Bletilla striata polysaccharide alleviates obesity by remodeling the gut microbiota-metabolite-liver axis and suppressing the hepatic AMPK-SREBP2/SQLE signaling pathway

Obesity is a global health crisis, yet the precise biochemical relay underlying the anti-obesity effects of Bletilla striata Polysaccharides (BSP) remains to be fully elucidated. We investigated the metabolic effects of BSP in a high-fat diet (HFD)-induced obese mouse model. Using an integrative multi-omics strategy combined with fecal microbiota transplantation (FMT) and functional validation, we aimed to decipher the "gut microbiota-metabolite-liver" regulatory axis. BSP supplementation significantly attenuated HFD-induced weight gain, improved glucose and lipid homeostasis, and mitigated systemic inflammation, oxidative stress, and hepatic steatosis in a dose-dependent manner. Multi-omics analyses revealed that BSP selectively remodeled the gut microbiota by suppressing obesity-associated genera while enriching beneficial taxa such as Allobaculum, Ileibacterium valens, and Dubosiella. These microbial shifts were accompanied by a reduction in deleterious bile acids and, crucially, a significant increase in the production and systemic circulation of short-chain fatty acids, providing a definitive physiological link between intestinal alterations and distal host responses. Hepatic transcriptomic and protein analyses further revealed that these gut-derived metabolites triggered the phosphorylation-mediated activation of AMPK signaling, which subsequently suppressed squalene epoxidase (SQLE)-mediated Cholesterol biosynthesis. Causal evidence was established through FMT, where recipient mice phenocopied the metabolic benefits of BSP donors. Furthermore, loss- and gain-of-function experiments using pharmacological inhibitors and AAV8-mediated gene delivery confirmed that SQLE is a necessary mediator of BSP's anti-obesity action. Collectively, our findings demonstrate that BSP alleviates obesity by orchestrating a microbiota-metabolite-host axis connecting gut microbial remodeling to the hepatic AMPK-SREBP2/SQLE signaling cascade, highlighting its potential as a targeted functional dietary intervention.