Bile acid metabolites control TH17 and Treg cell differentiation

Posted by: | January 8, 2020 | Comments

Abstract

Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules

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.

Read more at: Nature

Saiyu Hang, Donggi Paik, Lina Yao, Eunha Kim, Trinath Jamma, 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 & Jun R. Huh. Nature. DOI: https://doi.org/10.1038/s41586-019-1785-z. 27 November 2019.





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