Exploring the glycosyl structural specificity of multiple components involved in the gut microbiota-targeted anti-obesity effect of ginseng

The onset and progression of obesity are closely linked with disordered gut microbiota. Different gut bacteria have specific mechanistic roles in preventing or causing obesity. Therefore, manipulating gut microbiota has become a promising strategy for treating obesity. Ginseng, a commonly-used herbal medicine, has been experimentally/clinically shown to have therapeutic potential for obesity and its associated gut microbiota dysbiosis. While this finding is exciting, the exact molecular mechanisms by which gut microbiota mediates this anti- obesity effect of ginseng remain unknown. Our preliminary study indicates that the water extract of ginseng (WEG) alleviates obesity phenotypes (fat accumulation and inflammation) in high-fat diet (HFD)-induced obese mice, and that the WEG treatment can target some key obesity-related bacteria (e.g. Eubacterium, Desulfovibrio, Lactobacillus), yielding an improved commensal homeostasis of gut microbiota. On this basis, here we aim to further explore gut microbiota-targeted anti-obesity mechanisms of WEG. We hypothesize that ginsenosides and polysaccharides in WEG containing structurally diverse glycosyl groups (e.g. 1→2/4/6 linked β-D-glucopyranosyl, 1→4 linked β-D-galacturonopyranosyl, 1→3/4/5/6 linked α-L-rhamnopyranosyl, α-L-arabinofuranosyl, and β-D-galactopyranosyl) favor specific carbohydrate-active enzymes (CAZymes) (e.g. β-D-glucosidase, α-L-arabinofuranosidase, α-L-rhamnosidase, β-glucanase and pectinase) encoded in different obesity-related gut bacteria (e.g. Eubacterium, Desulfovibrio, Lactobacillus, Bifidobacterium) and thereby selectively stimulate the growth of these bacteria, consequently triggering multifaceted molecular mechanisms that reduce obesity (e.g. improving the metabolism of polysaccharides, bile acids and choline; inhibiting lipopolysaccharides that trigger inflammation and metabolic disorder; and regulating the expressions of certain lipid metabolism-related proteins). To test this hypothesis, in this project we propose: i) to acquire, from WEG, ginsenoside and polysaccharide fractions/compounds containing structurally specific glycosyl groups; ii) to determine effects of these fractions/compounds on HFD- induced obesity phenotypes and the associated gut microbiota dysbiosis; iii) to inspect specific CAZy-involved mechanisms underlying the effects of the fractions/compounds on the obese gut microbiota; iv) to investigate the multifaceted anti-obesity molecular mechanisms triggered by the gut microbiota after treatment with the fractions/compounds. Integrated analysis of the results will reveal the structural specificity of the glycosyl groups in ginsenosides and polysaccharides involved in their gut microbiota-targeted anti-obesity effects. The research deliverables will provide a scientific basis for understanding why WEG ameliorates obesity and for developing pharmaceutical products from WEG for the treatment of obesity. Moreover, because this study highlights different therapeutic mechanisms of ginsenosides and polysaccharides in WEG, it is expected to provide a new research perspective on how herbal medicine works through multiple components.