Mesona chinensis Benth polyphenols ameliorate type 2 diabetes mellitus in mice through coordinated regulation of gut microbiota, metabolic profiles, and host metabolic-inflammatory responses.

BACKGROUND: Mesona chinensis Benth polyphenols (MCP) have demonstrated potential anti-diabetic activity. However, the underlying mechanisms involved in their metabolic regulation remain incompletely understood. OBJECTIVE: This study aimed to investigate the anti-diabetic effects of MCP in HFD/STZ-induced type 2 diabetes mellitus (T2DM) mice through an integrated analysis combining network pharmacology, gut microbiota profiling, metabolomics, and molecular validation. MATERIALS AND METHODS: An HFD/STZ-induced T2DM mouse model was established to assess the effects of MCP on glucose metabolism, lipid metabolism, and tissue injury. Network pharmacology was performed to predict potential bioactive compounds, targets, and signaling pathways associated with MCP. Gut microbiota composition and metabolic profiles were analyzed to evaluate MCP-induced alterations in microbial and metabolic homeostasis. Representative proteins involved in glucose metabolism-associated signaling, inflammatory responses, and lipid metabolic regulation were further evaluated by Western blot analysis. RESULTS: MCP administration significantly improved diabetic phenotypes, as evidenced by reduced fasting blood glucose (FBG), improved oral glucose tolerance test (OGTT) responses, and decreased serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels. Network pharmacology analysis identified multiple candidate pathways potentially involved in the anti-diabetic effects of MCP. Integrated omics analysis revealed that MCP reshaped gut microbiota composition and altered metabolic profiles, particularly pathways related to fatty acid metabolism, including alpha-linolenic acid and linoleic acid metabolism and fatty acid biosynthesis. Molecular validation further demonstrated that MCP modulated representative proteins associated with PI3K-Akt/GLUT4-related glucose metabolism signaling, TNF/MAPK/NF-κB-mediated inflammatory responses, and lipid metabolic regulation. CONCLUSION: These findings suggest that MCP exerts anti-diabetic effects through coordinated regulation of gut microbiota remodeling, metabolic alterations, glucose metabolism-associated signaling, inflammatory responses, and lipid metabolic homeostasis. This study provides mechanistic insights into the potential hypoglycemic effects of MCP.