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The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (T H 17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits T H 17 cell differentiation 1 . Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed T H 17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key T H 17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase genes that are required for their biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of T H 17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit T H 17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.

Titel:	Human gut bacteria produce Τ <subscript>Η</subscript> 17-modulating bile acid metabolites.
Autor/in / Beteiligte Person:	Paik, D ; Yao, L ; Zhang, Y ; Bae, S ; D'Agostino, GD ; Zhang, M ; Kim, E ; Franzosa, EA ; Avila-Pacheco, J ; Bisanz, JE ; Rakowski, CK ; Vlamakis, H ; Xavier, RJ ; Turnbaugh, PJ ; Longman, RS ; Krout, MR ; Clish, CB ; Rastinejad, F ; Huttenhower, C ; Huh, JR ; Devlin, AS
Zeitschrift:	Nature, Jg. 603 (2022-03-01), Heft 7903, S. 907-912
Veröffentlichung:	Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: London, Macmillan Journals ltd., 2022
Medientyp:	academicJournal
ISSN:	1476-4687 (electronic)
DOI:	10.1038/s41586-022-04480-z
Schlagwort:	Cell Differentiation Gastrointestinal Tract microbiology Humans Interleukin-17 Lithocholic Acid metabolism Lithocholic Acid pharmacology Th17 Cells Bacteria metabolism Bile Acids and Salts Inflammatory Bowel Diseases metabolism Inflammatory Bowel Diseases microbiology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nature] 2022 Mar; Vol. 603 (7903), pp. 907-912. <i>Date of Electronic Publication: </i>2022 Mar 16. MeSH Terms: Bacteria* / metabolism ; Bile Acids and Salts* ; Inflammatory Bowel Diseases* / metabolism ; Inflammatory Bowel Diseases* / microbiology ; Cell Differentiation ; Gastrointestinal Tract / microbiology ; Humans ; Interleukin-17 ; Lithocholic Acid / metabolism ; Lithocholic Acid / pharmacology ; Th17 Cells Comments: Comment in: Gastroenterology. 2022 Jul;163(1):333-334. (PMID: 35525319) References: Hang, S. et al. Bile acid metabolites control T H 17 and T reg cell differentiation. Nature 576, 143–148 (2019). (PMID: 31776512694901910.1038/s41586-019-1785-z) ; Fiorucci, S. & Distrutti, E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol. Med. 21, 702–714 (2015). 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(PMID: 2719663810.1016/j.mimet.2016.05.008) Grant Information: P30 DK040561 United States DK NIDDK NIH HHS; R00 AI147165 United States AI NIAID NIH HHS; R01 DK110559 United States DK NIDDK NIH HHS; P30 DK043351 United States DK NIDDK NIH HHS; R01 DK120985 United States DK NIDDK NIH HHS; R35 GM128618 United States GM NIGMS NIH HHS; K99 AI147165 United States AI NIAID NIH HHS; T32 GM095450 United States GM NIGMS NIH HHS; R24 DK110499 United States DK NIDDK NIH HHS; 210664/Z/18/Z United Kingdom WT_ Wellcome Trust; U54 DE023798 United States DE NIDCR NIH HHS; P30 DK034854 United States DK NIDDK NIH HHS; R01 DK114252 United States DK NIDDK NIH HHS; R01 AR074500 United States AR NIAMS NIH HHS Substance Nomenclature: 0 (Bile Acids and Salts) ; 0 (IL17A protein, human) ; 0 (Interleukin-17) ; 5QU0I8393U (Lithocholic Acid) Entry Date(s): Date Created: 20220317 Date Completed: 20220415 Latest Revision: 20240210 Update Code: 20240210 PubMed Central ID: PMC9132548

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Human gut bacteria produce Τ <subscript>Η</subscript> 17-modulating bile acid metabolites.