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      Age-associated Impairment of the Mucus Barrier Function is Associated with Profound Changes in Microbiota and Immunity

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          Abstract

          Aging significantly increases the vulnerability to gastrointestinal (GI) disorders but there are few studies investigating the key factors in aging that affect the GI tract. To address this knowledge gap, we used 10-week- and 19-month-old litter-mate mice to investigate microbiota and host gene expression changes in association with ageing. In aged mice the thickness of the colonic mucus layer was reduced about 6-fold relative to young mice, and more easily penetrable by luminal bacteria. This was linked to increased apoptosis of goblet cells in the upper part of the crypts. The barrier function of the small intestinal mucus was also compromised and the microbiota were frequently observed in contact with the villus epithelium. Antimicrobial Paneth cell factors Ang4 and lysozyme were expressed in significantly reduced amounts. These barrier defects were accompanied by major changes in the faecal microbiota and significantly decreased abundance of Akkermansia muciniphila which is strongly and negatively affected by old age in humans. Transcriptomics revealed age-associated decreases in the expression of immunity and other genes in intestinal mucosal tissue, including decreased T cell-specific transcripts and T cell signalling pathways. The physiological and immunological changes we observed in the intestine in old age, could have major consequences beyond the gut.

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          Interactions between commensal intestinal bacteria and the immune system.

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            Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians

            Background Age-related physiological changes in the gastrointestinal tract, as well as modifications in lifestyle, nutritional behaviour, and functionality of the host immune system, inevitably affect the gut microbiota, resulting in a greater susceptibility to infections. Methodology/Principal Findings By using the Human Intestinal Tract Chip (HITChip) and quantitative PCR of 16S rRNA genes of Bacteria and Archaea, we explored the age-related differences in the gut microbiota composition among young adults, elderly, and centenarians, i.e subjects who reached the extreme limits of the human lifespan, living for over 100 years. We observed that the microbial composition and diversity of the gut ecosystem of young adults and seventy-years old people is highly similar but differs significantly from that of the centenarians. After 100 years of symbiotic association with the human host, the microbiota is characterized by a rearrangement in the Firmicutes population and an enrichment in facultative anaerobes, notably pathobionts. The presence of such a compromised microbiota in the centenarians is associated with an increased inflammatory status, also known as inflammageing, as determined by a range of peripheral blood inflammatory markers. This may be explained by a remodelling of the centenarians' microbiota, with a marked decrease in Faecalibacterium prauznitzii and relatives, symbiotic species with reported anti-inflammatory properties. As signature bacteria of the long life we identified specifically Eubacterium limosum and relatives that were more than ten-fold increased in the centenarians. Conclusions/Significance We provide evidence for the fact that the ageing process deeply affects the structure of the human gut microbiota, as well as its homeostasis with the host's immune system. Because of its crucial role in the host physiology and health status, age-related differences in the gut microbiota composition may be related to the progression of diseases and frailty in the elderly population.
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              The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract.

              A 16S rRNA-targeted probe, MUC-1437, was designed and validated in order to determine the presence and numbers of cells of Akkermansia muciniphila, a mucin degrader, in the human intestinal tract. As determined by fluorescent in situ hybridization, A. muciniphila accounted more than 1% of the total fecal cells and was shown to be a common bacterial component of the human intestinal tract.
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                Author and article information

                Contributors
                jerry.wells@wur.nl
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                5 February 2019
                5 February 2019
                2019
                : 9
                : 1437
                Affiliations
                [1 ]GRID grid.420129.c, Top Institute Food and Nutrition, ; Wageningen, The Netherlands
                [2 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Host-Microbe Interactomics Group, , Wageningen University and Research Center, ; Wageningen, The Netherlands
                [3 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Cell Biology and Immunology Group, , Wageningen University and Research Center, ; Wageningen, The Netherlands
                [4 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [5 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Laboratory of Microbiology, , Wageningen University and Research Center, ; Wageningen, The Netherlands
                [6 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Division of Human Nutrition, , Wageningen University and Research Center, ; Wageningen, The Netherlands
                Author information
                http://orcid.org/0000-0003-0786-1682
                Article
                35228
                10.1038/s41598-018-35228-3
                6363726
                30723224
                72dcc04a-7656-44f1-bc03-7765bc1d2af3
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 20 April 2016
                : 16 October 2018
                Funding
                Funded by: Top Institute Food and Nutrition grant GH002
                Funded by: Top InstituteFood and Nutrition Grant GH002
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