Human gut bacteria produce TH17-modulating bile acid metabolites

Paik, D.; Yao, L.; Zhang, Y.; Bae, S.; D'Agostino, G. D.; Kim, E.; Franzosa, E. A.; Avila-Pacheco, J.; Bisanz, J. E.; Rakowski, C. K.; Vlamakis, H.; Xavier, R. J.; Turnbaugh, P. J.; Longman, R. S.; Krout, M. R.; Clish, C. B.; Huttenhower, C.; Huh, J. R.; Devlin, A. S.

doi:10.1101/2021.01.08.425913

bioRxiv · 10.1101/2021.01.08.425913

Human gut bacteria produce TH17-modulating bile acid metabolites

Paik, D.·Yao, L.·Zhang, Y.·Bae, S.·D'Agostino, G. D.·Kim, E.·Franzosa, E. A.·Avila-Pacheco, J.·Bisanz, J. E.·Rakowski, C. K.·Vlamakis, H.·Xavier, R. J.·Turnbaugh, P. J.·Longman, R. S.·Krout, M. R.·Clish, C. B.·Huttenhower, C.·Huh, J. R.·Devlin, A. S.

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Abstract

The microbiota plays a pivotal role in 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. While it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown. Furthermore, it was not clear whether 3-oxoLCA and other immunomodulatory bile acids are associated with gut inflammatory pathologies in humans. Using a high-throughput screen, we identified 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). Like 3-oxoLCA, isoLCA suppressed TH17 differentiation by inhibiting ROR{gamma}t (retinoic acid receptor-related orphan nuclear receptor {gamma}t), a key TH17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3-hydroxysteroid dehydrogenase (3-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). Moreover, levels of these bile acids were inversely correlated with expression of TH17 cell-associated genes. Overall, our data suggest that bacterially produced TH17 cell-inhibitory bile acids may reduce the risk of autoimmune and inflammatory disorders such as IBD.

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Paik, D., Yao, L., Zhang, Y., Bae, S., D'Agostino, G. D., Kim, E., Franzosa, E. A., Avila-Pacheco, J., Bisanz, J. E., Rakowski, C. K., Vlamakis, H., Xavier, R. J., Turnbaugh, P. J., Longman, R. S., Krout, M. R., Clish, C. B., Huttenhower, C., Huh, J. R., Devlin, A. S.. 2021-01-09. Human gut bacteria produce TH17-modulating bile acid metabolites. https://doi.org/10.1101/2021.01.08.425913

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