in F prausnitzii that reduces the number of high butyrate and propionate producers, including those related to the strain A2-165, a lack of which has been implicated in patients with Crohn disease. The data suggest that feedback interactions between dysbiosis in F prausnitzii and dysregulation of gut epithelial inflammation might underlie the chronic progression of AD by resulting in impairment of the gut epithelial barrier, which ultimately leads to aberrant TH2-type immune responses to allergens in the skin. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Consequences of bisphenol a perinatal exposure on immune responses and gut barrier function in mice.

Science.gov (United States)

Malaisé, Yann; Ménard, Sandrine; Cartier, Christel; Lencina, Corinne; Sommer, Caroline; Gaultier, Eric; Houdeau, Eric; Guzylack-Piriou, Laurence

2018-01-01

The potent immunomodulatory effect of the endocrine disruptor bisphenol A during development and consequences during life span are of increasing concern. Particular interests have been raised from animal studies regarding the risk of developing food intolerance and infection. We aimed to identify immune disorders in mice triggered by perinatal exposure to bisphenol A. Gravid mice were orally exposed to bisphenol (50 μg/kg body weight/day) from day 15 of pregnancy until weaning. Gut barrier function, local and systemic immunity were assessed in adult female offspring. Mice perinatally exposed to bisphenol showed a decrease in ileal lysozyme expression and a fall of fecal antimicrobial activity. In offspring mice exposed to bisphenol, an increase in colonic permeability was observed associated with an increase in interferon-γ level and a drop of colonic IgA + cells and fecal IgA production. Interestingly, altered frequency of innate lymphoid cells type 3 occurred in the small intestine, with an increase in IgG response against commensal bacteria in sera. These effects were related to a defect in dendritic cell maturation in the lamina propria and spleen. Activated and regulatory T cells were decreased in the lamina propria. Furthermore, perinatal exposure to bisphenol promoted a sharp increase in interferon-γ and interleukin-17 production in the intestine and elicited a T helper 17 profile in the spleen. To conclude, perinatal exposure to bisphenol weakens protective and regulatory immune functions in the intestine and at systemic level in adult offspring. The increased susceptibility to inflammatory response is an interesting lead supporting bisphenol-mediated adverse consequences on food reactions and infections.

Evidence for a common mucosal immune system in the pig.

Science.gov (United States)

Wilson, Heather L; Obradovic, Milan R

2015-07-01

The majority of lymphocytes activated at mucosal sites receive instructions to home back to the local mucosa, but a portion also seed distal mucosa sites. By seeding distal sites with antigen-specific effector or memory lymphocytes, the foundation is laid for the animal's mucosal immune system to respond with a secondary response should to this antigen be encountered at this site in the future. The common mucosal immune system has been studied quite extensively in rodent models but less so in large animal models such as the pig. Reasons for this paucity of reported induction of the common mucosal immune system in this species may be that distal mucosal sites were examined but no induction was observed and therefore it was not reported. However, we suspect that the majority of investigators simply did not sample distal mucosal sites and therefore there is little evidence of immune response induction in the literature. It is our hope that more pig immunologists and infectious disease experts who perform mucosal immunizations or inoculations on pigs will sample distal mucosal sites and report their findings, whether results are positive or negative. In this review, we highlight papers that show that immunization/inoculation using one route triggers mucosal immune system induction locally, systemically, and within at least one distal mucosal site. Only by understanding whether immunizations at one site triggers immunity throughout the common mucosal immune system can we rationally develop vaccines for the pig, and through these works we can gather evidence about the mucosal immune system that may be extrapolated to other livestock species or humans. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sucralfate for the treatment of radiation induced mucositis

International Nuclear Information System (INIS)

Belka, C.; Hoffmann, W.; Paulsen, F.; Bamberg, M.

1997-01-01

Purpose: Radiotherapy, a cornerstone in the management of head and neck cancer, pelvic cancer, and esophageal cancer is associated with a marked mucosal toxicity. Pain, malnutrition and diarrhea are the most prevalent clinical symptoms of radiation induced mucosal damage. Because there is no known way to obviate radiation mucositis all efforts to prevent aggravation and accelerate healing of mucosal changes are of great importance. Numerous agents including antimicrobials, local and systemic analgesics, antiinflammatory drugs, antidiarrheal drugs, in combination with intensive dietetic care are used to relieve symptoms. Recently coating agents like the polyaluminum-sucrose complex sucralfate were suggested for the prevention and treatment of mucosal reactions. Since sucralfate protects ulcerated epithelium by coating, liberates protective prostaglandins and increases the local availability of protective factors this drug might directly interact with the pathogenesis of mucositis. Patients and Method: The results of available studies are analysed and discussed. Results: The results of several studies indicate that sucralfate treatment especially during radiotherapy for pelvic cancer leads to a significant amelioration of clinical symptoms and morphological changes. An application of sucralfate during radiotherapy of head and neck cancer reveals only limited benefits in most studies performed. Conclusion: Nevertheless sucralfate is a save, cheap and active drug for the prevention and treatment of radiation mucositis especially in patients with pelvic irradiation. (orig.) [de

The pathophysiology of necrotizing enterocolitis in preterm infants : New insights in the interaction between the gut and its microbiota

NARCIS (Netherlands)

Heida, Fardou Hadewych

2016-01-01

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disorder affecting the preterm infant. The underlying cause of NEC is partly unknown. This thesis studied the gut flora, the intestinal barrier function, and the intestinal bloodcirculation contributing to NEC. We observed NEC-associated

Proton pump inhibitors alter the composition of the gut microbiota.

Science.gov (United States)

Jackson, Matthew A; Goodrich, Julia K; Maxan, Maria-Emanuela; Freedberg, Daniel E; Abrams, Julian A; Poole, Angela C; Sutter, Jessica L; Welter, Daphne; Ley, Ruth E; Bell, Jordana T; Spector, Tim D; Steves, Claire J

2016-05-01

Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation.

Science.gov (United States)

Sung, Lillian; Robinson, Paula; Treister, Nathaniel; Baggott, Tina; Gibson, Paul; Tissing, Wim; Wiernikowski, John; Brinklow, Jennifer; Dupuis, L Lee

2017-03-01

To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0-18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Cutaneous and mucosal pain syndromes

Directory of Open Access Journals (Sweden)

Siddappa K

2002-01-01

Full Text Available The cutaneous and mucosal pain syndromes are characterized by pain, burning sensation, numbness or paraesthesia of a particular part of the skin or mucosal surface without any visible signs. They are usually sensory disorders, sometimes with a great deal of psychologic overlay. In this article various conditions have been listed and are described. The possible causative mechanisms are discussed when they are applicable and the outline of their management is described.

Gut microbiome and bone.

Science.gov (United States)

Ibáñez, Lidia; Rouleau, Matthieu; Wakkach, Abdelilah; Blin-Wakkach, Claudine

2018-04-11

The gut microbiome is now viewed as a tissue that interacts bidirectionally with the gastrointestinal, immune, endocrine and nervous systems, affecting the cellular responses in numerous organs. Evidence is accumulating of gut microbiome involvement in a growing number of pathophysiological processes, many of which are linked to inflammatory responses. More specifically, data acquired over the last decade point to effects of the gut microbiome on bone mass regulation and on the development of bone diseases (such as osteoporosis) and of inflammatory joint diseases characterized by bone loss. Mice lacking a gut microbiome have bone mass alteration that can be reversed by gut recolonization. Changes in the gut microbiome composition have been reported in mice with estrogen-deficiency osteoporosis and have also been found in a few studies in humans. Probiotic therapy decreases bone loss in estrogen-deficient animals. The effect of the gut microbiome on bone tissue involves complex mechanisms including modulation of CD4 + T cell activation, control of osteoclastogenic cytokine production and modifications in hormone levels. This complexity may contribute to explain the discrepancies observed betwwen some studies whose results vary depending on the age, gender, genetic background and treatment duration. Further elucidation of the mechanisms involved is needed. However, the available data hold promise that gut microbiome manipulation may prove of interest in the management of bone diseases. Copyright © 2018 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Radiation and Gut

International Nuclear Information System (INIS)

Potten, C.S.; Hendry, J.H.

1995-08-01

Texts on gut with reference to radiation (or other cytotoxic and carcinogenic agents) consist of primary research papers, review articles, or books which are now very out-of-date. With this in mind, the present book was conceived. Here, with chapters by experts in the field, we cover the basic structure and cell replacement process in the gut, the physical situation relevant for gut radiation exposure and a description of some of the techniques used to study radiation effects, in particular the clonal regeneration assay that assesses stem cell functional capacity. Chapters comprehensively cover the effects of radiation in experimental animal model systems and clinical experiences. The effects of radiation on the supportive tissue of the gut is also reviewed. The special radiation situation involving ingested radionuclides is reviewed and the most important late response-carcinogenesis-within the gut is considered. This book follows a volume on 'Radiation and Skin' (1985) and another on 'Radiation and Bone Marrow' is in preparation. The present volume is intended to cover the anatomy and renewal characteristics of the gut, and its response in terms of carcinogenicity and tissue injury in mammalian species including in particular man. The book is expected to be useful to students and teachers in these topics, as well as clinical oncologists (radiotherapists) and medical oncologists, and industrial health personnel. 70 figs., 20 tabs., 869 refs

Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease.

Directory of Open Access Journals (Sweden)

Gideon Steinbach

Full Text Available Severe intestinal graft-vs-host disease (GVHD after allogeneic hematopoietic cell transplantation (HCT causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3, would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3 in the duodenum or colon. We observed that 8 of 12 patients (67% had a complete remission (CR of GVHD and survived more than 1 year (median 5 years when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80% had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with

Comparative gut physiology symposium: The microbe-gut-brain axis

Science.gov (United States)

The Comparative Gut Physiology Symposium titled “The Microbe-Gut-Brain Axis” was held at the Joint Annual Meeting of the American Society of Animal Science and the American Dairy Science Association on Thursday, July 21, 2016, in Salt Lake City Utah. The goal of the symposium was to present basic r...

