24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting T<sub>H</sub>17 pathogenicity and transdifferentiation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40032499.
- Also identified by DOI 10.1136/gutjnl-2024-333297 and PMC identifier 12322472.
- Licence recorded as CC BY-NC.
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Abstract
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 (T<sub>H</sub>17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on T<sub>H</sub>17 cells. NorUDCA's impact on T<sub>H</sub>17 differentiation was assessed using a CD4<sup>+</sup>T<sub>Naive</sub> adoptive transfer mouse model, and on intraepithelial T<sub>H</sub>17 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) T<sub>H</sub>17. Pathogenicity of pT<sub>H</sub>17 exposed to NorUDCA <i>in vitro</i> 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 T<sub>H</sub>17 effector function and enriched regulatory T cell (Treg) abundance upon CD4<sup>+</sup>T<sub>Naive</sub> cell transfer. NorUDCA mitigated intraepithelial T<sub>H</sub>17 pathogenicity and decreased the generation of proinflammatory 'T<sub>H</sub>1-like-T<sub>H</sub>17' cells, and enhanced T<sub>H</sub>17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. <i>In vivo</i> ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on T<sub>H</sub>17 pathogenicity. Mechanistically, NorUDCA restrained pT<sub>H</sub>17 effector function and simultaneously promoted functional Treg formation <i>in vitro</i>, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pT<sub>H</sub>17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on T<sub>H</sub>17 inflammation was corroborated in the humanised NSG mouse model. NorUDCA restricts T<sub>H</sub>17 inflammation in multiple mouse models, potentiating future clinical applications for treating T<sub>H</sub>17-mediated intestinal diseases and beyond.
Medical subject headings
- Th17 Cells
- Cell Transdifferentiation
- Ursodeoxycholic Acid
- Cholangitis, Sclerosing