Railway signals passed at danger: psychology matters
Authors: G. Bennet
Journal: BMJ (2000)

<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<sub>H</sub>17/Treg imbalance, we aimed to explore NorUDCA’s immunomodulatory potential on intestinal T<sub>H</sub>17/Treg balance. <h3>Design</h3> NorUDCA’s impact on T<sub>H</sub>17/Treg tissue distribution was first assessed in <i>Mdr2</i><sup><i>–/–</i></sup> mouse model of PSC. We specifically investigated NorUDCA’s effect on modulating T<sub>H</sub>17/Treg balance in a CD4<sup>+</sup> T cell driven colitis model induced by adoptive transfer of CD25<sup>−</sup>CD44<sup>low</sup>CD45RB<sup>high</sup>CD4<sup>+</sup> T<sub>Naïve</sub> cells into <i>Rag2</i><sup><i>–/–</i></sup> mice, mimicking human IBD. Mechanistic studies were performed using molecular approaches, flow cytometry and metabolic assays in murine T<sub>H</sub>17 cells <i>in vitro</i>. NorUDCA’s signaling effects observed in murine system were further validated in circulating CD4<sup>+</sup> 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><sup><i>–/–</i></sup> model. In the experimental IBD model, NorUDCA attenuated intestinal immunopathology. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in counteracting T<sub>H</sub>17/Treg imbalance by restricting glutaminolysis in differentiating T<sub>H</sub>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<sup>+</sup> T-cells from PSC patients with IBD. <h3>Conclusion</h3> NorUDCA possesses direct immunometabolic modulatory potency to counteract T<sub>H</sub>17/Treg imbalance and ameliorate excessive T<sub>H</sub>17 cell driven intestinal immunopathology. These findings extend future clinical applications of NorUDCA for treatment of T<sub>H</sub>17 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<sub>H</sub>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<sup>+</sup> T cell metabolism, lymphoblastogenesis and clonal expansion through targeting mTORC1 signaling. Since mTORC1 serves as critical metabolic checkpoint orchestrating T<sub>H</sub>17/Treg axis, inhibiting mTORC1 activity represents a potential treatment avenue counteracting T<sub>H</sub>17/Treg imbalance under intestinal inflammatory conditions. <h3>What are the new findings?</h3> NorUDCA enriches FOXP3<sup>+</sup> Treg population in both liver and intestinal tissue in the cholestatic <i>Mdr2</i><sup><i>–/–</i></sup> mouse model of PSC. NorUDCA exhibits direct immunomodulatory efficacies in suppressing excess T<sub>H</sub>17 cell-mediated intestinal immunopathology and promotes FOXP3<sup>+</sup> Treg generation in an experimental IBD model. Mechanistically, NorUDCA counteracts T<sub>H</sub>17/Treg imbalance by restricting glutaminolysis in differentiating T<sub>H</sub>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<sup>+</sup> 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<sub>H</sub>17-mediated intestinal diseases.