Effect of Antibiotics on Gut Microbiota, Gut Hormones and Glucose Metabolism

DEFF Research Database (Denmark)

Mikkelsen, Kristian H; Frost, Morten; Bahl, Martin Iain

2015-01-01

The gut microbiota has been designated as an active regulator of glucose metabolism and metabolic phenotype in a number of animal and human observational studies. We evaluated the effect of removing as many bacteria as possible by antibiotics on postprandial physiology in healthy humans. Meal tests...... tolerance, insulin secretion or plasma lipid concentrations were found. Apart from an acute and reversible increase in peptide YY secretion, no changes were observed in postprandial gut hormone release. As evaluated by selective cultivation of gut bacteria, a broad-spectrum 4-day antibiotics course...... with vancomycin, gentamycin and meropenem induced shifts in gut microbiota composition that had no clinically relevant short or long-term effects on metabolic variables in healthy glucose-tolerant males. clinicaltrials.gov NCT01633762....

White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate.

Science.gov (United States)

Monk, Jennifer M; Zhang, Claire P; Wu, Wenqing; Zarepoor, Leila; Lu, Jenifer T; Liu, Ronghua; Pauls, K Peter; Wood, Geoffrey A; Tsao, Rong; Robinson, Lindsay E; Power, Krista A

2015-07-01

Common beans are a rich source of nondigestible fermentable components and phenolic compounds that have anti-inflammatory effects. We assessed the gut-health-promoting potential of kidney beans in healthy mice and their ability to attenuate colonic inflammation following dextran sodium sulphate (DSS) exposure (via drinking water, 2% DSS w/v, 7 days). C57BL/6 mice were fed one of three isocaloric diets: basal diet control (BD), or BD supplemented with 20% cooked white (WK) or dark red kidney (DK) bean flour for 3 weeks. In healthy mice, anti-inflammatory microbial-derived cecal short chain fatty acid (SCFA) levels (acetate, butyrate and propionate), colon crypt height and colonic Mucin 1 (MUC1) and Resistin-like Molecule beta (Relmβ) mRNA expression all increased in WK- and DK-fed mice compared to BD, indicative of enhanced microbial activity, gut barrier integrity and antimicrobial defense response. During colitis, both bean diets reduced (a) disease severity, (b) colonic histological damage and (c) increased mRNA expression of antimicrobial and barrier integrity-promoting genes (Toll-like Receptor 4 (TLR4), MUC1-3, Relmβ and Trefoil Factor 3 (TFF3)) and reduced proinflammatory mediator expression [interleukin (IL)-1β, IL-6, interferon (IFN)γ, tumor necrosis factor (TNF)α and monocyte chemoattractant protein-1], which correlated with reduced colon tissue protein levels. Further, bean diets exerted a systemic anti-inflammatory effect during colitis by reducing serum levels of IL-17A, IFNγ, TNFα, IL-1β and IL-6. In conclusion, both WK and DK bean-supplemented diets enhanced microbial-derived SCFA metabolite production, gut barrier integrity and the microbial defensive response in the healthy colon, which supported an anti-inflammatory phenotype during colitis. Collectively, these data demonstrate a beneficial colon-function priming effect of bean consumption that mitigates colitis severity. Crown Copyright © 2015. Published by Elsevier Inc. All rights

Management of mucositis in oral irradiation

Energy Technology Data Exchange (ETDEWEB)

Feber, T. [Cookridge Hospital, Leeds (United Kingdom)

1996-10-01

Mucositis significantly affects quality of life and tolerance of treatment in oral irradiation. Effective management of this complication is therefore very important. However, there is a scarcity of up-to-date oral care protocols, with most centres using ritualized regimens. The literature on oral rinses in radiation mucositis is at best inconclusive and at worst confusing. In this study, patients undergoing radical radiotherapy treatment (55-60 Gy in 4 weeks) to more than 50% of the oral cavity and oropharynx were randomized to a research based oral care protocol with either saline 0.9% or hydrogen peroxide 3.5 volumes (HP) as rinses. The results of this study show that, on average, the group receiving saline rinses appeared to do better on some outcomes than the group receiving HP. This suggests that frequent mechanical cleansing of the mouth may be more important than the antiseptic properties of a mouthwash. Antiseptic mouthwashes may be contra-indicated in radiation mucositis. In order to determine best practice in mucositis management, multicentre, multidisciplinary trials should be conducted. (Author).

Management of mucositis in oral irradiation

International Nuclear Information System (INIS)

Feber, T.

1996-01-01

Mucositis significantly affects quality of life and tolerance of treatment in oral irradiation. Effective management of this complication is therefore very important. However, there is a scarcity of up-to-date oral care protocols, with most centres using ritualized regimens. The literature on oral rinses in radiation mucositis is at best inconclusive and at worst confusing. In this study, patients undergoing radical radiotherapy treatment (55-60 Gy in 4 weeks) to more than 50% of the oral cavity and oropharynx were randomized to a research based oral care protocol with either saline 0.9% or hydrogen peroxide 3.5 volumes (HP) as rinses. The results of this study show that, on average, the group receiving saline rinses appeared to do better on some outcomes than the group receiving HP. This suggests that frequent mechanical cleansing of the mouth may be more important than the antiseptic properties of a mouthwash. Antiseptic mouthwashes may be contra-indicated in radiation mucositis. In order to determine best practice in mucositis management, multicentre, multidisciplinary trials should be conducted. (Author)

Allopurinol gel mitigates radiation-induced mucositis and dermatitis

International Nuclear Information System (INIS)

Kitagawa, Junichi; Nasu, Masanori; Okumura, Hayato; Matsumoto, Shigeji; Shibata, Akihiko; Makino, Kimiko; Terada, Hiroshi

2008-01-01

It has not been verified whether allopurinol application is beneficial in decreasing the severity of radiation-induced oral mucositis and dermatitis. Rats were divided into 4 groups and received 15 Gy irradiation on the left whisker pad. Group 1 received only irradiation. Group 2 was maintained by applying allopurinol/carrageenan-mixed gel (allopurinol gel) continuously from 2 days before to 20 days after irradiation. Group 3 had allopurinol gel applied for 20 days after radiation. Group 4 was maintained by applying carrageenan gel continuously from 2 days before to 20 days after irradiation. The intra oral mucosal and acute skin reactions were assessed daily using mucositis and skin score systems. The escape thresholds for mechanical stimulation to the left whisker pad were measured daily. In addition, the irradiated tissues at the endpoint of this study were compared with naive tissue. Escape threshold in group 2 was significantly higher than that in group 1, and mucositis and skin scores were much improved compared with those of group 1. Concerning escape threshold, mucositis and skin scores in group 3 began to improve 10 days after irradiation. Group 4 showed severe symptoms of mucositis and dermatitis to the same extent as that observed in group 1. In the histopathological study, the tissues of group 1 showed severe inflammatory reactions, compared with those of group 2. These results suggest that allopurinol gel application can mitigate inflammation reactions associated with radiation-induced oral mucositis and dermatitis. (author)

Changes in natural Foxp3(+Treg but not mucosally-imprinted CD62L(negCD38(+Foxp3(+Treg in the circulation of celiac disease patients.

Directory of Open Access Journals (Sweden)

Marieke A van Leeuwen

Full Text Available BACKGROUND: Celiac disease (CD is an intestinal inflammation driven by gluten-reactive CD4(+ T cells. Due to lack of selective markers it has not been determined whether defects in inducible regulatory T cell (Treg differentiation are associated with CD. This is of importance as changes in numbers of induced Treg could be indicative of defects in mucosal tolerance development in CD. Recently, we have shown that, after encounter of retinoic acid during differentiation, circulating gut-imprinted T cells express CD62L(negCD38(+. Using this new phenotype, we now determined whether alterations occur in the frequency of natural CD62L(+Foxp3(+ Treg or mucosally-imprinted CD62L(negCD38(+Foxp3(+ Treg in peripheral blood of CD patients. In particular, we compared pediatric CD, aiming to select for disease at onset, with adult CD. METHODS: Cell surface markers, intracellular Foxp3 and Helios were determined by flow cytometry. Foxp3 expression was also detected by immunohistochemistry in duodenal tissue of CD patients. RESULTS: In children, the percentages of peripheral blood CD4(+Foxp3(+ Treg were comparable between CD patients and healthy age-matched controls. Differentiation between natural and mucosally-imprinted Treg on the basis of CD62L and CD38 did not uncover differences in Foxp3. In adult patients on gluten-free diet and in refractory CD increased percentages of circulating natural CD62L(+Foxp3(+ Treg, but normal mucosally-imprinted CD62L(negCD38(+Foxp3(+ Treg frequencies were observed. CONCLUSIONS: Our data exclude that significant numeric deficiency of mucosally-imprinted or natural Foxp3(+ Treg explains exuberant effector responses in CD. Changes in natural Foxp3(+ Treg occur in a subset of adult patients on a gluten-free diet and in refractory CD patients.

Profiling of G protein-coupled receptors in vagal afferents reveals novel gut-to-brain sensing mechanisms.

Science.gov (United States)

Egerod, Kristoffer L; Petersen, Natalia; Timshel, Pascal N; Rekling, Jens C; Wang, Yibing; Liu, Qinghua; Schwartz, Thue W; Gautron, Laurent

2018-06-01

G protein-coupled receptors (GPCRs) act as transmembrane molecular sensors of neurotransmitters, hormones, nutrients, and metabolites. Because unmyelinated vagal afferents richly innervate the gastrointestinal mucosa, gut-derived molecules may directly modulate the activity of vagal afferents through GPCRs. However, the types of GPCRs expressed in vagal afferents are largely unknown. Here, we determined the expression profile of all GPCRs expressed in vagal afferents of the mouse, with a special emphasis on those innervating the gastrointestinal tract. Using a combination of high-throughput quantitative PCR, RNA sequencing, and in situ hybridization, we systematically quantified GPCRs expressed in vagal unmyelinated Na v 1.8-expressing afferents. GPCRs for gut hormones that were the most enriched in Na v 1.8-expressing vagal unmyelinated afferents included NTSR1, NPY2R, CCK1R, and to a lesser extent, GLP1R, but not GHSR and GIPR. Interestingly, both GLP1R and NPY2R were coexpressed with CCK1R. In contrast, NTSR1 was coexpressed with GPR65, a marker preferentially enriched in intestinal mucosal afferents. Only few microbiome-derived metabolite sensors such as GPR35 and, to a lesser extent, GPR119 and CaSR were identified in the Na v 1.8-expressing vagal afferents. GPCRs involved in lipid sensing and inflammation (e.g. CB1R, CYSLTR2, PTGER4), and neurotransmitters signaling (CHRM4, DRD2, CRHR2) were also highly enriched in Na v 1.8-expressing neurons. Finally, we identified 21 orphan GPCRs with unknown functions in vagal afferents. Overall, this study provides a comprehensive description of GPCR-dependent sensing mechanisms in vagal afferents, including novel coexpression patterns, and conceivably coaction of key receptors for gut-derived molecules involved in gut-brain communication. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Protective Effects of Bifidobacterium on Intestinal Barrier Function in LPS-Induced Enterocyte Barrier Injury of Caco-2 Monolayers and in a Rat NEC Model.

