Ulcerative colitis (UC), a chronic inflammatory bowel condition, lacks effective treatments. We aimed to examine the therapeutic potential of Jiayi Huatu Decoction (JHD), a traditional Chinese formula, in treating UC in mice, focusing on its modulation of gut microbiota and metabolites. JHD significantly alleviated intestinal fibrosis and chronic inflammation. Mechanistically, JHD promoted beneficial gut bacteria, specifically Faecalibaculum rodentium and Akkermansia muciniphila. Integrated metabolomics and proteomics identified excessive 2-piperidone and taurocholic acid accumulation as colonic fibrosis and inflammation drivers. F. rodentium-derived butyric acid suppressed copper amine oxidase 3, reducing 2-piperidone production, while A. muciniphila-derived 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine (LysoPE16:0) activated farnesoid X receptor (FXR) to decrease taurocholic acid. Genetic ablation of FXR abolished LysoPE16:0 anti-fibrotic and anti-inflammatory activities. JHD exerts therapeutic effects by modulating gut microbiota and supporting F. rodentium and A. muciniphila propagation, which synergistically regulate extracellular matrix deposition and cell adhesion signaling pathways through specific metabolites, offering a strategy for UC treatment.