Parkinson's disease (PD) is a common neurodegenerative disease worldwide. Current treatment methods for PD are unable to halt disease progression. The gut microbiota contributes to the neurodevelopment of PD
however, the gut-brain connections and underlying neural bases that regulate this complex behavior are not yet clear. Enterococcus faecalis (EF) is a common commensal bacterium of the gut and a common pathogen associated with hospital-acquired infections. Here, we demonstrated the significant therapeutic effects of a non-pathogenic strain of EF (EF ATCC19433) on PD. In this study, we established a mouse model of PD by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that EF treatment alleviated behavioral impairment, dopaminergic neuronal loss, blood-brain barrier damage, and neuroinflammation induced by MPTP in the mice. Additionally, 16S rRNA sequencing revealed that dysbiosis of PD-related microbial communities induced by MPTP was reversed by EF treatment. Moreover, EF treatment relieved gastrointestinal dysfunction in the mice. The therapeutic efficacy of EF in MPTP-induced PD mice is markedly diminished when the activity of EF is lost. Further mechanistic studies indicated that the neuroprotective effects of EF in PD were associated with the vagus nerve pathway. Following the surgical severance of the vagus nerve through subdiaphragmatic vagotomy, the protective effects of EF on PD were markedly diminished. Our study suggests that EF can alleviate neurofunctional impairments and gastrointestinal disorders associated with PD, indicating that gut-derived microbes influence brain function through the vagus nerve pathway.