Science.gov (United States)

Ling, Xiang; Linglong, Peng; Weixia, Du; Hong, Wei

2016-01-01

Zonulin protein is a newly discovered modulator which modulates the permeability of the intestinal epithelial barrier by disassembling intercellular tight junctions (TJ). Disruption of TJ is associated with neonatal necrotizing enterocolitis (NEC). It has been shown bifidobacterium could protect the intestinal barrier function and prophylactical administration of bifidobacterium has beneficial effects in NEC patients and animals. However, it is still unknown whether the zonulin is involved in the gut barrier dysfunction of NEC, and the protective mechanisms of bifidobacterium on intestinal barrier function are also not well understood. The present study aims to investigate the effects of bifidobacterium on intestinal barrier function, zonulin regulation, and TJ integrity both in LPS-induced enterocyte barrier injury of Caco-2 monolayers and in a rat NEC model. Our results showed bifidobacterium markedly attenuated the decrease in transepithelial electrical resistance and the increase in paracellular permeability in the Caco-2 monolayers treated with LPS (P zonulin release (P zonulin (P zonulin protein release and improvement of intestinal TJ integrity.

Probiotic supplements and debridement of peri-implant mucositis

DEFF Research Database (Denmark)

Hallström, Hadar; Lindgren, Susann; Widén, Cecilia

2016-01-01

OBJECTIVE: The aim of this double-blind randomized placebo-controlled trial was to evaluate the effects of probiotic supplements in adjunct to conventional management of peri-implant mucositis. MATERIALS AND METHODS: Forty-nine adult patients with peri-implant mucositis were consecutively recruited...... debridement and oral hygiene reinforcement resulted in clinical improvement of peri-implant mucositis and a reduction in cytokine levels. Probiotic supplements did not provide added benefit to placebo....

Gastrointestinal mucosal abnormalities using videocapsule endoscopy in systemic sclerosis.

Science.gov (United States)

Marie, I; Antonietti, M; Houivet, E; Hachulla, E; Maunoury, V; Bienvenu, B; Viennot, S; Smail, A; Duhaut, P; Dupas, J-L; Dominique, S; Hatron, P-Y; Levesque, H; Benichou, J; Ducrotté, P

2014-07-01

To date, there are no large studies on videocapsule endoscopy in systemic sclerosis (SSc). Consequently, the prevalence and features of gastrointestinal mucosal abnormalities in SSc have not been determined. To determine both prevalence and characteristics of gastrointestinal mucosal abnormalities in unselected patients with SSc, using videocapsule endoscopy. To predict which SSc patients are at risk of developing potentially bleeding gastrointestinal vascular mucosal abnormalities. Videocapsule endoscopy was performed on 50 patients with SSc. Prevalence of gastrointestinal mucosal abnormalities was 52%. Potentially bleeding vascular mucosal lesions were predominant, including: watermelon stomach (34.6%), gastric and/or small intestinal telangiectasia (26.9%) and gastric and/or small intestinal angiodysplasia (38.5%). SSc patients with gastrointestinal vascular mucosal lesions more often exhibited: limited cutaneous SSc (P = 0.06), digital ulcers (P = 0.05), higher score of nailfold videocapillaroscopy (P = 0.0009), anaemia (P = 0.02), lower levels of ferritin (P correlation between gastrointestinal vascular mucosal lesions and presence of severe extra-digestive vasculopathy (digital ulcers and higher nailfold videocapillaroscopy scores). This latter supports the theory that SSc-related diffuse vasculopathy is responsible for both cutaneous and digestive vascular lesions. Therefore, we suggest that nailfold videocapillaroscopy may be a helpful test for managing SSc patients. In fact, nailfold videocapillaroscopy score should be calculated routinely, as it may result in identification of SSc patients at higher risk of developing potentially bleeding gastrointestinal vascular mucosal lesions. © 2014 John Wiley & Sons Ltd.

A regenerative approach towards mucosal fenestration closure

Science.gov (United States)

Gandi, Padma; Anumala, Naveen; Reddy, Amarender; Viswa Chandra, Rampalli

2013-01-01

Mucosal fenestration is an opening or an interstice through the oral mucosa. A lesion which occurs with greater frequency than generally realised, its occurrence is attributed to a myriad of causes. Mucogingival procedures including connective tissue grafts, free gingival grafts and lateral pedicle grafts are generally considered to be the treatment of choice in the closure of a mucosal fenestration. More often, these procedures are performed in conjunction with other procedures such as periradicular surgery and with bone grafts. However, the concomitant use of gingival grafts and bone grafts in mucosal fenestrations secondary to infections in sites exhibiting severe bone loss is highly debatable. In this article, we report two cases of mucosal fenestrations secondary to trauma and their management by regenerative periodontal surgery with the placement of guided tissue regeneration membrane and bone graft. The final outcome was a complete closure of the fenestration in both the cases. PMID:23749826

Acrolein Disrupts Tight Junction Proteins and Causes Endoplasmic Reticulum Stress-Mediated Epithelial Cell Death Leading to Intestinal Barrier Dysfunction and Permeability.

Science.gov (United States)

Chen, Wei-Yang; Wang, Min; Zhang, Jingwen; Barve, Shirish S; McClain, Craig J; Joshi-Barve, Swati

2017-12-01

Increasing evidence suggests that environmental and dietary factors can affect intestinal epithelial integrity leading to gut permeability and bacterial translocation. Intestinal barrier dysfunction is a pathogenic process associated with many chronic disorders. Acrolein is an environmental and dietary pollutant and a lipid-derived endogenous metabolite. The impact of acrolein on the intestine has not been investigated before and is evaluated in this study, both in vitro and in vivo. Our data demonstrate that oral acrolein exposure in mice caused damage to the intestinal epithelial barrier, resulting in increased permeability and subsequently translocation of bacterial endotoxin-lipopolysaccharide into the blood. Similar results were seen in vitro using established Caco-2 cell monolayers wherein acrolein decreased barrier function and increased permeability. Acrolein also caused the down-regulation and/or redistribution of three representative tight junction proteins (ie, zonula occludens-1, Occludin, Claudin-1) that critically regulate epithelial paracellular permeability. In addition, acrolein induced endoplasmic reticulum stress-mediated death of epithelial cells, which is an important mechanism contributing to intestinal barrier damage/dysfunction, and gut permeability. Overall, we demonstrate that exposure to acrolein affects the intestinal epithelium by decrease/redistribution of tight junction proteins and endoplasmic reticulum stress-mediated epithelial cell death, thereby resulting in loss of barrier integrity and function. Our findings highlight the adverse consequences of environmental and dietary pollutants on intestinal barrier integrity/function with relevance to gut permeability and the development of disease. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

[Gut microbiome and psyche: paradigm shift in the concept of brain-gut axis].

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Konturek, Peter C; Zopf, Yurdagül

2016-05-25

The concept of the brain-gut axis describes the communication between the central and enteric nervous system. The exchange of information takes place in both directions. The great advances in molecular medicine in recent years led to the discovery of an enormous number of microorganisms in the intestine (gut microbiome), which greatly affect the function of the brain-gut axis. Overview Numerous studies indicate that the dysfunction of the brain-gut axis could lead to both inflammatory and functional diseases of the gastrointestinal tract. Moreover, it was shown that a faulty composition of the gut microbiota in childhood influences the maturation of the central nervous system and thus may favor the development of mental disorders such as autism, depression, or other. An exact causal relationship between psyche and microbiome must be clarified by further studies in order to find new therapeutic options.

[Effects of acupuncture stimulation of different acupoint groups on sleeping duration and serum and striatal dopamine contents in rats with gastric mucosal injury].

Science.gov (United States)

Yang, Ping; Peng, Lei; Li, Jie-Ting; Ma, Hui-Fang

2014-02-01

To observe the effect of acupuncture intervention on gastric ulcer (GU) and sleeping quality from the viewpoint of brain-gut axis which plays an important role in the regulation of many vital functions in health and disease. Forty male Wistar rats were randomized into normal control, GU model, acupuncture of "Zhongwan" (CV 12)-"Zusanli" (ST 36, gastric treatment acupoints), acupuncture of "Shenmai" (BL 62)-"Zhaohai" (KI 6, sleep-promotion acupoints), and acupuncture of CV 12-ST 36-BL 62-KI 6 (combined treatment) groups, with 8 rats in each group. GU model was established by intragastric perfusion of dehydrated alcohol (1 mL/rat), and sleep model established by intraperitoneal injection of pentobarbital sodium (40 mg/kg) after the last treatment. The abovementioned acupoints were punctured with filiform needles and stimulated by manipulating the needle for about 30 s, once every 5 mm during 20 mm of needle retention. The treatment was conducted once daily for five days. Gastric mucosal lesion index was assessed by Guth's method, and the mucosal pathological changes were observed under microscope after H. E. staining. The contents of dopamine (DA) in the serum and striatal tissues were detected by ELISA kit. Compared with the normal control group, the rats' sleeping duration, and serum DA content were markedly decreased and the gastric mucosal lesion index, and the striatal DA content remarkably increased in the model group (P sleeping duration, and serum DA content were significantly increased, and the gastric mucosal lesion index, and the striatal DA content remarkably down-regulated in the CV 12-ST 36 (gastric treatment acupoints), BL 62-KI 6 (sleep-promotion acupoints) and CV 12-ST 36-BL 62-KI 6 (combined treatment) groups (P sleep promotion acupoints group in reducing mucosal lesion index and in increasing serum DA level (P sleeping duration in gastric lesion rats, which may be related to its effects in increasing blood DA and lowering striatal DA level

Effect of Antibiotics on Gut Microbiota, Gut Hormones and Glucose Metabolism

DEFF Research Database (Denmark)

Mikkelsen, Kristian H; Frost, Morten; Bahl, Martin Iain

2015-01-01

The gut microbiota has been designated as an active regulator of glucose metabolism and metabolic phenotype in a number of animal and human observational studies. We evaluated the effect of removing as many bacteria as possible by antibiotics on postprandial physiology in healthy humans. Meal tests...... with measurements of postprandial glucose tolerance and postprandial release of insulin and gut hormones were performed before, immediately after and 6 weeks after a 4-day, broad-spectrum, per oral antibiotic cocktail (vancomycin 500 mg, gentamycin 40 mg and meropenem 500 mg once-daily) in a group of 12 lean...... and glucose tolerant males. Faecal samples were collected for culture-based assessment of changes in gut microbiota composition. Acute and dramatic reductions in the abundance of a representative set of gut bacteria was seen immediately following the antibiotic course, but no changes in postprandial glucose...

