Korean red ginseng extract ameliorates high-fat diet-induced hyperlipidemia by modulating the gut microbiota-liver metabolic axis

Background: Korean Red Ginseng is recognized for its ability to modulate immune responses, alleviate fatigue, and combat aging, and shows promise in treating hyperlipidemia. However, comprehensive insights into its gut-liver axis mechanisms remain limited. Methods: Rats were assigned to a normal control group, an HFD-fed model group, and four groups treated with Korean Red Ginseng extract (RGE) at doses of 125 mg/kg, 250 mg/kg, 500 mg/kg, and 1000 mg/kg. The treatment groups administered RGE by gavage for 60 days while on an HFD. The study evaluated RGE's effects on hyperlipidemia and gut microbiota through serum biochemical analysis, hepatic histopathology, cecal metabolomics, 16S rRNA sequencing, and further investigated hepatic regulatory mechanisms using molecular biology techniques. Results: After 60 days of treatment, RGE significantly reduced serum lipid levels and liver injury markers. Histological analysis using H&E and Oil Red O staining showed that RGE significantly reduced hepatic steatosis in comparison to the model group. LC-MS and 16S rRNA sequencing of cecal contents revealed that RGE remodeled gut microbiota composition, enhancing microbiota-derived metabolite production. Molecular analysis indicated that RGE activated hepatic PPARα, downregulated SREBP-1c, and partially restored basal cholesterol biosynthesis by upregulating HMGCR mRNA. These changes collectively reduced hepatic triglyceride accumulation and promoted cholesterol excretion. Conclusions: RGE alleviates HFD-induced hyperlipidemia and hepatic steatosis through a coordinated gut-liver axis mechanism, involving microbiota modulation, metabolic reprogramming, and regulation of hepatic lipid factors. These findings support RGE as a potential therapeutic option for hyperlipidemia and related metabolic disorders, using an "excretion-centric" strategy.