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      Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis

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          Abstract

          T-cells are crucial in maintanence of intestinal homeostasis, however, it is still unclear how microbiota metabolites regulate T-effector cells. Here we show gut microbiota-derived short-chain fatty acids (SCFAs) promote microbiota antigen-specific Th1 cell IL-10 production, mediated by G-protein coupled receptors 43 (GPR43). Microbiota antigen-specific Gpr43 −/− CBir1 transgenic (Tg) Th1 cells, specific for microbiota antigen CBir1 flagellin, induce more severe colitis compared with wide type (WT) CBir1 Tg Th1 cells in Rag −/− recipient mice. Treatment with SCFAs limits colitis induction by promoting IL-10 production, and administration of anti-IL-10R antibody promotes colitis development. Mechanistically, SCFAs activate Th1 cell STAT3 and mTOR, and consequently upregulate transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1), which mediates SCFA-induction of IL-10. SCFA-treated Blimp1 −/− Th1 cells produce less IL-10 and induce more severe colitis compared to SCFA-treated WT Th1 cells. Our studies, thus, provide insight into how microbiota metabolites regulate Th1 cell functions to maintain intestinal homeostasis.

          Abstract

          T cells play a critical role in intestinal homeostasis, with increasing evidence suggesting a role for the microbiome metabolome in modulating this response. Here the authors show short-chain fatty acids promote IL-10 production in Th1 cells.

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          Most cited references23

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          Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells.

          Blimp-1 is a transcriptional repressor able to drive the terminal differentiation of B cells into Ig-secreting plasma cells. We have created mice with a B cell-specific deletion of prdm1, the gene encoding Blimp-1. B cell development and the number of B cells responding to antigen appear to be normal in these mice. However, in response to either TD or TI antigen, serum Ig, short-lived plasma cells, post-GC plasma cells, and plasma cells in a memory response are virtually absent, demonstrating that Blimp-1 is required for plasmacytic differentiation and Ig secretion. In the absence of Blimp-1, CD79b(+)B220(-) pre-plasma memory B cell development is also defective, providing evidence that this subset is an intermediate in plasma cell development. B cells lacking Blimp-1 cannot secrete Ig or induce muS mRNA when stimulated ex vivo. Furthermore, although prdm1-/- B cells fail to induce XBP-1, XBP-1 cannot rescue plasmacytic differentiation without Blimp-1.
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            Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis.

            Short-chain fatty acid irrigation has been shown to ameliorate inflammation in diversion colitis. In this study the effect of butyrate enemas was tested in 10 patients with distal ulcerative colitis who had been unresponsive to or intolerant of standard therapy for 8 weeks. They were treated for 2 weeks with sodium butyrate (100 mmol/L) and 2 weeks with placebo in random order (single-blind trial). Before and after treatment, clinical symptoms were noted and the degree of inflammation was graded endoscopically and histologically. Rectal proliferation was assessed by autoradiography. After butyrate irrigation, stool frequency (n/day) decreased from 4.7 +/- 0.5 to 2.1 +/- 0.4 (P less than 0.01) and discharge of blood ceased in 9 of 10 patients. The endoscopic score fell from 6.5 +/- 0.4 to 3.8 +/- 0.8 (P less than 0.01). The histological degree of inflammation decreased from 2.4 +/- 0.3 to 1.5 +/- 0.3 (P less than 0.02). Overall crypt proliferation was unchanged, but the upper crypt-labeling index fell from 0.086 +/- 0.019 to 0.032 +/- 0.003 (P less than 0.03). On placebo, all of these parameters were unchanged. These data support the view that butyrate deficiency may play a role in the pathogenesis of distal ulcerative colitis and that butyrate irrigation ameliorates this condition.
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              A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota.

              A T cell receptor transgenic mouse line reactive to a microbiota flagellin, CBir1, was used to define mechanisms of host microbiota homeostasis. Intestinal IgA, but not serum IgA, was found to block mucosal flagellin uptake and systemic T cell activation in mice. Depletion of CD4(+)CD25(+) Tregs decreased IgA(+) B cells, total IgA, and CBir1-specific IgA in gut within days. Repletion of T cell-deficient mice with either CD4(+)CD25(+) or CD4(+)foxp3(+) Tregs restored intestinal IgA to a much greater extent than their reciprocal CD4(+) subsets, indicating that Tregs are the major helper cells for IgA responses to microbiota antigens such as flagellin. We propose that the major role of this coordinated Treg-IgA response is to maintain commensalism with the microbiota.
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                Author and article information

                Contributors
                liuzhanju88@126.com
                yicong@utmb.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                3 September 2018
                3 September 2018
                2018
                : 9
                : 3555
                Affiliations
                [1 ]ISNI 0000000123704535, GRID grid.24516.34, Department of Gastroenterology, The Shanghai Tenth Peoples Hospital, , Tongji University, ; 200072 Shanghai, China
                [2 ]ISNI 0000 0001 1547 9964, GRID grid.176731.5, Department of Microbiology and Immunology, , The University of Texas Medical Branch, ; Galveston, TX 77555 USA
                [3 ]ISNI 0000 0001 1547 9964, GRID grid.176731.5, Department of Pathology, , University of Texas Medical Branch, ; Galveston, TX 77555 USA
                [4 ]ISNI 0000 0001 1547 9964, GRID grid.176731.5, Department of Internal Medicine, , The University of Texas Medical Branch, ; Galveston, TX 77555 USA
                [5 ]GRID grid.419971.3, Bristol-Myers Squibb, ; Princeton, NJ 08540 USA
                Author information
                http://orcid.org/0000-0003-4167-7395
                Article
                5901
                10.1038/s41467-018-05901-2
                6120873
                30177845
                3262a841-7516-4407-a22e-7bb162a51842
                © The Author(s) 2018

                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
                : 7 December 2017
                : 20 July 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: DK098370
                Award ID: DK105585
                Award ID: DK112436
                Award Recipient :
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