Gut-Brain Axis and Behavior.

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Martin, Clair R; Mayer, Emeran A

2017-01-01

In the last 5 years, interest in the interactions among the gut microbiome, brain, and behavior has exploded. Preclinical evidence supports a role of the gut microbiome in behavioral responses associated with pain, emotion, social interactions, and food intake. Limited, but growing, clinical evidence comes primarily from associations of gut microbial composition and function to behavioral and clinical features and brain structure and function. Converging evidence suggests that the brain and the gut microbiota are in bidirectional communication. Observed dysbiotic states in depression, chronic stress, and autism may reflect altered brain signaling to the gut, while altered gut microbial signaling to the brain may play a role in reinforcing brain alterations. On the other hand, primary dysbiotic states due to Western diets may signal to the brain, altering ingestive behavior. While studies performed in patients with depression and rodent models generated by fecal microbial transfer from such patients suggest causation, evidence for an influence of acute gut microbial alterations on human behavioral and clinical parameters is lacking. Only recently has an open-label microbial transfer therapy in children with autism tentatively validated the gut microbiota as a therapeutic target. The translational potential of preclinical findings remains unclear without further clinical investigation. © 2017 Nestec Ltd., Vevey/S. Karger AG, Basel.

Metagenomic Surveys of Gut Microbiota

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Rahul Shubhra Mandal

2015-06-01

Full Text Available Gut microbiota of higher vertebrates is host-specific. The number and diversity of the organisms residing within the gut ecosystem are defined by physiological and environmental factors, such as host genotype, habitat, and diet. Recently, culture-independent sequencing techniques have added a new dimension to the study of gut microbiota and the challenge to analyze the large volume of sequencing data is increasingly addressed by the development of novel computational tools and methods. Interestingly, gut microbiota maintains a constant relative abundance at operational taxonomic unit (OTU levels and altered bacterial abundance has been associated with complex diseases such as symptomatic atherosclerosis, type 2 diabetes, obesity, and colorectal cancer. Therefore, the study of gut microbial population has emerged as an important field of research in order to ultimately achieve better health. In addition, there is a spontaneous, non-linear, and dynamic interaction among different bacterial species residing in the gut. Thus, predicting the influence of perturbed microbe–microbe interaction network on health can aid in developing novel therapeutics. Here, we summarize the population abundance of gut microbiota and its variation in different clinical states, computational tools available to analyze the pyrosequencing data, and gut microbe–microbe interaction networks.

Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses.

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Macal, M; Sankaran, S; Chun, T-W; Reay, E; Flamm, J; Prindiville, T J; Dandekar, S

2008-11-01

Human immunodeficiency virus (HIV) infection leads to severe CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) that persists despite the initiation of highly active antiretroviral therapy (HAART). It is not known whether restoration of gut mucosal CD4+ T cells and their functions is feasible during therapy and how that relates to immune correlates and viral reservoirs. Intestinal biopsies and peripheral blood samples from HIV-infected patients who were either HAART naive or on long-term HAART were evaluated. Our data demonstrated that gut CD4+ T-cell restoration ranged from modest (50%), compared with uninfected controls. Despite persistent CD4+ T-cell proviral burden and residual immune activation in GALT during HAART, effective CD4+ T-cell restoration (>50%) was achieved, which was associated with enhanced Th17 CD4+ T-cell accumulation and polyfunctional anti-HIV cellular responses. Our findings suggest that a threshold of>50% CD4+ T-cell restoration may be sufficient for polyfunctional HIV-specific T cells with implications in the evaluation of vaccines and therapeutics.

Carbohydrates and the human gut microbiota.

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Chassard, Christophe; Lacroix, Christophe

2013-07-01

Due to its scale and its important role in maintaining health, the gut microbiota can be considered as a 'new organ' inside the human body. Many complex carbohydrates are degraded and fermented by the human gut microbiota in the large intestine to both yield basic energy salvage and impact gut health through produced metabolites. This review will focus on the gut microbes and microbial mechanisms responsible for polysaccharides degradation and fermentation in the large intestine. Gut microbes and bacterial metabolites impact the host at many levels, including modulation of inflammation, and glucose and lipid metabolisms. A complex relationship occurs in the intestine between the human gut microbiota, diet and the host. Research on carbohydrates and gut microbiota composition and functionality is fast developing and will open opportunities for prevention and treatment of obesity, diabetes and other related metabolic disorders through manipulation of the gut ecosystem.

Fish oil enhances recovery of intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplant.

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Qiurong Li

Full Text Available BACKGROUND: The intestinal chronic rejection (CR is the major limitation to long-term survival of transplanted organs. This study aimed to investigate the interaction between intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplantation, and to find out whether fish oil enhances recovery of intestinal microbiota and epithelial integrity. METHODS/PRINCIPAL FINDINGS: The luminal and mucosal microbiota composition of CR rats were characterized by DGGE analysis at 190 days after intestinal transplant. The specific bacterial species were determined by sequence analysis. Furthermore, changes in the localization of intestinal TJ proteins were examined by immunofluorescent staining. PCR-DGGE analysis revealed that gut microbiota in CR rats had a shift towards Escherichia coli, Bacteroides spp and Clostridium spp and a decrease in the abundance of Lactobacillales bacteria in the intestines. Fish oil supplementation could enhance the recovery of gut microbiota, showing a significant decrease of gut bacterial proportions of E. coli and Bacteroides spp and an increase of Lactobacillales spp. In addition, CR rats showed pronounced alteration of tight junction, depicted by marked changes in epithelial cell ultrastructure and redistribution of occuldin and claudins as well as disruption in TJ barrier function. Fish oil administration ameliorated disruption of epithelial integrity in CR, which was associated with an improvement of the mucosal structure leading to improved tight junctions. CONCLUSIONS/SIGNIFICANCE: Our study have presented novel evidence that fish oil is involved in the maintenance of epithelial TJ integrity and recovery of gut microbiota, which may have therapeutic potential against CR in intestinal transplantation.

Food allergy: separating the science from the mythology.

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Brandtzaeg, Per

2010-07-01

Numerous genes are involved in innate and adaptive immunity and these have been modified over millions of years. During this evolution, the mucosal immune system has developed two anti-inflammatory strategies: immune exclusion by the use of secretory antibodies to control epithelial colonization of microorganisms and to inhibit the penetration of potentially harmful agents; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens, such as food proteins. The latter strategy is called oral tolerance when induced via the gut. Homeostatic mechanisms also dampen immune responses to commensal bacteria. The mucosal epithelial barrier and immunoregulatory network are poorly developed in newborns. The perinatal period is, therefore, critical with regard to the induction of food allergy. The development of immune homeostasis depends on windows of opportunity during which innate and adaptive immunity are coordinated by antigen-presenting cells. The function of these cells is not only orchestrated by microbial products but also by dietary constituents, including vitamin A and lipids, such as polyunsaturated omega-3 fatty acids. These factors may in various ways exert beneficial effects on the immunophenotype of the infant. The same is true for breast milk, which provides immune-inducing factors and secretory immunoglobulin A, which reinforces the gut epithelial barrier. It is not easy to dissect the immunoregulatory network and identify variables that lead to food allergy. This Review discusses efforts to this end and outlines the scientific basis for future food allergy prevention.

Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy.

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Benjamin Krämer

2017-05-01

Full Text Available Innate lymphocyte cells (ILCs, a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(- individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+ patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+ and HIV(- individuals.

Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients

NARCIS (Netherlands)

Saunders, Deborah P.; Epstein, Joel B.; Elad, Sharon; Allemano, Justin; Bossi, Paolo; van de Wetering, Marianne D.; Rao, Nikhil G.; Potting, Carin; Cheng, Karis K.; Freidank, Annette; Brennan, Michael T.; Bowen, Joanne; Dennis, Kristopher; Lalla, Rajesh V.

2013-01-01

The aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients. A systematic review of the available literature was conducted. The body

Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients.

NARCIS (Netherlands)

Saunders, D.P.; Epstein, J.B.; Elad, S.; Allemano, J.; Bossi, P.; Wetering, M.D. van de; Rao, N.G.; Potting, C.M.J.; Cheng, K.K.; Freidank, A.; Brennan, M.T.; Bowen, J.; Dennis, K.; Lalla, R.V.

