Depleting gut microbiota resistance in Alzheimer's disease enhances the therapeutic effect of mesenchymal stem cell-derived exosomes

Abstract Mesenchymal stem cell-derived exosomes (MSCs-exo) can be used for treating Alzheimer’s disease (AD) by promoting amyloid-β (Aβ) degradation, modulating immune responses, protecting neurology, promoting axonal growth, and improving cognitive impairment. Increasing evidence suggests that the alteration of gut microbiota is closely related to the occurrence and development of Alzheimer's disease. In this study, we hypothesized that dysbiosis of gut microbiota might limit the effectiveness of MSCs-exo, whereas regulating the gut microbiota would improve the therapy of MSCs-exo. Methods: In this original research study, we used MSCs-exo to treat 5×FAD mice and fed them antibiotic cocktails for 1 week to detect cognitive ability and neuropathy. The mice’s feces were collected to investigate alterations in the microbiota and metabolites. Results: The results revealed that the AD gut microbiota eliminated the therapeutic effect of MSCs-exo, whereas antibiotic modulation of disordered gut microbiota and associated metabolites enhanced the therapeutic effect of MSCs-exo. Conclusions: These results encourage the research of novel therapeutics to enhance MSCs-exo treatment for AD, which could benefit a broader range of patients with AD.