Abstract
BACKGROUND: 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC). OBJECTIVE: Since PSC strongly associates with T helper-type-like 17 (T(H)17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on T(H)17 cells. DESIGN: NorUDCA's impact on T(H)17 differentiation was assessed using a CD4(+)T(Naive) adoptive transfer mouse model, and on intraepithelial T(H)17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) T(H)17. Pathogenicity of pT(H)17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC. RESULTS: NorUDCA suppressed T(H)17 effector function and enriched regulatory T cell (Treg) abundance upon CD4(+)T(Naive) cell transfer. NorUDCA mitigated intraepithelial T(H)17 pathogenicity and decreased the generation of proinflammatory 'T(H)1-like-T(H)17' cells, and enhanced T(H)17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on T(H)17 pathogenicity. Mechanistically, NorUDCA restrained pT(H)17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pT(H)17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on T(H)17 inflammation was corroborated in the humanised NSG mouse model. CONCLUSION: NorUDCA restricts T(H)17 inflammation in multiple mouse models, potentiating future clinical applications for treating T(H)17-mediated intestinal diseases and beyond.