Journal Article

Human gut bacteria produce TH17-modulating bile acid metabolites

Zhang, Yancong, Avila-Pacheco, Julian, Clish, Clary B., Franzosa, Eric A., Yao, Lina, Zhang, Minghao, Devlin, A. Sloan, D’Agostino, Gabriel D., Turnbaugh, Peter J., Kim, Eunha, Krout, Michael R., Rastinejad, Fraydoon, Paik, Donggi, Bae, Sena, Xavier, Ramnik J., Huttenhower, Curtis, Bisanz, Jordan E., Huh, Jun R., Rakowski, Christopher K., Vlamakis, Hera, Longman, Randy S.

2022

Overview

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 (BA) metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. While 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 BAs are associated with inflammatory pathologies in humans. Here, we identify human gut bacteria and corresponding enzymes that convert the secondary BA lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Like 3-oxoLCA, isoLCA suppressed TH17 differentiation by inhibiting RORγt (retinoic acid receptor-related orphan nuclear receptor γt), a key TH17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase (3α-HSDH) genes required for their biosynthesis were significantly reduced in inflammatory bowel disease (IBD) patients. Moreover, levels of these BAs were inversely correlated with expression of TH17 cell-associated genes. Overall, our data suggest that bacterially produced BAs inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as IBD.