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 (T H 17 cells). We previously reported that the bile acid (BA) metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits T H 17 cell d...

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Published inNature (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
LanguageEnglish
Published 31.03.2022
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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 (T H 17 cells). We previously reported that the bile acid (BA) metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits T H 17 cell differentiation 1 . 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 T H 17 differentiation by inhibiting RORγt (retinoic acid receptor-related orphan nuclear receptor γt), a key T H 17 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 T H 17 cell-associated genes. Overall, our data suggest that bacterially produced BAs inhibit T H 17 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