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 ß (Aß) and donepezil treatment of Aß-injected mice using metataxonomics and metabolomics. Aß treatment caused cognitive dysfunction, while donepezil resulted in the successful recovery of memory impairment. The Aß + donepezil group showed a significantly higher relative abundance of Verrucomicrobia than the Aß group. The relative abundance of 12 taxa, including Blautia and Akkermansia, differed significantly between the groups. The Aß + 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 Aß 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 Aß or donepezil treatment of Aß-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 Aß-induced cognitive dysfunction via the gut-brain axis. This study could provide basic data on the effects of Aß and donepezil on gut microbiota and metabolites in an Aß-induced cognitive impairment mouse model.