Ileitis abolishes tolerogenic functions of the enterohepatic bile acid pool

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 immunoregulatory outputs of the enterohepatic BA pools 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 Crohns disease patients and TnfδARE mice depleted primary BAs by reducing the number and function of BA transporting enterocytes. In mice, ileitis driven tβMCA depletion enhanced tDCA and tLCA mediated RORγt activation and supported Th17 cell function. Replenishing tβMCA in TnfδARE mice reestablished BA dependent Th17 cell regulation. Thus, intra pool competition underpins BA immunoregulatory functions and reveals new opportunities for precision Crohns disease therapy.