Paeoniflorin protects against NAFLD through antioxidant, anti-inflammatory effects and restoration of gut microbiota homeostasis.

Non-alcoholic fatty liver disease (NAFLD) is a widespread chronic metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, inflammation and gut dysbiosis. Paeoniflorin (PAF) exhibits potential against NAFLD, yet its antioxidant mechanism via the gut-liver axis remains unclear. In a high-fat/sucrose (HFS) diet-induced NAFLD mouse model, C57BL/6 mice received PAF (50 or 100 mg/kg/day) for 10 weeks. Oxidative stress markers, histopathology, gut microbiota, and serum metabolomics were conducted, with fecal microbiota transplantation (FMT) applied for causal validation. PAF ameliorated metabolic disorders by suppressing hepatic lipogenesis and promoting cholesterol excretion. PAF significantly ameliorated oxidative stress by enhancing hepatic and colonic anti-oxidant capacity, evidenced by increased SOD activity and decreased MDA levels. It concurrently reduced systemic inflammation and enhanced intestinal barrier integrity via upregulation of tight junction proteins. Furthermore, PAF reshaped the gut microbiota, elevating beneficial Akkermansia and microbial-derived SCFAs, while suppressing pro-oxidant and pro-inflammatory pathogens like Desulfovibrio and Helicobacter. FMT confirmed that these antioxidant and metabolic benefits were mediated by the gut microbiota. In conclusion, PAF alleviates NAFLD primarily through potent antioxidant actions and anti-inflammatory, achieved via remodeling gut microbial ecology and reinforcing intestinal barrier.