24-Nor-ursodeoxycholic acid counteracts TH17/Treg imbalance and ameliorates intestinal inflammation by restricting glutaminolysis in differentiating TH17 cells

Abstract Objective 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 H 17/Treg imbalance, we aimed to explore NorUDCA’s immunomodulatory potential on intestinal T H 17/Treg balance. Design NorUDCA’s impact on T H 17/Treg tissue distribution was first assessed in Mdr2 –/– mouse model of PSC. We specifically investigated NorUDCA’s effect on modulating T H 17/Treg balance in a CD4 + T cell driven colitis model induced by adoptive transfer of CD25 − CD44 low CD45RB high CD4 + T Naïve cells into Rag2 –/– mice, mimicking human IBD. Mechanistic studies were performed using molecular approaches, flow cytometry and metabolic assays in murine T H 17 cells in vitro . NorUDCA’s signaling effects observed in murine system were further validated in circulating CD4 + T cells from PSC patients with co-existing IBD. Results NorUDCA promoted Treg generation in both liver and intestine in the Mdr2 –/– model. In the experimental IBD model, NorUDCA attenuated intestinal immunopathology. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in counteracting T H 17/Treg imbalance by restricting glutaminolysis in differentiating T H 17 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. Conclusion NorUDCA possesses direct immunometabolic modulatory potency to counteract T H 17/Treg imbalance and ameliorate excessive T H 17 cell driven intestinal immunopathology. These findings extend future clinical applications of NorUDCA for treatment of T H 17 cell-mediated disorders along the gut-liver axis and beyond. Significance of this study What is already known on this subject? PSC is an immune-mediated cholestatic liver disease highly associated with IBD where T H 17/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 H 17/Treg axis, inhibiting mTORC1 activity represents a potential treatment avenue counteracting T H 17/Treg imbalance under intestinal inflammatory conditions. What are the new findings? NorUDCA enriches FOXP3 + Treg population in both liver and intestinal tissue in the cholestatic Mdr2 –/– mouse model of PSC. NorUDCA exhibits direct immunomodulatory efficacies in suppressing excess T H 17 cell-mediated intestinal immunopathology and promotes FOXP3 + Treg generation in an experimental IBD model. Mechanistically, NorUDCA counteracts T H 17/Treg imbalance by restricting glutaminolysis in differentiating T H 17 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. How might it impact on clinical practice in the foreseeable future? 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 H 17-mediated intestinal diseases.