2013-01-01

PURPOSE: The aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients. METHODS: A systematic review of the available literature was

Intestinal microbiota in pathophysiology and management of irritable bowel syndrome

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Lee, Kang Nyeong; Lee, Oh Young

2014-01-01

Irritable bowel syndrome (IBS) is a functional bowel disorder without any structural or metabolic abnormalities that sufficiently explain the symptoms, which include abdominal pain and discomfort, and bowel habit changes such as diarrhea and constipation. Its pathogenesis is multifactorial: visceral hypersensitivity, dysmotility, psychosocial factors, genetic or environmental factors, dysregulation of the brain-gut axis, and altered intestinal microbiota have all been proposed as possible causes. The human intestinal microbiota are composed of more than 1000 different bacterial species and 1014 cells, and are essential for the development, function, and homeostasis of the intestine, and for individual health. The putative mechanisms that explain the role of microbiota in the development of IBS include altered composition or metabolic activity of the microbiota, mucosal immune activation and inflammation, increased intestinal permeability and impaired mucosal barrier function, sensory-motor disturbances provoked by the microbiota, and a disturbed gut-microbiota-brain axis. Therefore, modulation of the intestinal microbiota through dietary changes, and use of antibiotics, probiotics, and anti-inflammatory agents has been suggested as strategies for managing IBS symptoms. This review summarizes and discusses the accumulating evidence that intestinal microbiota play a role in the pathophysiology and management of IBS. PMID:25083061

Intestinal microbiota in pathophysiology and management of irritable bowel syndrome.

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Lee, Kang Nyeong; Lee, Oh Young

2014-07-21

Irritable bowel syndrome (IBS) is a functional bowel disorder without any structural or metabolic abnormalities that sufficiently explain the symptoms, which include abdominal pain and discomfort, and bowel habit changes such as diarrhea and constipation. Its pathogenesis is multifactorial: visceral hypersensitivity, dysmotility, psychosocial factors, genetic or environmental factors, dysregulation of the brain-gut axis, and altered intestinal microbiota have all been proposed as possible causes. The human intestinal microbiota are composed of more than 1000 different bacterial species and 10(14) cells, and are essential for the development, function, and homeostasis of the intestine, and for individual health. The putative mechanisms that explain the role of microbiota in the development of IBS include altered composition or metabolic activity of the microbiota, mucosal immune activation and inflammation, increased intestinal permeability and impaired mucosal barrier function, sensory-motor disturbances provoked by the microbiota, and a disturbed gut-microbiota-brain axis. Therefore, modulation of the intestinal microbiota through dietary changes, and use of antibiotics, probiotics, and anti-inflammatory agents has been suggested as strategies for managing IBS symptoms. This review summarizes and discusses the accumulating evidence that intestinal microbiota play a role in the pathophysiology and management of IBS.

Probiotics as Complementary Treatment for Metabolic Disorders

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Mélanie Le Barz

2015-08-01

Full Text Available Over the past decade, growing evidence has established the gut microbiota as one of the most important determinants of metabolic disorders such as obesity and type 2 diabetes. Indeed, obesogenic diet can drastically alter bacterial populations (i.e., dysbiosis leading to activation of pro-inflammatory mechanisms and metabolic endotoxemia, therefore promoting insulin resistance and cardiometabolic disorders. To counteract these deleterious effects, probiotic strains have been developed with the aim of reshaping the microbiome to improve gut health. In this review, we focus on benefits of widely used probiotics describing their potential mechanisms of action, especially their ability to decrease metabolic endotoxemia by restoring the disrupted intestinal mucosal barrier. We also discuss the perspective of using new bacterial strains such as butyrate-producing bacteria and the mucolytic Akkermansia muciniphila, as well as the use of prebiotics to enhance the functionality of probiotics. Finally, this review introduces the notion of genetically engineered bacterial strains specifically developed to deliver anti-inflammatory molecules to the gut.

Transgenic Killer Commensal Bacteria as Mucosal Protectants

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Luciano Polonelli

2001-01-01

Full Text Available As first line of defense against the majority of infections and primary site for their transmission, mucosal surfaces of the oral cavity and genitourinary, gastrointestinal, and respiratory tracts represent the most suitable sites to deliver protective agents for the prevention of infectious diseases. Mucosal protection is important not only for life threatening diseases but also for opportunistic infections which currently represent a serious burden in terms of morbidity, mortality, and cost of cures. Candida albicans is among the most prevalent causes of mucosal infections not only in immuno- compromised patients, such as HIV-infected subjects who are frequently affected by oral and esophageal candidiasis, but also in otherwise healthy individuals, as in the case of acute vaginitis. Unfortunately, current strategies for mucosal protection against candidiasis are severely limited by the lack of effective vaccines and the relative paucity and toxicity of commercially available antifungal drugs. An additional option has been reported in a recent

Microneedle and mucosal delivery of influenza vaccines

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Kang, Sang-Moo; Song, Jae-Min; Kim, Yeu-Chun

2017-01-01

In recent years with the threat of pandemic influenza and other public health needs, alternative vaccination methods other than intramuscular immunization have received great attention. The skin and mucosal surfaces are attractive sites probably because of both non-invasive access to the vaccine delivery and unique immunological responses. Intradermal vaccines using a microinjection system (BD Soluvia) and intranasal vaccines (FluMist) are licensed. As a new vaccination method, solid microneedles have been developed using a simple device that may be suitable for self-administration. Because coated micorneedle influenza vaccines are administered in the solid state, developing formulations maintaining the stability of influenza vaccines is an important issue to be considered. Marketable microneedle devices and clinical trials remain to be developed. Other alternative mucosal routes such as oral and intranasal delivery systems are also attractive for inducing cross protective mucosal immunity but effective non-live mucosal vaccines remain to be developed. PMID:22697052

Diminution of the gut resistome after a gut microbiota-targeted dietary intervention in obese children.

Science.gov (United States)

Wu, Guojun; Zhang, Chenhong; Wang, Jing; Zhang, Feng; Wang, Ruirui; Shen, Jian; Wang, Linghua; Pang, Xiaoyan; Zhang, Xiaojun; Zhao, Liping; Zhang, Menghui

2016-04-05

The gut microbiome represents an important reservoir of antibiotic resistance genes (ARGs). Effective methods are urgently needed for managing the gut resistome to fight against the antibiotic resistance threat. In this study, we show that a gut microbiota-targeted dietary intervention, which shifts the dominant fermentation of gut bacteria from protein to carbohydrate, significantly diminished the gut resistome and alleviated metabolic syndrome in obese children. Of the non-redundant metagenomic gene catalog of ~2 × 10(6) microbial genes, 399 ARGs were identified in 131 gene types and conferred resistance to 47 antibiotics. Both the richness and diversity of the gut resistome were significantly reduced after the intervention. A total of 201 of the 399 ARGs were carried in 120 co-abundance gene groups (CAGs) directly binned from the gene catalog across both pre-and post-intervention samples. The intervention significantly reduced several CAGs in Klebsiella, Enterobacter and Escherichia, which were the major hubs for multiple resistance gene types. Thus, dietary intervention may become a potentially effective method for diminishing the gut resistome.

Mucosal barrier injury laboratory-confirmed bloodstream infection: results from a field test of a new National Healthcare Safety Network definition.

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See, Isaac; Iwamoto, Martha; Allen-Bridson, Kathy; Horan, Teresa; Magill, Shelley S; Thompson, Nicola D

2013-08-01

To assess challenges to implementation of a new National Healthcare Safety Network (NHSN) surveillance definition, mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI). Multicenter field test. Selected locations of acute care hospitals participating in NHSN central line-associated bloodstream infection (CLABSI) surveillance. Hospital staff augmented their CLABSI surveillance for 2 months to incorporate MBI-LCBI: a primary bloodstream infection due to a selected group of organisms in patients with either neutropenia or an allogeneic hematopoietic stem cell transplant with gastrointestinal graft-versus-host disease or diarrhea. Centers for Disease Control and Prevention (CDC) staff reviewed submitted data to verify whether CLABSIs met MBI-LCBI criteria and summarized the descriptive epidemiology of cases reported. Eight cancer, 2 pediatric, and 28 general acute care hospitals including 193 inpatient units (49% oncology/bone marrow transplant [BMT], 21% adult ward, 20% adult critical care, 6% pediatric, 4% step-down) conducted field testing. Among 906 positive blood cultures reviewed, 282 CLABSIs were identified. Of the 103 CLABSIs that also met MBI-LCBI criteria, 100 (97%) were reported from oncology/BMT locations. Agreement between hospital staff and CDC classification of reported CLABSIs as meeting the MBI-LCBI definition was high (90%; κ = 0.82). Most MBI-LCBIs (91%) occurred in patients meeting neutropenia criteria. Some hospitals indicated that their laboratories' methods of reporting cell counts prevented application of neutropenia criteria; revised neutropenia criteria were created using data from field testing. Hospital staff applied the MBI-LCBI definition accurately. Field testing informed modifications for the January 2013 implementation of MBI-LCBI in the NHSN.

Differential Apoptosis in Mucosal and Dermal Wound Healing

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Johnson, Ariel; Francis, Marybeth; DiPietro, Luisa Ann

2014-01-01

Objectives: Dermal and mucosal healing are mechanistically similar. However, scarring and closure rates are dramatically improved in mucosal healing, possibly due to differences in apoptosis. Apoptosis, nature's preprogrammed form of cell death, occurs via two major pathways, extrinsic and intrinsic, which intersect at caspase3 (Casp3) cleavage and activation. The purpose of this experiment was to identify the predominant pathways of apoptosis in mucosal and dermal wound healing. Approach: Wounds (1 mm biopsy punch) were made in the dorsal skin (n=3) or tongue (n=3) of female Balb/C mice aged 6 weeks. Wounds were harvested at 6 h, 24 h, day 3 (D3), D5, D7, and D10. RNA was isolated and analyzed using real time reverse transcriptase–polymerase chain reaction. Expression levels for genes in the intrinsic and extrinsic apoptotic pathways were compared in dermal and mucosal wounds. Results: Compared to mucosal healing, dermal wounds exhibited significantly higher expression of Casp3 (at D5; phealing compared to skin. Conclusion: Expression patterns of key regulators of apoptosis in wound healing indicate that apoptosis occurs predominantly through the intrinsic pathway in the healing mucosa, but predominantly through the extrinsic pathway in the healing skin. The identification of differences in the apoptotic pathways in skin and mucosal wounds may allow the development of therapeutics to improve skin healing. PMID:25493209

The intestinal barrier function and its involvement in digestive disease

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Eloísa Salvo-Romero

2015-11-01

Full Text Available The gastrointestinal mucosal surface is lined with epithelial cells representing an effective barrier made up with intercellular junctions that separate the inner and the outer environments, and block the passage of potentially harmful substances. However, epithelial cells are also responsible for the absorption of nutrients and electrolytes, hence a semipermeable barrier is required that selectively allows a number of substances in while keeping others out. To this end, the intestine developed the "intestinal barrier function", a defensive system involving various elements, both intra- and extracellular, that work in a coordinated way to impede the passage of antigens, toxins, and microbial byproducts, and simultaneously preserves the correct development of the epithelial barrier, the immune system, and the acquisition of tolerance against dietary antigens and the intestinal microbiota. Disturbances in the mechanisms of the barrier function favor the development of exaggerated immune responses; while exact implications remain unknown, changes in intestinal barrier function have been associated with the development of inflammatory conditions in the gastrointestinal tract. This review details de various elements of the intestinal barrier function, and the key molecular and cellular changes described for gastrointestinal diseases associated with dysfunction in this defensive mechanism.

