Ci Zhu Ci Zhu Nicole Boucheron Nicole Boucheron Osamah Al-Rubaye Osamah Al-Rubaye Brian K. Chung Brian K. Chung Liv Wenche Thorbjornsen Liv Wenche Thorbjornsen Thomas Koecher Thomas Koecher M. Schuster M. Schuster Thierry Claudel Thierry Claudel Emina Halilbasic Emina Halilbasic Victoria Kunczer Victoria Kunczer Fanziska Muscate Fanziska Muscate Lois L. Cavanagh Lois L. Cavanagh Darina Waltenberger Darina Waltenberger ´Alexander Lercher ´Alexander Lercher Anna Ohradanova-Repic Anna Ohradanova-Repic Philipp Schatzlmaier Philipp Schatzlmaier Tatjana Stojakovic Tatjana Stojakovic Hubert Scharnagl Hubert Scharnagl Andreas Bergthaler Andreas Bergthaler Hannes Stockinger Hannes Stockinger Samuel Huber Samuel Huber Christoph Bock Christoph Bock Lukas Kenner Lukas Kenner Tom Karlsen Tom Karlsen Wilfried Ellmeier Wilfried Ellmeier Michael Trauner Michael Trauner BMJ Publishing Group 2025 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 (TH17)-mediated intestinal inflammation, we explored NorUDCA’s immunomodulatory potential on TH17 cells. Design NorUDCA’s impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 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) TH17. Pathogenicity of pTH17 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 TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory ‘TH1-like-TH17’ cells, and enhanced TH17 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 TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA’s impact on TH17 inflammation was corroborated in the humanised NSG mouse model. Conclusion NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond. PDFDocument eng 2025-10-22T08:35:59.794705Z 2025 10539156 b application/pdf http://creativecommons.org/licenses/by-nc/4.0/