Matrine improves bile acid metabolism and reduces inflammatory and oxidative stress in colitis via the JAK2 pathway.

BACKGROUND: Dysbiosis during colitis alters the conversion of primary to secondary bile acids by gut microbiota, which affects bile acid receptor signaling and may exacerbate mucosal inflammation in experimental colitis models. While the natural compound matrine has known anti-inflammatory properties, its therapeutic mechanism in colitis remains unclear. This study aims to elucidate matrine's potential by identifying its molecular targets and effects in colitis. METHODS: Bioinformatics and molecular docking were used to identify potential drug targets. A multi-model approach was then employed, using a dextran sulfate sodium (DSS)-induced murine model of colitis, a lipopolysaccharide (LPS)-stimulated intestinal epithelial cell model, and clinical colon and serum samples from ulcerative colitis (UC) patients. The effects of matrine on inflammatory cytokines, oxidative stress markers, and bile acid levels were detected using ELISA and various commercial kits. Intracellular reactive oxygen species (ROS) were measured by flow cytometry. RESULTS: JAK2 as a key hub target for matrine, and molecular docking predicted a direct binding interaction. The JAK2 level was found to be upregulated, while bile acid transporters and overall serum bile acid levels were decreased in human UC patients and correlated negatively with disease severity. In a DSS-induced murine model of colitis, matrine treatment mitigated disease symptoms, reduced key inflammatory markers (IL-1β, TNF-α, IL-6) and oxidative stress indicators (including ROS), and restored bile acid homeostasis by upregulating transporters (MRP3 and MRP4) and bile acid receptor FXR. Critically, the mechanism was confirmed to be JAK2-dependent in vitro; experiments demonstrated that JAK2 overexpression alone was sufficient to induce pathology and that it completely reversed the therapeutic effects of matrine. CONCLUSION: This study is the first to comprehensively demonstrate that matrine directly targets the JAK2/STAT3 signaling axis to restore bile acid homeostasis and suppress inflammation in experimental colitis with validation in human UC patients, providing novel mechanistic and translational insight into how matrine may benefit colitis.