Ginsenoside F2 alleviates high-fat diet-induced obesity via enriching Akkermansia to remodel gut microbiota and protect intestinal mucosal barrier

: Background Obesity and its associated gut microbiota dysbiosis, chronic inflammation, and metabolic disorders pose significant challenges to public health. Existing anti-obesity drugs face limited clinical application due to their prominent side effects, making gut microbiota-targeting strategies using natural products a focus of attention. Although ginsenoside F2 (GF2) reportedly exerts anti-obesity effects by directly activating the AMPK pathway, whether its anti-obesity efficacy is gut microbiota-dependent remains unclarified. Purpose This study aims to explore the effects and potential mechanisms of GF2 in exerting its anti-obesity effects by regulating gut microbiota. Methods The anti-obesity mechanism of GF2 mediated by gut microbiota was investigated using a high-fat diet (HFD) induced obese mouse model, combined with 16S rDNA sequencing, histopathology, UPLC-MS/MS, and fecal microbiota transplantation (FMT). Results GF2 significantly rescued HFD-induced gut microbiota dysbiosis, reduced the Firmicutes / Bacteroidetes ratio, and markedly increased the relative abundance of the genus Akkermansia (AKK). Morevoer, GF2 upregulated the expression of intestinal mucins, protected the intestinal mucosal barrier, and promoted its conversion into compounds K and protopanaxadiol in the gut. FMT experiments further confirmed that GF2-remodeled gut microbiota effectively suppressed body weight gain, alleviated fat deposition, and improved oral glucose tolerance and insulin sensitivity in obese mice. Conclusion GF2 exerts potential anti-obesity effects likely through altering intestinal mucin-related genes expression to promote the bacterial strain of genus AKK proliferation, thereby remodeling the gut microbiota structure and improving intestinal histological features, as well as the host’s glucose and lipid metabolism. These findings support GF2 as a promising candidate for the development of novel anti-obesity therapeutics.