Zhu Ci, Boucheron Nicole, Al-Rubaye Osamah, Chung Brian K, Thorbjørnsen Liv Wenche, Köcher Thomas, Schuster Michael, Claudel Thierry, Halilbasic Emina, Kunczer Victoria, Muscate Fanziska, Cavanagh Lois L, Waltenberger Darina, Lercher Alexander, Ohradanova-Repic Anna, Schatzlmaier Philipp, Stojakovic Tatjana, Scharnagl Hubert, Bergthaler Andreas, Stockinger Hannes, Huber Samuel, Bock Christoph, Kenner Lukas, Karlsen Tom H, Ellmeier Wilfried, Trauner Michael
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Gut. 2025 Jun 6;74(7):1079-1093. doi: 10.1136/gutjnl-2024-333297.
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 (T17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on T17 cells.
NorUDCA's impact on T17 differentiation was assessed using a CD4T adoptive transfer mouse model, and on intraepithelial T17 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) T17. Pathogenicity of pT17 exposed to NorUDCA 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 T17 effector function and enriched regulatory T cell (Treg) abundance upon CD4T cell transfer. NorUDCA mitigated intraepithelial T17 pathogenicity and decreased the generation of proinflammatory 'T1-like-T17' cells, and enhanced T17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on T17 pathogenicity. Mechanistically, NorUDCA restrained pT17 effector function and simultaneously promoted functional Treg formation , by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pT17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on T17 inflammation was corroborated in the humanised NSG mouse model.
NorUDCA restricts T17 inflammation in multiple mouse models, potentiating future clinical applications for treating T17-mediated intestinal diseases and beyond.
24-去甲熊去氧胆酸（NorUDCA）是一种用于治疗免疫介导的胆汁淤积性肝病（如原发性硬化性胆管炎（PSC））的新型治疗性胆汁酸。
由于PSC与辅助性T细胞样17（T17）介导的肠道炎症密切相关，我们探究了NorUDCA对T17细胞的免疫调节潜力。
使用CD4T过继转移小鼠模型评估NorUDCA对T17分化的影响，并使用αCD3刺激模型结合白细胞介素-17A命运图谱评估其对上皮内T17致病性和转分化的影响。机制研究采用分子和多组学方法、流式细胞术以及对致病性（p）T17进行代谢分析。在肠道组织或中枢神经系统（CNS）过继转移后，评估暴露于NorUDCA的pT17的致病性。在用PSC患者外周血单核细胞重建的αCD3刺激的人源化NSG小鼠模型中验证关键发现。
在CD4T细胞转移后，NorUDCA抑制T17效应功能并增加调节性T细胞（Treg）丰度。在αCD3模型中，NorUDCA减轻上皮内T17致病性并减少促炎性“T1样-T17”细胞的产生，并增强T17向Treg和Tr1（调节性1型）细胞的转分化。去除Treg显示Treg诱导对于NorUDCA对T17致病性的抗炎作用至关重要。机制上，NorUDCA通过减弱谷氨酰胺-mTORC1-糖酵解信号轴，抑制pT17效应功能并同时促进功能性Treg形成。pT17暴露于NorUDCA会减弱其在转移后在肠道或CNS中的致病性和扩增。NorUDCA对T17炎症的影响在人源化NSG小鼠模型中得到证实。
NorUDCA在多个小鼠模型中限制T17炎症，增强了其未来在治疗T17介导的肠道疾病及其他疾病中的临床应用潜力。
