Naringin alleviates autoimmune hepatitis in mice via the gut-liver Axis through modulation of microbiota, metabolites, and immune responses.

Abstract

Autoimmune hepatitis (AIH) is an immune-mediated liver disease that could be impacted by gut microbiota dysbiosis. Naringin, a flavonoid derived from citrus fruits, has been reported to modulate gut microbial composition and alleviate liver diseases, but its role in AIH remains incompletely understood. In this study, we used multi-omics analysis and fecal microbiota transplantation (FMT) to examine the protective benefits of naringin in a ConA-induced AIH mouse model. To strengthen mechanistic conclusions, histopathological scoring, liver function indices, and immune cell profiling were determined. Naringin reduced IFN-γ and IL-17A, improved oxidative balance, remodeled hepatic transcriptome, and corrected microbial dysbiosis. Integrated multi-omics analysis revealed associations with altered MAPK, NF-κB, JAK-STAT, and autophagy pathways. Additional investigations revealed that naringin increased the expression of the tight junction proteins ZO-1 and occludin, improved intestinal barrier integrity, and decreased Th1/Th17 cell proportions without significantly altering Th2 cells, as validated by flow cytometry and immunohistochemistry. Importantly, FMT from naringin-treated donors provided hepatoprotective benefits in recipient mice. These findings shed fresh information on the gut-liver axis in AIH, highlighting naringin as a potential therapeutic agent through coordinated regulation of oxidative stress, immune responses, and gut microbiota-associated metabolic profiles.