Rhamnocitrin Ameliorates the Intestinal Fibrosis in DSS-Induced Colitis Mice by Modulating Host-Metabolites and Remodeling the Gut Microbiome.

Ulcerative colitis (UC) is characterized by barrier disruption, microbiota dysbiosis, fibrosis, and impaired autophagy. We investigated the effects of Rhamnocitrin (Rha) in dextran sulfate sodium (DSS)-induced chronic UC mice using histological analysis, molecular assays, and multiomics profiling. Rha alleviated weight loss and colon shortening; improved mucus secretion and tight junction protein expression; suppressed NLRP3 inflammasome activation; activated autophagy via AMPK activation and consequent Akt/mTOR inhibition; and attenuated colonic fibrosis. Multiomics analysis integrating 16S rRNA sequencing, metagenomics, and metabolomics revealed that Rha remodels the gut microbiota and is associated with elevated levels of beneficial metabolites, including butyrate in the colon, glutamate and γ-aminobutyric acid in the liver, and α-linolenic acid in the serum. Correlation analysis revealed close associations between microbiota and metabolite alterations, and improved barrier integrity, reduced inflammation, and attenuated fibrosis. These findings suggest that Rha ameliorates chronic UC by modulating autophagy, microbiota composition, and host metabolism across the gut-liver axis.