Human gut bacteria produce ΤΗ17-modulating bile acid metabolites

Donggi Paik, Lina Yao, Yancong Zhang, Sena Bae, Gabriel D. D’Agostino, Minghao Zhang, Eunha Kim, Eric A. Franzosa, Julian Avila-Pacheco, Jordan E. Bisanz, Christopher K. Rakowski, Hera Vlamakis, Ramnik J. Xavier, Peter J. Turnbaugh, Randy S. Longman, Michael R. Krout, Clary B. Clish, Fraydoon Rastinejad, Curtis Huttenhower, Jun R. Huh () and A. Sloan Devlin ()
Additional contact information
Donggi Paik: Harvard Medical School
Lina Yao: Harvard Medical School
Yancong Zhang: Broad Institute of MIT and Harvard
Sena Bae: Harvard T. H. Chan School of Public Health
Gabriel D. D’Agostino: Harvard Medical School
Minghao Zhang: University of Oxford
Eunha Kim: Harvard Medical School
Eric A. Franzosa: Harvard T. H. Chan School of Public Health
Julian Avila-Pacheco: Broad Institute of MIT and Harvard
Jordan E. Bisanz: University of California San Francisco
Christopher K. Rakowski: Bucknell University
Hera Vlamakis: Broad Institute of MIT and Harvard
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Peter J. Turnbaugh: University of California San Francisco
Randy S. Longman: Weill Cornell Medicine
Michael R. Krout: Bucknell University
Clary B. Clish: Broad Institute of MIT and Harvard
Fraydoon Rastinejad: University of Oxford
Curtis Huttenhower: Broad Institute of MIT and Harvard
Jun R. Huh: Harvard Medical School
A. Sloan Devlin: Harvard Medical School

Nature, 2022, vol. 603, issue 7903, 907-912

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04480-z

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