Effects of Donepezil Treatment on Brain Metabolites, Gut Microbiota, and Gut Metabolites in an Amyloid Beta-Induced Cognitive Impairment Mouse Pilot Model

Abstract

Accumulated clinical and biomedical evidence indicates that the gut microbiota and their metabolites affect brain function and behavior in various central nervous system disorders. This study was performed to investigate the changes in brain metabolites and composition of the fecal microbial community following injection of amyloid beta (A beta) and donepezil treatment of A beta-injected mice using metataxonomics and metabolomics. A beta treatment caused cognitive dysfunction, while donepezil resulted in the successful recovery of memory impairment. The A beta + donepezil group showed a significantly higher relative abundance of Verrucomicrobia than the A beta group. The relative abundance of 12 taxa, including Blautia and Akkermansia, differed significantly between the groups. The A beta + donepezil group had higher levels of oxalate, glycerol, xylose, and palmitoleate in feces and oxalate, pyroglutamic acid, hypoxanthine, and inosine in brain tissues than the A beta group. The levels of pyroglutamic acid, glutamic acid, and phenylalanine showed similar changes in vivo and in vitro using HT-22 cells. The major metabolic pathways in the brain tissues and gut microbiota affected by A beta or donepezil treatment of A beta-injected mice were related to amino acid pathways and sugar metabolism, respectively. These findings suggest that alterations in the gut microbiota might influence the induction and amelioration of A beta-induced cognitive dysfunction via the gut-brain axis. This study could provide basic data on the effects of A beta and donepezil on gut microbiota and metabolites in an A beta-induced cognitive impairment mouse model.