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• W2068477809 abstract "<h3>Abstract</h3> <h3>Objective</h3> 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating primary sclerosing cholangitis (PSC), an immune-mediated cholestatic liver disease. Since PSC strongly associates with inflammatory bowel diseases (IBD) driven by T_H17/Treg imbalance, we aimed to explore NorUDCA’s immunomodulatory potential on intestinal T_H17/Treg balance. <h3>Design</h3> NorUDCA’s impact on T_H17/Treg tissue distribution was first assessed in <i>Mdr2</i>^{<i>–/–</i>} mouse model of PSC. We specifically investigated NorUDCA’s effect on modulating T_H17/Treg balance in a CD4⁺ T cell driven colitis model induced by adoptive transfer of CD25⁻CD44^lowCD45RB^highCD4⁺ T_Naïve cells into <i>Rag2</i>^{<i>–/–</i>} mice, mimicking human IBD. Mechanistic studies were performed using molecular approaches, flow cytometry and metabolic assays in murine T_H17 cells <i>in vitro</i>. NorUDCA’s signaling effects observed in murine system were further validated in circulating CD4⁺ T cells from PSC patients with co-existing IBD. <h3>Results</h3> NorUDCA promoted Treg generation in both liver and intestine in the <i>Mdr2</i>^{<i>–/–</i>} model. In the experimental IBD model, NorUDCA attenuated intestinal immunopathology. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in counteracting T_H17/Treg imbalance by restricting glutaminolysis in differentiating T_H17 cells, thus suppressed α-Ketoglutarate-dependent mTORC1 activation, glycolysis and enhanced FOXP3 expression. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating CD4⁺ T-cells from PSC patients with IBD. <h3>Conclusion</h3> NorUDCA possesses direct immunometabolic modulatory potency to counteract T_H17/Treg imbalance and ameliorate excessive T_H17 cell driven intestinal immunopathology. These findings extend future clinical applications of NorUDCA for treatment of T_H17 cell-mediated disorders along the gut-liver axis and beyond. <h3>Significance of this study</h3> <h3>What is already known on this subject?</h3> PSC is an immune-mediated cholestatic liver disease highly associated with IBD where T_H17/Treg imbalance drives immunopathogenesis; seeking effective therapeutics covering both liver and intestinal disease in PSC is of high clinical relevance. Independent of anti-cholestatic effects, NorUDCA has recently been shown to possess direct immunomodulatory properties on CD8⁺ T cell metabolism, lymphoblastogenesis and clonal expansion through targeting mTORC1 signaling. Since mTORC1 serves as critical metabolic checkpoint orchestrating T_H17/Treg axis, inhibiting mTORC1 activity represents a potential treatment avenue counteracting T_H17/Treg imbalance under intestinal inflammatory conditions. <h3>What are the new findings?</h3> NorUDCA enriches FOXP3⁺ Treg population in both liver and intestinal tissue in the cholestatic <i>Mdr2</i>^{<i>–/–</i>} mouse model of PSC. NorUDCA exhibits direct immunomodulatory efficacies in suppressing excess T_H17 cell-mediated intestinal immunopathology and promotes FOXP3⁺ Treg generation in an experimental IBD model. Mechanistically, NorUDCA counteracts T_H17/Treg imbalance by restricting glutaminolysis in differentiating T_H17 cells, thus suppresses α-Ketoglutarate-dependent mTORC1 activation, glycolysis and enhances FOXP3 expression. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating CD4⁺ T cells from patients with PSC and IBD. <h3>How might it impact on clinical practice in the foreseeable future?</h3> These findings advance our current understanding of therapeutic potentials of NorUDCA, which might represent a novel therapeutic strategy in the treatment of PSC and concomitant IBD and other T_H17-mediated intestinal diseases." @default.
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• W2068477809 date "2000-06-03" @default.
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• W2068477809 title "Railway signals passed at danger: psychology matters" @default.
• W2068477809 doi "https://doi.org/10.1136/bmj.320.7248.1549" @default.
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