24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting T_H17 pathogenicity and transdifferentiation

Area of Science:

• Immunology
• Gastroenterology
• Hepatology

Background:

• 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel bile acid therapeutic.
• Immune-mediated cholestatic liver diseases, like primary sclerosing cholangitis (PSC), involve T helper 17 (T_H17) cell inflammation.

Purpose of the Study:

• To investigate NorUDCA's immunomodulatory effects on T_H17 cells.
• To explore NorUDCA's potential in treating T_H17-mediated intestinal inflammation associated with PSC.

Main Methods:

• Utilized CD4+T_Naive adoptive transfer and αCD3 stimulation mouse models.
• Assessed T_H17 differentiation, pathogenicity, and transdifferentiation using fate-mapping, flow cytometry, and multiomics.
• Validated findings in a humanized NSG mouse model with PSC patient cells.

Main Results:

• NorUDCA suppressed T_H17 effector function and increased regulatory T cell (Treg) abundance.
• NorUDCA reduced intraepithelial T_H17 pathogenicity and inhibited pro-inflammatory T_H1-like-T_H17 cells.
• Mechanistically, NorUDCA attenuated the glutamine-mTORC1-glycolysis axis, dampening pathogenic T_H17 cell function.

Conclusions:

• NorUDCA effectively restricts T_H17-mediated inflammation across multiple models.
• NorUDCA demonstrates therapeutic potential for T_H17-driven intestinal diseases and potentially other conditions.