Bile acid metabolites control TH17 and Treg cell differentiation

Saiyu Hang, Donggi Paik, Lina Yao, Eunha Kim, Jamma Trinath, Jingping Lu, Soyoung Ha, Brandon N. Nelson, Samantha P. Kelly, Lin Wu, Ye Zheng, Randy S. Longman, Fraydoon Rastinejad, A. Sloan Devlin, Michael R. Krout, Michael A. Fischbach (), Dan R. Littman () and Jun R. Huh ()
Additional contact information
Saiyu Hang: Blavatnik Institute, Harvard Medical School
Donggi Paik: Blavatnik Institute, Harvard Medical School
Lina Yao: Blavatnik Institute, Harvard Medical School
Eunha Kim: Blavatnik Institute, Harvard Medical School
Jamma Trinath: Birla Institute of Technology and Science
Jingping Lu: University of Oxford
Soyoung Ha: Blavatnik Institute, Harvard Medical School
Brandon N. Nelson: Bucknell University
Samantha P. Kelly: Bucknell University
Lin Wu: New York University School of Medicine
Ye Zheng: The Salk Institute for Biological Studies
Randy S. Longman: Jill Roberts Center for IBD, Weill Cornell Medicine
Fraydoon Rastinejad: University of Oxford
A. Sloan Devlin: Blavatnik Institute, Harvard Medical School
Michael R. Krout: Bucknell University
Michael A. Fischbach: Stanford University
Dan R. Littman: New York University School of Medicine
Jun R. Huh: Blavatnik Institute, Harvard Medical School

Nature, 2019, vol. 576, issue 7785, 143-148

Abstract: Abstract Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (TH17 cells) or regulatory T cells (Treg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of TH17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced TH17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of TH17 and Treg cells.

Date: 2019
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DOI: 10.1038/s41586-019-1785-z

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