![]() ![]() ![]() ![]() Notably, both the levels of isoalloLCA and the abundance of isoalloLCA-producing bacterial genes are significantly reduced in human inflammatory bowel disease (IBD) cohorts compared with healthy controls. IsoalloLCA treatments result in the increased binding of NR4A1 at the Foxp3 locus, leading to enhanced Foxp3 gene transcription. We also demonstrate that isoalloLCA induces the differentiation of naive T cells to T reg cells through the nuclear hormone receptor NR4A1. Producer strains possess an inducible operon required for isoalloLCA synthesis in vitro and in vivo in germ-free (GF) mice monocolonized with Bacteroidetes species. Here, we identify species of Bacteroidetes, a phylum of bacteria that is abundant in the human gut, that produce isoalloLCA. In this work, we sought to determine whether human gut bacteria can biosynthesize isoalloLCA and to elucidate the mechanism by which isoalloLCA enhances T reg cell differentiation. Moreover, the levels of isoalloLCA and its biosynthetic genes are significantly reduced in patients with inflammatory bowel diseases, suggesting that isoalloLCA and its bacterial producers may play a critical role in maintaining immune homeostasis in humans. We also show that the nuclear hormone receptor NR4A1 is required for the effect of isoalloLCA on T reg cells. Here, we identify gut bacteria that synthesize isoalloLCA from 3-oxolithocholic acid and uncover a gene cluster responsible for the conversion in members of the abundant human gut bacterial phylum Bacteroidetes. The bile acid metabolite isoallolithocholic acid (isoalloLCA) enhances the differentiation of anti-inflammatory regulatory T cells (T reg cells) by facilitating the formation of a permissive chromatin structure in the promoter region of the transcription factor forkhead box P3 ( Foxp3). Bile acids act as signaling molecules that regulate immune homeostasis, including the differentiation of CD4 + T cells into distinct T cell subsets. ![]()
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