Human gut bacteria produce TH17-modulating bile acid metabolites

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 diffe...

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Bibliographic Details
Published in:	Nature (London) Vol. 603; no. 7903; pp. 907 - 912
Main Authors:	Paik, Donggi, Yao, Lina, Zhang, Yancong, Bae, Sena, D’Agostino, Gabriel D., Zhang, Minghao, Kim, Eunha, Franzosa, Eric A., Avila-Pacheco, Julian, Bisanz, Jordan E., Rakowski, Christopher K., Vlamakis, Hera, Xavier, Ramnik J., Turnbaugh, Peter J., Longman, Randy S., Krout, Michael R., Clish, Clary B., Rastinejad, Fraydoon, Huttenhower, Curtis, Huh, Jun R., Devlin, A. Sloan
Format:	Journal Article
Language:	English
Published:	31.03.2022
ISSN:	0028-0836, 1476-4687
Online Access:	Get full text
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Summary:	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.
Bibliography:	J.R.H. and A.S.D. conceptualized the study. D.P., L.Y., J.R.H., and A.S.D. conceived the project and designed the experiments. D.P. performed mouse experiments, in vitro T cell and reporter assays. L.Y. performed human isolate screen, bacterial in vitro culture experiments, and BA profiling. G.D.D. performed HSDH enzyme characterization. Y.Z. and S.B. performed the bioinformatics analyses. E.A.F. and C.H. supervised the computational analyses. J.A.P. and C.C. performed LCA derivative identification in PRISM and HMP2 metabolomics. E.K. performed T cell RNA-Seq analysis. M.Z. and F.R. performed in vitro protein binding assays. J.E.B. performed comparative genomics on E. lenta. C.K.R. and M.R.K. synthesized some of the BA derivatives. J.E.B. and P.J.T., supervised the E. lenta human isolate studies. H.V. and R.J.X. provided bacterial strains and technical support. R.L. provided the patient stool samples. D.P., L.Y., Y.Z., S.B., G.D.D., E.A.F., J.R.H., and A.S.D. wrote the manuscript, with contributions from all authors. These authors contributed equally: Donggi Paik, Lina Yao Author contributions
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-022-04480-z