Integrated anti-fatigue effects of polysaccharides and small molecules coexisting in water extracts of ginseng: Gut microbiota-mediated mechanisms.

Ethnopharmacological Relevance: Both clinical and animal studies have demonstrated that ginseng has curative effects on fatigue. Our previous study found that water extracts of ginseng (WEG) could significantly mitigate exercise-induced fatigue (EF). Notably, polysaccharides (GP) and small molecules (GS, mainly ginsenosides) coexist in WEG. Whether and how GP and GS contribute to the anti-EF effects of WEG remains unknown.

Aim Of The Study: To evaluate the contribution of GP and GS to the anti-EF effects of WEG and clarify the potential gut microbiota-mediated mechanisms.

Materials And Methods: Firstly, the anti-EF effects of WEG, GP and GS were comparatively investigated by determining fatigue phenotypes (energy metabolism and oxidative stress parameters), gut microbiota composition as well as exogenous and endogenous metabolites in EF modeling rats. Then, the gut microbiota mediated mechanisms were verified by antibiotics (ABX) intervention and fecal microbial transplantation (FMT).

Results: GP, GS and WEG each exhibited distinct anti-EF effects in differentially improving EF-induced energy metabolism abnormality and oxidative stress, reshaping gut microbiota composition, and elevating systemic metabolites. Notably, WEG showed stronger anti-EF effects than both GP and GS, characterized by better alleviation of disturbances in energy metabolism (e.g. Glc) and oxidative stress parameters (e.g. SOD), regulation of gut microbiota homeostasis (e.g. enriching the genus Coprococcus and species Collinsella provencensis etc.), as well as increases in exogenous secondary ginsenosides (e.g. 20(S)-Rg, 20(R)-Rg, CK), endogenous bile acids (BAs) (e.g. CA, DCA, LCA), and short chain fatty acids (SCFAs) (e.g. butyric acid). The stronger anti-EF effects of WEG compared to GP and GS could be abolished by ABX intervention, and transferred by FMT.

Conclusion: GP and GS could collectively contribute to the anti-EF effects of WEG through integrated actions. Gut microbiota mediate the integrated anti-EF effects of GP and GS in WEG, potentially by regulating the levels of exogenous bioactive secondary ginsenosides, as well as endogenous BAs and SCFAs, thereby alleviating fatigue-related energy metabolic abnormalities and oxidative stress.