Human Intestinal Barrier Function in Health and Disease

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Abstract

The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed.

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Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

J Hugot, M Chamaillard, H Zouali … (2001)

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

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Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis

Claudia Günther, Eva Martini, Nadine Wittkopf … (2011)

Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum 1 . Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium 2 . Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans 3 . However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8 ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8 ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8 ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.

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Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens.

Alain L Servin (2004)

The gastrointestinal tract is a complex ecosystem that associates a resident microbiota and cells of various phenotypes lining the epithelial wall expressing complex metabolic activities. The resident microbiota in the digestive tract is a heterogeneous microbial ecosystem containing up to 1 x 10(14) colony-forming units (CFUs) of bacteria. The intestinal microbiota plays an important role in normal gut function and maintaining host health. The host is protected from attack by potentially harmful microbial microorganisms by the physical and chemical barriers created by the gastrointestinal epithelium. The cells lining the gastrointestinal epithelium and the resident microbiota are two partners that properly and/or synergistically function to promote an efficient host system of defence. The gastrointestinal cells that make up the epithelium, provide a physical barrier that protects the host against the unwanted intrusion of microorganisms into the gastrointestinal microbiota, and against the penetration of harmful microorganisms which usurp the cellular molecules and signalling pathways of the host to become pathogenic. One of the basic physiological functions of the resident microbiota is that it functions as a microbial barrier against microbial pathogens. The mechanisms by which the species of the microbiota exert this barrier effect remain largely to be determined. There is increasing evidence that lactobacilli and bifidobacteria, which inhabit the gastrointestinal microbiota, develop antimicrobial activities that participate in the host's gastrointestinal system of defence. The objective of this review is to analyze the in vitro and in vivo experimental and clinical studies in which the antimicrobial activities of selected lactobacilli and bifidobacteria strains have been documented.

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Journal

Journal ID (nlm-ta): Clin Transl Gastroenterol

Journal ID (iso-abbrev): Clin Transl Gastroenterol

Title: Clinical and Translational Gastroenterology

Publisher: Nature Publishing Group

ISSN (Electronic): 2155-384X

Publication date (Print): October 2016

Publication date (Electronic): 20 October 2016

Publication date PMC-release: 1 October 2016

Volume: 7

Issue: 10

Page: e196

Affiliations

[1 ]Nutrition–Gut–Brain Interactions Research Centre, Faculty of Health and Medicine, School of Medical Sciences, Örebro University , Örebro, Sweden

[2 ]Host–Microbe Interactomics, Animal Sciences, Wageningen University , Wageningen, The Netherlands

[3 ]Metabolism and Nutrition Research Group, WELBIO—Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université Catholique de Louvain , Brussels, Belgium

[4 ]Nutrition and Health Research, Nestlé Research Center , Lausanne, Switzerland

[5 ]Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , London, UK

[6 ]European Branch, The International Life Sciences Institute , Brussels, Belgium

[7 ]Division of Gastroenterology-Hepatology, Department of Internal Medicine, University Hospital Maastricht, Maastricht University Medical Centre , Maastricht, The Netherlands

Author notes

[* ]Nutrition–Gut–Brain Interactions Research Centre, Faculty of Health and Medicine, School of Medical Science, Örebro University , Örebro, Sweden. E-mail: publications@ 123456ilsieurope.be

Article

Publisher Item ID: ctg201654

DOI: 10.1038/ctg.2016.54

PMC ID: 5288588

PubMed ID: 27763627

SO-VID: d9b879ea-312b-4f48-987b-e4a9c4612f8d

License:

Clinical and Translational Gastroenterology is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

History

Date received : 05 April 2016

Date accepted : 14 September 2016

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Human Intestinal Barrier Function in Health and Disease

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Karger: Gastroenterology

Most cited references 140

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis

Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens.

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