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 Thorbjornsen; Thomas Koecher; M. 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 Karlsen; Wilfried Ellmeier; Michael Trauner

doi:10.1136/gutjnl-2024-333297

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Title (eng)

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

Author

Ci Zhu

Nicole Boucheron

Osamah Al-Rubaye

Brian K. Chung

Liv Wenche Thorbjornsen

Thomas Koecher

M. 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

University of Veterinary Medicine Vienna

Tom Karlsen

Wilfried Ellmeier

Michael Trauner

Abstract (eng)

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.

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4464

DOI

10.1136/gutjnl-2024-333297

Is in series

Title (eng)

GUT

Volume