胆酸
胆汁酸
免疫系统
细菌
G蛋白偶联胆汁酸受体
维甲酸
生物
代谢物
生物化学
核受体
肠道菌群
细胞
化学
微生物学
转录因子
免疫学
基因
遗传学
作者
Donggi Paik,Lina Yao,Yancong Zhang,Sena Bae,Gabriel D. D’Agostino,Minghao Zhang,Eunha Kim,Eric A. Franzosa,Julián Ávila-Pacheco,Jordan E. Bisanz,Christopher K. Rakowski,Hera Vlamakis,Ramnik J. Xavier,Peter J. Turnbaugh,Randy Longman,Michael R. Krout,Clary B. Clish,Fraydoon Rastinejad,Curtis Huttenhower,Jun R. Huh,A. Sloan Devlin
出处
期刊:Nature
[Springer Nature]
日期:2022-03-16
卷期号:603 (7903): 907-912
被引量:205
标识
DOI:10.1038/s41586-022-04480-z
摘要
The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. 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 TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key TH17-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 TH17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.
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