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

Ci Zhu; Nicole Boucheron; Osamah Al-Rubaye; Brian K Chung; Liv Wenche Thorbjørnsen; Thomas Köcher; Michael Schuster; Thierry Claudel; Emina Halilbasic; Victoria Kunczer; Fanziska Muscate; Lois L Cavanagh; Darina Waltenberger; Alexander Lercher; Anna Ohradanova-Repic; Philipp Schatzlmaier; Tatjana Stojakovic; Hubert Scharnagl; Andreas Bergthaler; Hannes Stockinger; Samuel Huber; Christoph Bock; Lukas Kenner; Tom H Karlsen; Wilfried Ellmeier; Michael Trauner

doi:10.1136/gutjnl-2024-333297

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

Gut. 2025 Mar 7:gutjnl-2024-333297. doi: 10.1136/gutjnl-2024-333297. Online ahead of print.

Authors

Ci Zhu^{1

2}, Nicole Boucheron², Osamah Al-Rubaye², Brian K Chung³, Liv Wenche Thorbjørnsen³, Thomas Köcher⁴, Michael Schuster⁵, Thierry Claudel¹, Emina Halilbasic¹, Victoria Kunczer¹, Fanziska Muscate⁶, Lois L Cavanagh², Darina Waltenberger², Alexander Lercher⁷, Anna Ohradanova-Repic⁸, Philipp Schatzlmaier⁸, Tatjana Stojakovic⁹, Hubert Scharnagl¹⁰, Andreas Bergthaler^{7

8}, Hannes Stockinger⁸, Samuel Huber¹¹, Christoph Bock⁵, Lukas Kenner^{12

13}, Tom H Karlsen³, Wilfried Ellmeier¹⁴, Michael Trauner¹⁵

Affiliations

¹ Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
² Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
³ Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁴ Vienna BioCenter Core Facilities, Metabolomics, Vienna BioCenter, Vienna, Austria.
⁵ Biomedical Sequencing Facility, Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
⁶ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
⁷ Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
⁸ Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria.
¹⁰ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
¹¹ I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹² Division of Experimental and Translational Pathology, Department of Pathology, Medical University of Vienna, Vienna, Austria.
¹³ Unit of Laboratory Animal Pathology, Department for Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
¹⁴ Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria michael.trauner@meduniwien.ac.at wilfried.ellmeier@meduniwien.ac.at.
¹⁵ Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria michael.trauner@meduniwien.ac.at wilfried.ellmeier@meduniwien.ac.at.

PMID: 40032499
DOI: 10.1136/gutjnl-2024-333297

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_H17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on T_H17 cells.

Design: 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.

Results: 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.

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

Keywords: AUTOIMMUNE LIVER DISEASE; BILE ACID; INFLAMMATORY BOWEL DISEASE; INTESTINAL T CELLS; PRIMARY SCLEROSING CHOLANGITIS.