Gut microbiota-derived deoxycholic acid mediates the exercise performance-potentiating efficacy of gypenosides

Pharmacological interventions of exercise adaptation offer a viable strategy to enhance athletic performance and improve the quality of life in both the elderly and manual workers. Gypenosides (Gyp), a group of bioactive dammarane-type triterpenoid saponins from genus Gynostemma, can increase exercise performance and muscle function in rodents and healthy males, whose mechanism remains unclear.

We explored the role of the gut microbiota (GM) in exercise performance-potentiation by Gyp administration.

Multiple behavioral tests, immunofluorescence staining, 16 s rRNA gene sequencing, and targeted metabolomics were assessed to demonstrate the altered endurance phenotype induced by Gyp. GM depletion and bile acid pool depletion models were introduced to evaluate the effects of these two factors on the performance-enhancing efficacy of Gyp. UPLC-Q/TOF-MS analysis and luciferase assays were performed to identify FXR antagonists in Gyp. In vitro and in vivo experiments were validated whether deoxycholic acid (DCA) can mimic the benefits of Gyp.

Preventive Gyp treatment led to an improved endurance exercise phenotype and shifted oxidative metabolic pattern of myofibers from Type II to I in sedentary mice. Gyp reshaped the GM and enriched a group of secondary bile acids (BAs), which were the key signature of global metabolic remodeling. Mechanistically, Gypenosides including gypenoside V specifically inhibited the intestinal farnesoid X receptor (FXR) signaling and increased secondary BA levels such as DCA. DCA enhanced myogenic differentiation and myoblast fusion in C2C12 myotubes, and mimicked performance-enhancing effect of Gyp in vivo by activating TGR5-cAMP-PKA signaling pathway.

We identified gypenosides as a promising exercise mimetic and suggested the potential of the GM as a key target for physical performance enhancement. DCA-mediated TGR5 activation provides novel mechanistic insight into the pharmacological targeting of exercise adaptations.