Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells.

Abstract

Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. Foxp3 expression defines this lineage and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by the Foxp3 enhancer CNS1 (conserved non-coding sequence 1)2–4. Microbial fermentation products including butyrate facilitate the generation of peripherally-induced Treg (pTreg) cells5–7, indicating that metabolites shape colonic immune cell composition. In addition to dietary components, bacteria modify host-derived molecules, generating a number of bioactive substances. This is epitomized by transformation of bile acids (BAs), which creates a complex pool of steroids8 presenting a range of physiological functions9. Here, we screened the major species of deconjugated BAs for their ability to potentiate pTreg cell differentiation. We found that the secondary BA 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Farnesoid X receptor ablation in DCs enhanced Treg cell generation and imposed a transcriptional profile similar to isoDCA, suggesting interaction between this BA/nuclear receptor pair. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased colonic RORγt+ Treg cells in a CNS1-dependent manner, indicative of enhanced extrathymic differentiation.