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      Bile acid metabolites control Th17 and Treg cell differentiation

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          Abstract

          Bile acids are abundant in the mammalian gut where they undergo bacteria-mediated transformation, generating a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells expressing IL-17a (Th17 cells) and regulatory T cells (Tregs). By screening a library of bile acid metabolites, we identified two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators. 3-oxoLCA inhibited Th17 cell differentiation by directly binding to its key transcription factor RORγt (retinoid-related orphan receptor γt) and isoalloLCA enhanced Treg differentiation through the production of mitochondrial reactive oxygen species (mitoROS), leading to increased FoxP3 expression. IsoalloLCA-mediated Treg enhancement required an intronic FoxP3 enhancer, the conserved noncoding sequence 3 (CNS3), a distinct mode of action from previously-identified Treg enhancing metabolites that require CNS1. Administration of 3-oxoLCA and isoalloLCA to mice reduced Th17 and increased Treg cell differentiation in the intestinal lamina propria. Our data suggest novel mechanisms by which bile acid metabolites control host immune responses by directly modulating the Th17 and Treg balance.

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          Most cited references34

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          Is Open Access

          T cell metabolism drives immunity

          Buck et al. discuss the role of lymphocyte metabolism on immune cell development and function.
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            Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

            Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.
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              Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

              Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                11 November 2019
                27 November 2019
                December 2019
                27 May 2020
                : 576
                : 7785
                : 143-148
                Affiliations
                [1 ]Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
                [2 ]Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
                [3 ]Department of Biological Sciences, Birla Institute of Technology & Science, Pilani-Hyderabad, Hyderabad 500078, Telangana, India
                [4 ]Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, United Kingdom
                [5 ]Department of Chemistry, Bucknell University, Lewisburg, PA 17837, USA
                [6 ]The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
                [7 ]Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
                [8 ]Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY, 10021, USA
                [9 ]Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
                [10 ]Howard Hughes Medical Institute, New York, NY 10016, USA
                [11 ]Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                Author Contributions

                M.A.F., J.R.H., and D.R.L. conceptualized the study. S.H., D.P., A.S.D., M.R.K., M.A.F., D.R.L., and J.R.H. conceived and designed the experiments; S.H. and D.P. performed most of the experiments; L.Y., E.K., T.J., A.S.D., J.L., S.H., B.N.N., S.P.K., and L.W. provided help with experiments; J.L. and F.R. designed and performed the RORγt binding assay; B.N.N., S.P.K., and M.R.K. synthesized certain bile acid derivatives; L.Y. and A.S.D. performed in vivo bile acid analyses; R.S.L. and Y.Z. provided critical materials; and S.H., D.P., and J.R.H. wrote the manuscript, with contributions from all authors.

                Article
                NIHMS1540223
                10.1038/s41586-019-1785-z
                6949019
                31776512
                d4f040ea-9c42-4785-8ed4-9574c9b9f2b0

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