The cardioprotective mechanism of total saponins from mountain cultivated ginseng against doxorubicin-induced heart failure: Insights from gut-heart axis modulation based on gut microbiota and fecal metabolomics

Mountain cultivated ginseng (MCG) has been reported to exert superior therapeutic efficacy in heart failure (HF) models, but the mechanism of total saponins from MCG (TSMCG) remains unclear. This study aimed to elucidate the mechanism of TSMCG protects against doxorubicin-induced HF through the gut-heart axis. The phytochemical profile of TSMCG was identified using UPLC/Q-TOF-MS. TSMCG (50 or 200 mg/kg) was administered to mice daily for one week before and after doxorubicin exposure. Cardiac function was evaluated via echocardiography, followed by blood biochemical and cardiac histological analyses. Metabolic profiles and gut microbiota composition were analyzed. Fecal microbiota transplantation experiments were employed for mechanistic validation. TSMCG treatment significantly improved cardiac function in HF mice, as evidenced by increased ejection fraction. TSMCG markedly attenuated doxorubicin-induced myocardial injury (CK-MB, NT-proBNP, AST, LDH), oxidative stress (SOD, MDA, CAT, GSH), and cardiac fibrosis. TSMCG effectively regulated key metabolic pathways, particularly tryptophan and bile acid metabolism, and alleviated gut microbiota dysbiosis, particularly Parasutterella and Akkermansia , in HF mice. Close associations between differential microbiota and metabolites were observed. The cardioprotective effects of TSMCG were associated with fecal microbiota transplantation. These findings elucidated the gut-heart axis-based mechanism by which TSMCG alleviated doxorubicin-induced HF and highlighted its potential as a candidate for HF intervention. • TSMCG improves cardiac dysfunction and myocardial fibrosis in heart failure mice. • TSMCG reverses fecal microbiota and metabolome dysbiosis in heart failure mice. • Alterations in fecal metabolites are related to gut microbiota regulated by TSMCG. • Gut-heart axis modulation is involved in the anti-heart failure mechanism of TSMCG.