Gegen Qinlian decoction alleviates ulcerative colitis by remodeling the gut microbiota-bile acid axis and inhibiting NLRP3-mediated pyroptosis
Abstract
Gegen Qinlian Decoction (GQD) is used to treat intestinal disorders, but its mechanism in ulcerative colitis (UC) induced by combined high-fat diet (HFD) and dextran sulfate sodium (DSS) exposure remains unclear. A UC mouse model was induced by HFD plus DSS. GQD constituents were identified by UPLC–MS/MS. Colonic pathology and barrier integrity were assessed by H&E and immunofluorescence. Gut microbiota and bile acids were analyzed by 16S rRNA gene sequencing and targeted metabolomics. Transcriptomics, ELISA, Western blotting, fecal microbiota transplantation (FMT), and molecular docking were used to investigate mechanisms. LPS-stimulated Caco-2 cells were treated with 20 or 50 μM DCA; cell viability, NLRP3 inflammasome-related gene expression, and ZO-1/Occludin immunofluorescence were evaluated. GQD ameliorated gut dysbiosis, decreasing the Firmicutes/Bacteroidetes ratio, increasing Akkermansia muciniphila , and reducing Clostridium perfringens . It remodeled bile acid metabolism, decreasing primary bile acids (CA, TCA, and CDCA, etc.) and increasing secondary bile acids (DCA, 6,7-DKLCA and 3β-DCA, etc.). Transcriptomics indicated inhibition of NOD-like receptor signaling. GQD suppressed NLRP3 inflammasome activation and reduced ASC, pro-caspase-1, cleaved caspase-1, GSDMD-N, and IL-18. Docking prioritized DCA as a candidate NLRP3-interacting metabolite. In Caco-2 cells, DCA dose-dependently reduced LPS-induced NLRP3, ASC, GSDMD, IL1B, and IL18 mRNA expression and partially restored ZO-1 and Occludin signals without appreciable cytotoxicity. FMT supported the involvement of gut microbiota in GQD-mediated anti-inflammatory effects. GQD alleviates UC induced by combined HFD and DSS exposure by reshaping the gut microbiota and correcting bile acid dysregulation, thereby inhibiting NLRP3 inflammasome activation. This study highlights the gut microbiota–bile acid axis in GQD’s therapeutic effects.