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

Intestinal health relies on the immunosuppressive activity of CD4⁺ regulatory T (T_reg) cells¹. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)^2-4. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced T_reg (pT_reg) cells^5-7, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids⁸ with a range of physiological functions⁹. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pT_reg cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of T_reg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing T_reg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.