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      Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation

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          Abstract

          Diverse microbial signatures within the intestinal microbiota have been associated with intestinal and systemic inflammatory diseases, but whether these candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem is frequently not known. Here we demonstrate that colonization of mice with a member of the genus Prevotella, which has been previously associated to colitis in mice, exacerbates intestinal inflammation. Our analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, we conclude that intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.

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          Most cited references77

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          The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

          Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
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            Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

            Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.
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              Enterotypes of the human gut microbiome.

              Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.
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                Author and article information

                Contributors
                till.strowig@helmholtz-hzi.de
                Journal
                Mucosal Immunol
                Mucosal Immunol
                Mucosal Immunology
                Nature Publishing Group US (New York )
                1933-0219
                1935-3456
                20 May 2020
                20 May 2020
                2021
                : 14
                : 1
                : 113-124
                Affiliations
                [1 ]GRID grid.7490.a, ISNI 0000 0001 2238 295X, Department of Microbial Immune Regulation, , Helmholtz Center for Infection Research, ; Braunschweig, Germany
                [2 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Hannover Medical School, ; Hannover, Germany
                [3 ]GRID grid.420081.f, ISNI 0000 0000 9247 8466, Bacterial Metabolomics, Leibniz institute DSMZ-German Collection of Microorganisms and Cell Cultures, ; Braunschweig, Germany
                [4 ]GRID grid.6738.a, ISNI 0000 0001 1090 0254, Department of Bioinformatics and Biochemistry, , BRICS, Technische Universität Braunschweig, ; Braunschweig, Germany
                [5 ]GRID grid.7490.a, ISNI 0000 0001 2238 295X, Mouse Pathology, Helmholtz Center for Infection Research, ; Braunschweig, Germany
                [6 ]Centre for Individualised Infection Medicine, Hannover, Germany
                Author information
                http://orcid.org/0000-0003-0185-1459
                Article
                296
                10.1038/s41385-020-0296-4
                7790746
                32433514
                92475890-0109-41ab-a958-f53bf52d66fa
                © The Author(s) 2020

                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
                : 17 September 2019
                : 6 April 2020
                : 23 April 2020
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                © Society for Mucosal Immunology 2021

                Immunology
                Immunology

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