Effect of gene time on acute radiation mucositis and dermatitis

International Nuclear Information System (INIS)

Li Suyan; Gao Li; Yin Weibo; Xu Guozhen; Xiao Guangli

2002-01-01

Objective: To evaluate the effect of recombinant human epidermal growth factor (Gene Time) on acute mucositis and dermatitis induced by radiation. Methods: 120 head and neck cancer patients were randomized into 3 groups: 1. Mucositis prophylactic application (MPA) group with control, 2. Mucositis therapeutic application (MTA) group with control and 3. Dermatitis therapeutic application (DTA) group with control. Prophylactic application of drug consisted of spraying the Gene Time preparation on the irradiated skin or mucous membrane as radiotherapy was being carried out. This was compared with control patients who received routine conventional skin care. Therapeutic application was started as grade I radiation mucositis or dermatitis appeared. The evaluation of acute radiation mucositis and dermatitis was done according to the systems proposed by RTOG or EORTC. Results: The results showed that in the MPA group, the rate of radiation mucositis at ≤10 Gy was 20% (4/20) as compared to the 70% (14/20) of the control (P = 0.004). During the course of radiation, the incidences of grade III, IV acute radiation mucositis and dermatitis were always lower than the control. In therapeutic application of Gene Time, the response rate of acute radiation mucositis was also better than the control (90% vs 50%) (P = 0.016) and that of acute dermatitis was similar (95% vs 50%) (P = 0.005). Moreover, the ≤3 d rate of healing of grade III dermatitis in the application group was 3/7 as compared to the 0/14 of the control. Conclusion: Prophylactic application of recombinant human epidermal growth factor is able to postpone the development of radiation mucositis. This preparation is also able to lower the incidence of grade III, IV mucositis and dermatitis both by therapeutic and prophylactic application in addition to the hastened healing of grade III dermatitis

Gut Microbiota Mediates the Protective Effects of Dietary Capsaicin against Chronic Low-Grade Inflammation and Associated Obesity Induced by High-Fat Diet

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Chao Kang

2017-05-01

Full Text Available Metabolic endotoxemia originating from dysbiotic gut microbiota has been identified as a primary mediator for triggering the chronic low-grade inflammation (CLGI responsible for the development of obesity. Capsaicin (CAP is the major pungent bioactivator in chili peppers and has potent anti-obesity functions, yet the mechanisms linking this effect to gut microbiota remain obscure. Here we show that mice fed a high-fat diet (HFD supplemented with CAP exhibit lower levels of metabolic endotoxemia and CLGI associated with lower body weight gain. High-resolution responses of the microbiota were examined by 16S rRNA sequencing, short-chain fatty acid (SCFA measurements, and phylogenetic reconstruction of unobserved states (PICRUSt analysis. The results showed, among others, that dietary CAP induced increased levels of butyrate-producing Ruminococcaceae and Lachnospiraceae, while it caused lower levels of members of the lipopolysaccharide (LPS-producing family S24_7. Predicted function analysis (PICRUSt showed depletion of genes involved in bacterial LPS synthesis in response to CAP. We further identified that inhibition of cannabinoid receptor type 1 (CB1 by CAP also contributes to prevention of HFD-induced gut barrier dysfunction. Importantly, fecal microbiota transplantation experiments conducted in germfree mice demonstrated that dietary CAP-induced protection against HFD-induced obesity is transferrable. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block the CAP-induced protective phenotype against obesity, further suggesting the role of microbiota in this context. Together, our findings uncover an interaction between dietary CAP and gut microbiota as a novel mechanism for the anti-obesity effect of CAP acting through prevention of microbial dysbiosis, gut barrier dysfunction, and chronic low-grade inflammation.

Gut Microbiome and Infant Health: Brain-Gut-Microbiota Axis and Host Genetic Factors.

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Cong, Xiaomei; Xu, Wanli; Romisher, Rachael; Poveda, Samantha; Forte, Shaina; Starkweather, Angela; Henderson, Wendy A

2016-09-01

The development of the neonatal gut microbiome is influenced by multiple factors, such as delivery mode, feeding, medication use, hospital environment, early life stress, and genetics. The dysbiosis of gut microbiota persists during infancy, especially in high-risk preterm infants who experience lengthy stays in the Neonatal intensive care unit (NICU). Infant microbiome evolutionary trajectory is essentially parallel with the host (infant) neurodevelopmental process and growth. The role of the gut microbiome, the brain-gut signaling system, and its interaction with the host genetics have been shown to be related to both short and long term infant health and bio-behavioral development. The investigation of potential dysbiosis patterns in early childhood is still lacking and few studies have addressed this host-microbiome co-developmental process. Further research spanning a variety of fields of study is needed to focus on the mechanisms of brain-gut-microbiota signaling system and the dynamic host-microbial interaction in the regulation of health, stress and development in human newborns.

Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex.

Science.gov (United States)

Rizzetto, Lisa; Fava, Francesca; Tuohy, Kieran M; Selmi, Carlo

2018-05-31

Unresolved low grade systemic inflammation represents the underlying pathological mechanism driving immune and metabolic pathways involved in autoimmune diseases (AID). Mechanistic studies in animal models of AID and observational studies in patients have found alterations in gut microbiota communities and their metabolites, suggesting a microbial contribution to the onset or progression of AID. The gut microbiota and its metabolites have been shown to influence immune functions and immune homeostasis both within the gut and systematically. Microbial derived-short chain fatty acid (SCFA) and bio-transformed bile acid (BA) have been shown to influence the immune system acting as ligands specific cell signaling receptors like GPRCs, TGR5 and FXR, or via epigenetic processes. Similarly, intestinal permeability (leaky gut) and bacterial translocation are important contributors to chronic systemic inflammation and, without repair of the intestinal barrier, might represent a continuous inflammatory stimulus capable of triggering autoimmune processes. Recent studies indicate gender-specific differences in immunity, with the gut microbiota shaping and being concomitantly shaped by the hormonal milieu governing differences between the sexes. A bi-directional cross-talk between microbiota and the endocrine system is emerging with bacteria being able to produce hormones (e.g. serotonin, dopamine and somatostatine), respond to host hormones (e.g. estrogens) and regulate host hormones' homeostasis (e.g by inhibiting gene prolactin transcription or converting glucocorticoids to androgens). We review herein how gut microbiota and its metabolites regulate immune function, intestinal permeability and possibly AID pathological processes. Further, we describe the dysbiosis within the gut microbiota observed in different AID and speculate how restoring gut microbiota composition and its regulatory metabolites by dietary intervention including prebiotics and probiotics could help in

The microbiota and the gut-brain axis: insights from the temporal and spatial mucosal alterations during colonisation of the germfree mouse intestine.

NARCIS (Netherlands)

Aidy, El S.F.; Kunze, W.; Bienenstock, J.; Kleerebezem, M.

2012-01-01

The influence of the gut microbiota on the nervous system, brain development and behaviour, in particular during microbial colonisation of the host, has recently been receiving profound interest. Our time-resolved mining of combined data analyses of the ex-germfree mouse intestine during a 30-day

Oral mucositis in head and neck cancer: risk, biology, and management.

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Sonis, Stephen T

2013-01-01

Of the toxicities associated with conventional forms of treatment for head and neck cancers, probably none has such a consistent legacy as oral mucositis.1 Despite the fact that mucosal injury was noted as far back as Marie Curie's first forays into therapeutic radiation, an effective intervention has yet to be developed. In addition to its historic link to radiation, new therapeutic strategies including induction chemotherapy often produce mucositis, and targeted therapies appear to alter mucositis risk and its severity and course.2 The symptomatic effect of oral mucositis is profound. Disabling oral and oropharyngeal pain prevents patients from eating normally, requires opiate analgesics, and in some cases results in alteration or discontinuation of anticancer therapy.3 Furthermore, the health and economic consequences of oral mucositis are far from trivial. The incremental cost of oral mucositis in patients with head and neck cancer exceeds $17,000 (USD).4.

A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality

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Holmkvist, P.; Roepstorff, K.; Uronen-Hansson, H.

2015-01-01

induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα+DR3+CD4+ T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively......, these results suggest that human memory IL-18Rα+DR3+CD4+ T cells may contribute to antigen-independent innate responses at barrier surfaces.......Mucosal tissues contain large numbers of memory CD4+ T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4+ Tcells at barrier...

Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88.

