Sea buckthorn polyphenols improve lipid metabolism via gut–liver axis modulation in db/db mice

Sea buckthorn polyphenol extract (SPE) has been reported to exert beneficial effects on lipid metabolism, yet its bioactive constituents and underlying mechanisms remain insufficiently defined. In this study, SPE was administered to db/db mice to evaluate its impact on lipid metabolism and gut microbiota, and key polyphenols were further investigated in HepG2 cells combined with a network pharmacology approach. In db/db mice, SPE restored serum high-density lipoprotein (HDL) levels and alleviated hepatic steatosis, accompanied by a tendency toward reduced body weight gain. These changes were accompanied by marked improvements in gut dysbiosis, with increased relative abundances of beneficial genera such as Lactobacillus and Akkermansia. High-performance liquid chromatography (HPLC) analysis identified isorhamnetin, myricetin, kaempferol, quercetin, and rutin as the major polyphenols in SPE, and all of these constituents decreased intracellular cholesterol and triglyceride accumulation in HepG2 cells without obvious cytotoxicity. Network pharmacology analysis focusing on isorhamnetin and myricetin revealed overlapping targets with obesity-, nonalcoholic fatty liver disease-, and diabetes-related genes that were mainly enriched in lipid-metabolism–related processes and pathways, including fatty acid metabolism, cholesterol homeostasis, nonalcoholic fatty liver disease, lipid and atherosclerosis, and PPAR/AMPK signaling. Integration of gut microbiota, fecal metabolite, and target information further suggested a gut microbiota–metabolite–host target axis involving beneficial taxa such as Akkermansia and Enterococcus and central hubs including PPARG, TNF, and IL6. Overall, these findings indicate that SPE improves lipid metabolism through coordinated modulation of gut microbiota and hepatic cholesterol–lipid homeostasis, supporting its potential use in the dietary management of obesity and dyslipidemia.