24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting TH17 pathogenicity and transdifferentiation

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.