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Larsson, Erik; Tremaroli, Valentina; Lee, Ying Shiuan; Koren, Omry; Nookaew, Intawat; Fricker, Ashwana; Nielsen, Jens; Ley, Ruth E; Bäckhed, Fredrik

2012-08-01

The gut microbiota has profound effects on host physiology but local host-microbial interactions in the gut are only poorly characterised and are likely to vary from the sparsely colonised duodenum to the densely colonised colon. Microorganisms are recognised by pattern recognition receptors such as Toll-like receptors, which signal through the adaptor molecule MyD88. To identify host responses induced by gut microbiota along the length of the gut and whether these required MyD88, transcriptional profiles of duodenum, jejunum, ileum and colon were compared from germ-free and conventionally raised wild-type and Myd88-/- mice. The gut microbial ecology was assessed by 454-based pyrosequencing and viruses were analysed by PCR. The gut microbiota modulated the expression of a large set of genes in the small intestine and fewer genes in the colon but surprisingly few microbiota-regulated genes required MyD88 signalling. However, MyD88 was essential for microbiota-induced colonic expression of the antimicrobial genes Reg3β and Reg3γ in the epithelium, and Myd88 deficiency was associated with both a shift in bacterial diversity and a greater proportion of segmented filamentous bacteria in the small intestine. In addition, conventionally raised Myd88-/- mice had increased expression of antiviral genes in the colon, which correlated with norovirus infection in the colonic epithelium. This study provides a detailed description of tissue-specific host transcriptional responses to the normal gut microbiota along the length of the gut and demonstrates that the absence of MyD88 alters gut microbial ecology.

Impact of Kefir Derived Lactobacillus kefiri on the Mucosal Immune Response and Gut Microbiota

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P. Carasi

2015-01-01

Full Text Available The evaluation of the impact of probiotics on host health could help to understand how they can be used in the prevention of diseases. On the basis of our previous studies and in vitro assays on PBMC and Caco-2 ccl20:luc reporter system presented in this work, the strain Lactobacillus kefiri CIDCA 8348 was selected and administrated to healthy Swiss mice daily for 21 days. The probiotic treatment increased IgA in feces and reduced expression of proinflammatory mediators in Peyer Patches and mesenteric lymph nodes, where it also increased IL-10. In ileum IL-10, CXCL-1 and mucin 6 genes were upregulated; meanwhile in colon mucin 4 was induced whereas IFN-γ, GM-CSF, and IL-1β genes were downregulated. Moreover, ileum and colon explants showed the anti-inflammatory effect of L. kefiri since the LPS-induced increment of IL-6 and GM-CSF levels in control mice was significantly attenuated in L. kefiri treated mice. Regarding fecal microbiota, DGGE profiles allowed differentiation of experimental groups in two separated clusters. Quantitative PCR analysis of different bacterial groups revealed only significant changes in Lactobacillus population. In conclusion, L. kefiri is a good candidate to be used in gut inflammatory disorders.

Impact of Kefir Derived Lactobacillus kefiri on the Mucosal Immune Response and Gut Microbiota

Science.gov (United States)

Carasi, P.; Racedo, S. M.; Jacquot, C.; Romanin, D. E.; Serradell, M. A.; Urdaci, M. C.

2015-01-01

The evaluation of the impact of probiotics on host health could help to understand how they can be used in the prevention of diseases. On the basis of our previous studies and in vitro assays on PBMC and Caco-2 ccl20:luc reporter system presented in this work, the strain Lactobacillus kefiri CIDCA 8348 was selected and administrated to healthy Swiss mice daily for 21 days. The probiotic treatment increased IgA in feces and reduced expression of proinflammatory mediators in Peyer Patches and mesenteric lymph nodes, where it also increased IL-10. In ileum IL-10, CXCL-1 and mucin 6 genes were upregulated; meanwhile in colon mucin 4 was induced whereas IFN-γ, GM-CSF, and IL-1β genes were downregulated. Moreover, ileum and colon explants showed the anti-inflammatory effect of L. kefiri since the LPS-induced increment of IL-6 and GM-CSF levels in control mice was significantly attenuated in L. kefiri treated mice. Regarding fecal microbiota, DGGE profiles allowed differentiation of experimental groups in two separated clusters. Quantitative PCR analysis of different bacterial groups revealed only significant changes in Lactobacillus population. In conclusion, L. kefiri is a good candidate to be used in gut inflammatory disorders. PMID:25811034

Impact of kefir derived Lactobacillus kefiri on the mucosal immune response and gut microbiota.

Science.gov (United States)

Carasi, P; Racedo, S M; Jacquot, C; Romanin, D E; Serradell, M A; Urdaci, M C

2015-01-01

The evaluation of the impact of probiotics on host health could help to understand how they can be used in the prevention of diseases. On the basis of our previous studies and in vitro assays on PBMC and Caco-2 ccl20:luc reporter system presented in this work, the strain Lactobacillus kefiri CIDCA 8348 was selected and administrated to healthy Swiss mice daily for 21 days. The probiotic treatment increased IgA in feces and reduced expression of proinflammatory mediators in Peyer Patches and mesenteric lymph nodes, where it also increased IL-10. In ileum IL-10, CXCL-1 and mucin 6 genes were upregulated; meanwhile in colon mucin 4 was induced whereas IFN-γ, GM-CSF, and IL-1β genes were downregulated. Moreover, ileum and colon explants showed the anti-inflammatory effect of L. kefiri since the LPS-induced increment of IL-6 and GM-CSF levels in control mice was significantly attenuated in L. kefiri treated mice. Regarding fecal microbiota, DGGE profiles allowed differentiation of experimental groups in two separated clusters. Quantitative PCR analysis of different bacterial groups revealed only significant changes in Lactobacillus population. In conclusion, L. kefiri is a good candidate to be used in gut inflammatory disorders.

Oral Candida as an aggravating factor of mucositis Induced by radiotherapy

International Nuclear Information System (INIS)

Simoes, Cristiane Araujo; Castro, Jurema Freire Lisboa de; Cazal, Claudia

2011-01-01

Antineoplastic treatment induces some undesirable consequences in head and neck cancer patients. Often, the emergence of major clinical manifestations, such as oral mucositis, results in temporary interruption of the treatment, decreasing the patients' quality of life, and increasing hospital costs. Radio-induced or chemo-induced oral mucositis is possibly aggravated by opportunist fungal infections, which turn the mucositis more resistant to the conventional treatments. Objective: this study aims to identify the presence of Candida sp. as a possible aggravating factor of oral mucositis in patients with head and neck cancer under antineoplastic treatment. Method: all patients with radio- or chemo-induced oral mucositis from the Cancer Hospital of Pernambuco, treated between October 2008 and April 2009, were selected for the study. The prevalence of Candida sp was measured through the cytological analysis of oral mucosa in patients with oral mucositis. The fungal presence was correlated with the mucositis severity. Results: the results showed a positive association between fungal colonization and more several lesions (degrees III and IV of mucositis). Conclusion: The outcomes shown may contribute to a solution for unconventional mucosites, which do not respond to the usual treatment. (author)

Cystic fibrosis: a mucosal immunodeficiency syndrome

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Cohen, Taylor Sitarik; Prince, Alice

2013-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes—airway inflammation and spontaneous infection—may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance. PMID:22481418

Alcaligenes is Commensal Bacteria Habituating in the Gut-Associated Lymphoid Tissue for the Regulation of Intestinal IgA Responses.

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Kunisawa, Jun; Kiyono, Hiroshi

2012-01-01

Secretory-immunoglobulin A (S-IgA) plays an important role in immunological defense in the intestine. It has been known for a long time that microbial stimulation is required for the development and maintenance of intestinal IgA production. Recent advances in genomic technology have made it possible to detect uncultivable commensal bacteria in the intestine and identify key bacteria in the regulation of innate and acquired mucosal immune responses. In this review, we focus on the immunological function of Peyer's patches (PPs), a major gut-associated lymphoid tissue, in the induction of intestinal IgA responses and the unique immunological interaction of PPs with commensal bacteria, especially Alcaligenes, a unique indigenous bacteria habituating inside PPs.

Role of airway epithelial barrier dysfunction in pathogenesis of asthma.

Science.gov (United States)

Gon, Yasuhiro; Hashimoto, Shu

2018-01-01

Bronchial asthma is characterized by persistent cough, increased sputum, and repeated wheezing. The pathophysiology underlying these symptoms is the hyper-responsiveness of the airway along with chronic airway inflammation. Repeated injury, repair, and regeneration of the airway epithelium following exposure to environmental factors and inflammation results in histological changes and functional abnormalities in the airway mucosal epithelium; such changes are believed to have a significant association with the pathophysiology of asthma. Damage to the barrier functions of the airway epithelium enhances mucosal permeability of foreign substances in the airway epithelium of patients with asthma. Thus, epithelial barrier fragility is closely involved in releasing epithelial cytokines (e.g., TSLP, IL-25, and IL-33) because of the activation of airway epithelial cells, dendritic cells, and innate group 2 innate lymphoid cells (ILC2). Functional abnormalities of the airway epithelial cells along with the activation of dendritic cells, Th2 cells, and ILC2 form a single immunopathological unit that is considered to cause allergic airway inflammation. Here we use the latest published literature to discuss the potential pathological mechanisms regarding the onset and progressive severity of asthma with regard to the disruption of the airway epithelial function. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Leaky gut and mycotoxins: Aflatoxin B1 does not increase gut permeability in broiler chickens

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Rosario eGalarza-Seeber

2016-02-01

Full Text Available Previous studies conducted in our laboratory have demonstrated that intestinal barrier function can be adversely affected by diet ingredients or feed restriction, resulting in increased intestinal inflammation-associated permeability. Two experiments were conducted in broilers to evaluate the effect of 3 concentrations of Aflatoxin B1 (AFB1; 2, 1.5 or 1 ppm on gastrointestinal leakage and liver bacterial translocation (BT. In Exp 1, 240 day-of-hatch male broilers were allocated in two groups, each group had six replicates of 20 chickens (n = 120/group: Control feed or feed + 2 ppm AFB1. In Exp 2, 240 day-of-hatch male broilers were allocated in three groups, each group had 5 replicates of 16 chickens (n = 80/group: Control feed; feed + 1 ppm AFB1; or feed + 1.5 ppm AFB1. In both experiments, chickens were fed starter (d1-d7 and grower diets (d8-d21 ad libitum and performance parameters were evaluated every week. At day 21, all chicks received an oral gavage dose of FITC-d (4.16 mg/kg 2.5h before collecting blood samples to evaluate gastrointestinal leakage of FITC-d. In Exp 2 a hematologic analysis was also performed. Liver sections were aseptically collected and cultured using TSA plates to determine BT. Cecal contents were collected to determine total cfu/g of Gram-negative bacteria; lactic acid bacteria (LAB or anaerobes by plating on selective media. In Exp 2, liver, spleen and bursa of Fabricius were removed to determine organ weight ratio, and also intestinal samples were obtained for morphometric analysis. Performance parameters, organ weight ratio and morphometric measurements were significantly different between control and AFB1 groups in both experiments. Gut leakage of FITC-d was not affected by the three concentrations of AFB1 evaluated (P > 0.05. Interestingly, a significant reduction in BT was observed in chickens that received 2 and 1 ppm AFB1. An increase (P < 0.05 in total aerobic bacteria, total Gram negatives, and total LAB

Compositional and Functional Differences in the Human Gut Microbiome Correlate with Clinical Outcome following Infection with Wild-Type Salmonella enterica Serovar Typhi.

