Cholic Acid Reprograms RORγt⁺ Th17 Cells into IL-10-Producing T Cells to Limit Experimental Colitis

Inflammatory bowel disease (IBD) is a relapsing-remitting inflammatory disorder of the gastrointestinal tract driven by dysregulated T helper (Th)-cell responses, gut microbiota imbalance, and altered bile acid metabolism. While cholic acid (CA), a primary bile acid, is immunotoxic at high concentrations, its immunomodulatory role at physiological levels remains unclear. Here, we evaluate the therapeutic potential of CA in an experimental colitis model. Administration of biologically tolerable CA significantly reduced disease activity, preserved colon length, and alleviated histological inflammation. Mechanistically, CA downregulated RORγt levels and promoted Th cell plasticity toward IL-10-producing phenotypes, resulting in diminished production of IFN-γ and IL-17. Dietary depletion of primary bile acid precursors and IL-10 neutralization confirmed IL-10-dependent immunoregulation as a key mechanism. Additionally, synthetic derivatives of CA, similar to CA, attenuated DSS-induced colitis by selectively expanding IL-10-producing Th cells. Collectively, these findings highlight CA and its synthetic derivatives as immunomodulatory candidates for the therapy of ulcerative colitis.