24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting T_H17 pathogenicity and transdifferentiation

24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC).

Since PSC strongly associates with T helper-type-like 17 (T_H17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on T_H17 cells.

NorUDCA's impact on T_H17 differentiation was assessed using a CD4⁺T_Naive adoptive transfer mouse model, and on intraepithelial T_H17 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_H17. Pathogenicity of pT_H17 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.

NorUDCA suppressed T_H17 effector function and enriched regulatory T cell (Treg) abundance upon CD4⁺T_Naive cell transfer. NorUDCA mitigated intraepithelial T_H17 pathogenicity and decreased the generation of proinflammatory 'T_H1-like-T_H17' cells, and enhanced T_H17 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_H17 pathogenicity. Mechanistically, NorUDCA restrained pT_H17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pT_H17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on T_H17 inflammation was corroborated in the humanised NSG mouse model.

NorUDCA restricts T_H17 inflammation in multiple mouse models, potentiating future clinical applications for treating T_H17-mediated intestinal diseases and beyond.