A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1

Bile acids act as signaling molecules that regulate immune homeostasis, including the differentiation of CD4(+) T cells into distinct T cell subsets. 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). 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. We also show that the nuclear hormone receptor NR4A1 is required for the effect of isoalloLCA on T-reg cells. 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.

Automated summary

Bile acids regulate immune balance by affecting T cell differentiation, with isoalloLCA promoting T-reg cell differentiation through chromatin structure changes; gut bacteria capable of producing isoalloLCA belong to common human gut bacterial phylum Bacteroidetes, and NR4A1 is essential for isoalloLCA's effects on T-reg cells; significantly reduced levels of isoalloLCA in patients with inflammatory bowel diseases suggest a critical role for isoalloLCA and its bacterial producers in maintaining immune homeostasis in humans.