Abstract
Gallic acid (GA), a plant phenol ubiquitously present in fruits and vegetables, has demonstrated efficacy in ameliorating ulcerative colitis (UC). Despite previous reports, the precise mechanism of GA's therapeutic action remains elusive. Herein, the present work aims to delineate the mechanism underlying the anti-UC effects of GA by focusing on the interplay of gut microbiota, microbial and host cometabolites, and gut immune regulation. The findings revealed that GA treatment improved the colitis symptoms and systematic inflammatory response, reliant on gut microbiota, as evidenced by microbiota depletion and fecal microbiota transplantation. According to the 16s rDNA sequencing results, GA altered the gut microbiota community structure and upregulated the biosynthesis of secondary bile acids (SBAs). Metabolomics and flow cytometry analysis (FCS) revealed a substantial increase in SBAs production, including UDCA, LCA, 3-oxo-LCA and IsoalloLCA, which further upregulated the proportion of regulatory T (Treg) cells and downregulated the proportion of T helper type 17 (Th17) cells in the colon, ultimately resulting in an improved Treg/Th17 balance. Further FCS and real-time quantitative PCR assays provided mechanistic insights, demonstrating that UDCA and IsoalloLCA facilitate Treg cell differentiation through the upregulation of nuclear hormone receptor 4A1 (NR4A1). This research elucidated that GA effectively mitigates colitis by modulating the Treg/Th17 balance, facilitated by the enhanced synthesis of microbiota-derived SBAs. These insights unveil innovative pathways through which GA exerts its anti-UC effects, emphasizing the potential therapeutic benefits of incorporating a GA-enriched diet into UC management.
