Panax notoginseng saponins ameliorates glucolipid metabolism disorders and hepatic injury in T2DM mice via gut microbiota modulation

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Background Despite low oral bioavailability, Panax notoginseng saponins (PNS) exert anti-diabetic effects, possibly through gut microbiota-mediated indirect mechanisms. Aim This study investigated whether PNS regulate glucolipid metabolism in T2DM by modulating gut microbiota and activating the FXR/SHP pathway via its metabolite PPT. Methods T2DM mice were induced by streptozotocin and high-fat diet, treated with PNS or metformin for 12 weeks, and subjected to fecal microbiota transplantation (FMT). Gut microbiota was analyzed by 16S rRNA sequencing. In vitro , insulin-resistant LO-2 and HepG2 cells were treated with PPT (a key metabolite of PNS), with or without guggulsterone (FXR inhibitor). To genetically validate FXR dependency, siRNA-mediated FXR knockdown was performed in HepG2 cells. Results PNS alleviated dysglycemia, dyslipidemia, and hepatic injury in T2DM mice. Three key differential gut microbial genera ( Dubosiella, Desulfovibrio, and Streptococcus ) whose abundances were modulated by PNS were identified. In vitro , PPT activated FXR/SHP and suppressed gluconeogenic and lipogenic genes—effects reversed by guggulsterone. Crucially, FXR knockdown abolished PPT-induced SHP upregulation and significantly attenuated PPT's suppression of metabolic genes, confirming that PPT's effects are primarily FXR-dependent. Conclusion PNS alleviate glucolipid metabolism disorders and hepatic injury in T2DM mice. The underlying mechanism may involve regulating the gut microbiota to increase PPT, a metabolite of PNS, which activates the hepatic FXR/SHP pathway.

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