Hyperoside ameliorates NAFLD in rats via remodeling gut microbiota and reprogramming serum metabolic networks

Objective This study explores hyperoside’s therapeutic efficacy in non-alcoholic fatty liver disease (NAFLD) rats and its gut–liver axis mechanisms through integrated gut microbiota and metabolomics analyses. Methods The SD rats were divided into five groups (normal control, NAFLD model, low-dose hyperoside [0.6 mg/kg/day], high-dose hyperoside [1.5 mg/kg/day], and rosiglitazone positive control [5 mg/kg/day]) and treated for 12 weeks. Body weight, serum biochemistry (ALT, AST, TC, TG), liver histopathology (H&E, Sirius Red), hepatic mRNA expression ( Tlr4, Tnf-α, and α-SMA ), gut microbiota (16S rRNA sequencing), and serum metabolites (untargeted metabolomics) were assessed. Results Hyperoside dose-dependently reduced high-fat, high-sugar diet-induced body weight gain, liver index, and hepatic steatosis/fibrosis, lowered serum liver enzymes and lipid levels, and downregulated pro-inflammatory/fibrotic genes. It remodeled gut microbiota by enriching Lactobacillus and suppressing pathobionts (e.g., Streptococcus , Escherichia-Shigella ), reversed metabolic disturbances (e.g., 3-hydroxybutyric acid, diacylglycerols), and targeted glycine/serine/threonine and alpha-linolenic acid metabolism. Beneficial bacteria were negatively correlated with pro-inflammatory metabolites like lysophosphatidylcholine. Conclusion Hyperoside ameliorates NAFLD, which is associated with gut microbiota remodeling and modulation of host metabolic networks, supporting its potential as a multi-target therapeutic agent for NAFLD.