Rifaximin ameliorates memory impairment and Alzheimer's pathological changes in APP/PS1 mice associated with changes in the gut microbiome–bile acids–serum metabolites networks

Background and Purpose Modifying the brain–gut–microbiota axis has emerged as a promising therapeutic strategy against Alzheimer's disease (AD). Whether rifaximin, a non‐absorbed and non‐systemic antibiotic, can be applied to the treatment of AD remains unexplored. In this study, we investigated the effects of rifaximin using a APP/PS1 double‐transgenic mouse model of AD. Experimental Approach Six‐month‐old male APP/PS1 mice were administered saline or rifaximin (100 mg·kg −1 ) via oral gavage for 2 months. Gut microbiota composition and metabolites were subsequently analysed to elucidate the underlying mechanisms of rifaximin in AD. Key Results Rifaximin modified gut microbiota composition, increasing abundance of Akkermansia muciniphila and Christensenellaceae , while decreasing abundance of Clostridia_UCG‐014 , Muribaculaceae , Lachnospiraceae , Turicibacter , Eubacterium_xylanophilum_group , Alistipes , Bacteroides_acidifaciens and Eubacterium_brachy groups. Furthermore, rifaximin alleviated memory impairment in APP/PS1 mice, decreased amyloid‐β (Aβ) burden and secondary neuroinflammation and attenuated neuronal death and synaptic dysfunction. Metabolomic analysis revealed that rifaximin altered the profile of gut bile acids by decreasing the concentrations of primary (cholic acid and taurocholic acid) and secondary (taurodeoxycholic acid and taurolithocholic acid) bile acids. Additionally, rifaximin enhanced tryptophan metabolism, shown by increased serum 5‐HT concentrations. Both microbial and metabolic shifts were closely correlated with gut microbiota composition. Conclusions and Implications Our results showed that rifaximin alleviated spatial working and short‐term recognition memory impairment and mitigated Alzheimer's‐like pathological changes in APP/PS1 mice, effects accompanied by alterations in the gut microbiota–intestinal bile acid profile–serum metabolites network. Rifaximin could provide a new therapeutic approach to the treatment of AD.