Effect of Diosmetin on Gut Microbiota and Serum Metabolites in Acute Pancreatitis Mice: A Metagenomic and Metabolomic Study

Diosmetin is a bioactive flavonoid that exhibits well-documented antioxidant, anti-inflammatory, and anti-tumor properties. However, its potential to attenuate acute pancreatitis (AP) progression through gut microbiota modulation has not yet been elucidated. In this study, mice were pretreated with varying oral doses of diosmetin for 1 week before AP induction via intraperitoneal (i.p.) caerulein injections. The therapeutic efficacy and optimal dosage were determined through histopathological analysis of pancreatic tissue and serological biomarker assessment. Additionally, transcriptomic profiling and western blot were employed to elucidate the underlying signaling pathways. Furthermore, based on integrated metagenomic and metabolomic analyses, a core gut microbiota-metabolite-gene interaction network modulated by diosmetin was constructed. Finally, fecal microbiota transplantation (FMT) experiments validated the critical role of gut microbiota in the effects of diosmetin against AP. The results showed that medium-dose diosmetin treatment significantly attenuated pancreatic histopathological damage and acinar cell apoptosis in AP mice, while suppressing the activation of the MAPK inflammatory signaling pathway. Notably, diosmetin treatment was associated with restored microbial diversity, altered bacterial community structure, and changes in key metabolic pathways, reversing gut microbiota dysbiosis. Specifically, a diosmetin-responsive interaction network was constructed, highlighting associations between core bacterial taxa (Butyricimonas faecalis, Enterocloster bolteae, Roseburia intestinalis), key metabolites (3-indoleacrylic acid, 2-methoxy-4-vinylphenol, nitrite), and MAPK pathway-related genes. Finally, the protective effect of diosmetin was further substantiated by FMT, suggesting a potential role of the gut microbiota in this process. In conclusion, diosmetin ameliorated pancreatic injury in a murine model of caerulein-induced AP by modulating gut microbiota composition and associated metabolic profiles. These findings suggested that diosmetin represented a promising therapeutic option for AP, offering a scientific foundation for its clinical application and the underlying mechanisms involved.