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      Layered defense: how mucus and tight junctions seal the intestinal barrier

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          Abstract

          The colonic mucosa provides a vital defensive barrier separating the body from the microbial populations residing in the intestinal lumen. Indeed, growing evidence shows that loss of this barrier may cause disease or exacerbate disease progression. The loss of barrier integrity increases the translocation of bacterial antigens and stimulates inflammation in the intestinal mucosa, which is the central pathological feature of inflammatory bowel diseases (IBDs). This review focuses on how intestinal mucus and intercellular tight junctions (TJs) act together to maintain the integrity of the colonic barrier and how barrier integrity is dysregulated in IBD.

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          Most cited references53

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          Tight junctions: from simple barriers to multifunctional molecular gates.

          Epithelia and endothelia separate different tissue compartments and protect multicellular organisms from the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma-membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Recent advances have broadened our understanding of the molecular architecture and cellular functions of tight junctions.
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            The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions.

            The normal intestinal microbiota inhabits the colon mucus without triggering an inflammatory response. The reason for this and how the intestinal mucus of the colon is organized have begun to be unraveled. The mucus is organized in two layers: an inner, stratified mucus layer that is firmly adherent to the epithelial cells and approximately 50 μm thick; and an outer, nonattached layer that is usually approximately 100 μm thick as measured in mouse. These mucus layers are organized around the highly glycosylated MUC2 mucin, forming a large, net-like polymer that is secreted by the goblet cells. The inner mucus layer is dense and does not allow bacteria to penetrate, thus keeping the epithelial cell surface free from bacteria. The inner mucus layer is converted into the outer layer, which is the habitat of the commensal flora. The outer mucus layer has an expanded volume due to proteolytic activities provided by the host but probably also caused by commensal bacterial proteases and glycosidases. The numerous O-glycans on the MUC2 mucin not only serve as nutrients for the bacteria but also as attachment sites and, as such, probably contribute to the selection of the species-specific colon flora. This observation that normal human individuals carry a uniform MUC2 mucin glycan array in colon may indicate such a specific selection.
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              Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration.

              Small populations of adult stem cells are responsible for the remarkable ability of the epithelial lining of the intestine to be efficiently renewed and repaired throughout life. The recent discovery of specific markers for these stem cells, together with the development of new technologies to track endogenous stem cell activity in vivo and to exploit their ability to generate new epithelia ex vivo, has greatly improved our understanding of stem cell-driven homeostasis, regeneration and cancer in the intestine. These exciting new insights into the biology of intestinal stem cells have the potential to accelerate the development of stem cell-based therapies and ameliorate cancer treatments.
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                Author and article information

                Contributors
                ccapald@emory.edu
                Journal
                J Mol Med (Berl)
                J. Mol. Med
                Journal of Molecular Medicine (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0946-2716
                1432-1440
                13 July 2017
                13 July 2017
                2017
                : 95
                : 9
                : 927-934
                Affiliations
                [1 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Cell Biology, , Emory University School of Medicine, ; 615 Michael Street. Whitehead Research Building #143, Atlanta, GA 30322 USA
                [2 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Pathology and Laboratory Medicine, , Emory University School of Medicine, ; Atlanta, GA USA
                Article
                1557
                10.1007/s00109-017-1557-x
                5548832
                28707083
                a36ee81d-1691-41b6-9a3f-f36ef7135e55
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 23 February 2017
                : 22 May 2017
                : 1 June 2017
                Funding
                Funded by: Crohn's and Colitis Foundation
                Award ID: Career Development award
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 2R01DK074731-04A1
                Award Recipient :
                Categories
                Review
                Custom metadata
                © Springer-Verlag GmbH Germany 2017

                Molecular medicine
                mucus,tight junction,epithelial barrier,inflammation,ibd
                Molecular medicine
                mucus, tight junction, epithelial barrier, inflammation, ibd

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