Ileitis abolishes tolerogenic functions of the enterohepatic bile acid pool

Abstract Bile acids (BAs) regulate lipid uptake, epithelial integrity, and immune responses in the gut. Hepatocytes synthesize primary BAs, which microbiota metabolize into secondary metabolites. Together, these species form a composite pool that circulates enterohepatically between the liver and intestines. Here, we show that immuno-regulatory outputs of the enterohepatic BA pool involve competition between multiple BA species for individual nuclear receptors and are dependent on intestinal health. In healthy mice, the primary BA, tauro-β-muricholic acid (tβMCA) antagonized RORγt-mediated Th17 function in the presence of two secondary BAs (tDCA, tLCA) which activated RORγt. Conversely, ileitis in Crohn’s disease patients and Tnf ΔARE/+ mice depleted primary BAs by reducing the number and function of BA-transporting enterocytes. In mice, ileitis-driven tβMCA depletion enhanced tDCA/tLCA-mediated RORγt activation and supported Th17 cell function, whereas replenishing tβMCA in Tnf ΔARE/+ mice reestablished BA regulation of ileal Th17 cells. Thus, intra-pool competition underpins BA immunoregulatory functions and may reveal new opportunities for precision Crohn’s disease therapy.