Science.gov (United States)

Zhang, Yan; Brady, Arthur; Jones, Cheron; Song, Yang; Darton, Thomas C; Jones, Claire; Blohmke, Christoph J; Pollard, Andrew J; Magder, Laurence S; Fasano, Alessio; Sztein, Marcelo B; Fraser, Claire M

2018-05-08

Insights into disease susceptibility as well as the efficacy of vaccines against typhoid and other enteric pathogens may be informed by better understanding the relationship between the effector immune response and the gut microbiota. In the present study, we characterized the composition (16S rRNA gene profiling) and function (RNA sequencing [RNA-seq]) of the gut microbiota following immunization and subsequent exposure to wild-type Salmonella enterica serovar Typhi in a human challenge model to further investigate the central hypothesis that clinical outcomes may be linked to the gut microbiota. Metatranscriptome analysis of longitudinal stool samples collected from study subjects revealed two stable patterns of gene expression for the human gut microbiota, dominated by transcripts from either Methanobrevibacter or a diverse representation of genera in the Firmicutes phylum. Immunization with one of two live oral attenuated vaccines against S.  Typhi had minimal effects on the composition or function of the gut microbiota. It was observed that subjects harboring the methanogen-dominated transcriptome community at baseline displayed a lower risk of developing symptoms of typhoid following challenge with wild-type S.  Typhi. Furthermore, genes encoding antioxidant proteins, metal homeostasis and transport proteins, and heat shock proteins were expressed at a higher level at baseline or after challenge with S.  Typhi in subjects who did not develop symptoms of typhoid. These data suggest that functional differences relating to redox potential and ion homeostasis in the gut microbiota may impact clinical outcomes following exposure to wild-type S.  Typhi. IMPORTANCE S.  Typhi is a significant cause of systemic febrile morbidity in settings with poor sanitation and limited access to clean water. It has been demonstrated that the human gut microbiota can influence mucosal immune responses, but there is little information available on the impact of the human gut

The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review.

Science.gov (United States)

Paganini, Daniela; Zimmermann, Michael B

2017-12-01

In infants and young children in Sub-Saharan Africa, iron-deficiency anemia (IDA) is common, and many complementary foods are low in bioavailable iron. In-home fortification of complementary foods using iron-containing micronutrient powders (MNPs) and oral iron supplementation are both effective strategies to increase iron intakes and reduce IDA at this age. However, these interventions produce large increases in colonic iron because the absorption of their high iron dose (≥12.5 mg) is typically iron supplements and iron fortification with MNPs on the gut microbiome and diarrhea. Iron-containing MNPs and iron supplements can modestly increase diarrhea risk, and in vitro and in vivo studies have suggested that this occurs because increases in colonic iron adversely affect the gut microbiome in that they decrease abundances of beneficial barrier commensal gut bacteria (e.g., bifidobacteria and lactobacilli) and increase the abundance of enterobacteria including entropathogenic Escherichia coli These changes are associated with increased gut inflammation. Therefore, safer formulations of iron-containing supplements and MNPs are needed. To improve MNP safety, the iron dose of these formulations should be reduced while maximizing absorption to retain efficacy. Also, the addition of prebiotics to MNPs is a promising approach to mitigate the adverse effects of iron on the infant gut. © 2017 American Society for Nutrition.

Increased melatonin in oral mucosal tissue of oral lichen planus (OLP) patients: A possible link between melatonin and its role in oral mucosal inflammation.

Science.gov (United States)

Luengtrakoon, Kirawut; Wannakasemsuk, Worraned; Vichitrananda, Vilasinee; Klanrit, Poramaporn; Hormdee, Doosadee; Noisombut, Rajda; Chaiyarit, Ponlatham

2017-06-01

The existence of extra-pineal melatonin has been observed in various tissues. No prior studies of melatonin in human oral mucosal tissue under the condition of chronic inflammation have been reported. The aim of this study was to investigate the presence of melatonin in oral mucosal tissue of patients with oral lichen planus (OLP) which was considered as a chronic inflammatory immune-mediated disease causing oral mucosal damage and ulcerations. Sections from formalin-fixed and paraffin-embedded oral mucosal tissue of OLP patients (n=30), and control subjects (n=30) were used in this study. Immunohistochemical staining was performed and the semiquantitative scoring system was used to assess the levels of arylalkylamine-N-acetyltransferase (AANAT: a rate-limiting enzyme in the biosynthesis pathway of melatonin), melatonin, and melatonin receptor 1 (MT1) in oral mucosa of OLP patients and normal oral mucosa of control subjects. AANAT, melatonin, and MT1were detected in oral mucosal tissue of OLP patients and control subjects. Immunostaining scores of AANAT, melatonin, and MT1 in oral mucosal tissue of OLP patients were significantly higher than those in control subjects (p=0.002, poral mucosal tissue of OLP patients imply that chronic inflammation may induce the local biosynthesis of melatonin via AANAT, and may enhance the action of melatonin via MT1. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

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Sergio Serrano-Villar

2016-01-01

Full Text Available Whether initiation of antiretroviral therapy (ART regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6, lipoteichoic acid (LTA, soluble CD14 (sCD14 and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively, with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease

Chemotherapy induced intestinal mucositis; from bench to bed

NARCIS (Netherlands)

B.A.E. Koning, de (Barbara)

2008-01-01

textabstractPart 1 focuses primarily on the pathophysiology of mucositis, in order to gain more insight different experimental mouse models were used. Chapter 2 describes mucositis induced by high dose doxorubicin (DOX)- treatment. DOX is a frequently used cytostatic drug in childhood cancer,

Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health.

Science.gov (United States)

Jost, Ted; Lacroix, Christophe; Braegger, Christian; Chassard, Christophe

2015-07-01

Neonatal gut microbiota establishment represents a crucial stage for gut maturation, metabolic and immunologic programming, and consequently short- and long-term health status. Human milk beneficially influences this process due to its dynamic profile of age-adapted nutrients and bioactive components and by providing commensal maternal bacteria to the neonatal gut. These include Lactobacillus spp., as well as obligate anaerobes such as Bifidobacterium spp., which may originate from the maternal gut via an enteromammary pathway as a novel form of mother-neonate communication. Additionally, human milk harbors a broad range of oligosaccharides that promote the growth and activity of specific bacterial populations, in particular, Bifidobacterium and Bacteroides spp. This review focuses on the diversity and origin of human milk bacteria, as well as on milk oligosaccharides that influence neonatal gut microbiota establishment. This knowledge can be used to develop infant formulae that more closely mimic nature's model and sustain a healthy gut microbiota. © The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

First Foods and Gut Microbes

DEFF Research Database (Denmark)

Laursen, Martin Frederik; Bahl, Martin Iain; Michaelsen, Kim F.

2017-01-01

, are generally recognized to be of particular importance for the healthy development of children. While dietary changes are known to affect the adult gut microbiota, there is a gap in our knowledge on how the introduction of new dietary components into the diet of infants/young children affects the gut...... microbiota development. This perspective paper summarizes the currently very few studies addressing the effects of complementary diet on gut microbiota, and highlights the recent finding that transition to family foods greatly impacts the development of gut microbial diversity. Further, we discuss potential......(breast/formula). Consequently, the neonatal period and early infancy has attracted much attention. However, after this first period the gut microbial composition continues to develop until the age of 3 years, and these 1st years have been designated "a window of opportunity" for microbial modulation. The beginning and end...

Hh pathway expression in human gut tissues and in inflammatory gut diseases

NARCIS (Netherlands)

Nielsen, Corinne M.; Williams, Jerrell; van den Brink, Gijs R.; Lauwers, Gregory Y.; Roberts, Drucilla J.

2004-01-01

Sonic hedgehog (Shh) directs early gut patterning via epithelial-mesenchymal signaling and remains expressed in endoderm-derived tissues into the adult period. In human adult gut epithelium SHH/SHH expression is strongest in basal layers, which suggests that SHH may function in the maintenance of

Gut-associated lymphoid tissue, gut microbes and susceptibility to experimental autoimmune encephalomyelitis.

Science.gov (United States)

Stanisavljević, S; Lukić, J; Momčilović, M; Miljković, M; Jevtić, B; Kojić, M; Golić, N; Mostarica Stojković, M; Miljković, D

2016-06-01

Gut microbiota and gut-associated lymphoid tissue have been increasingly appreciated as important players in pathogenesis of various autoimmune diseases, including multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis that can be induced with an injection of spinal cord homogenate emulsified in complete Freund's adjuvant in Dark Agouti (DA) rats, but not in Albino Oxford (AO) rats. In this study, mesenteric lymph nodes (MLN), Peyer's patches (PP) and gut microbiota were analysed in these two rat strains. There was higher proportion of CD4(+) T cells and regulatory T cells in non-immunised DA rats in comparison to AO rats. Also, DA rat MLN and PP cells were higher producers of pro-inflammatory cytokines interferon-γ and interleukin-17. Finally, microbial analyses showed that uncultivated species of Turicibacter and Atopostipes genus were exclusively present in AO rats, in faeces and intestinal tissue, respectively. Thus, it is clear that in comparison of an EAE-susceptible with an EAE-resistant strain of rats, various discrepancies at the level of gut associated lymphoid tissue, as well as at the level of gut microbiota can be observed. Future studies should determine if the differences have functional significance for EAE pathogenesis.

Lingonberries alter the gut microbiota and prevent low-grade inflammation in high-fat diet fed mice