Xanthoceraside exerts anti-Alzheimer's disease effect by remodeling gut microbiota and modulating microbial-derived metabolites level in rats

Microbial-derived metabolites play important roles in Alzheimer's disease (AD) pathology, yet how intestinal microbes influence AD progression remains uncertain. Xanthoceraside (XAN), a triterpenoid saponin with anti-AD activity, was extracted from the husks of Xanthoceras sorbifolia Bunge. However, it is still unclear that how XAN modulates the gut microbiota community to regulate AD progression through changing the levels of microbial-derived metabolites.In this study, we investigated the mechanism underlying the anti-AD effect of XAN.The current combination studies of multiple-targeted metabolomics, natural product chemistry and pharmacology revealed that oral XAN mediated intestinal microbiota to ameliorate Aβ1-42-induced learning and memory deficits in rats, which were confirmed through antibiotic treatments and fecal microbiota transplantation.As a poor water solubility and low permeability compound that hardly be absorbed into blood-brain barrier, XAN significantly regulated Aβ1-42-induced metabolism disorders directly or indirectly in gut, including neurotransmitters, amino acids, bile acids and SCFAs metabolism that were detected by UHPLC-MS/MS and GC-MS/MS. In particularly, the in vitro evaluation of XAN on SCFAs production not only found a striking increase in the production of SCFAs after fermentation, but revealed the inner relationship among XAN, gut microbiota and SCFAs in vivo. All results demonstrated that XAN could improve AD rats' learning and memory deficits by modulating the community of gut microbiota which was connected through 16S rRNA sequencing and CCA analyses.Our study provided a novel mechanism for developing XAN as a potential anti-AD drug and revealed that the gut microbiota might be a potential target for AD treatment .