Emerging evidence suggests that gut microbiota dysbiosis contributes to the initial stages of neuroinflammation and dopaminergic neurodegeneration in Parkinson's disease (PD). Probiotics are receiving attention as a treatment for PD because they restore gut microbiota balance and brain homeostasis. In this study, we demonstrated that Weissella cibaria SGW054 (SGW054), a probiotic strain, exhibited antibacterial activity against Proteus mirabilis (PM), which induces PD pathology. We evaluated the therapeutic effects of SGW054 on PD pathology in PM-induced PD model mice. Subsequently, we assessed the effects of SGW054 in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin commonly used to induce PD, and explored its influence on gut microbiota composition. SGW054 improved motor dysfunction and neurodegeneration in PM-treated PD model mice. Additionally, SGW054 reduced microgliosis, colonic inflammatory cytokine release, gut barrier disruption, and the translocation of α-synuclein aggregates from the gut to the brain by controlling fecal PM levels. In an MPTP-induced PD mouse model, SGW054 mitigated glial hyperactivation and lowered the release of proinflammatory cytokines, such as tumor necrosis factor-α, in both the brain and colon, thereby relieving dopaminergic neuronal damage and behavioral complications. Fecal microbiota analysis demonstrated that SGW054 administration alleviated MPTP-induced microbiota dysbiosis, decreasing PM and Lachnospiraceae abundance while increasing probiotic bacteria levels (Bacteroidaceae, Bacteroides, and Faecalibacterium), which strongly correlated with the anti-inflammatory and neuroprotective effects of SGW054. Collectively, our findings indicate that SGW054 may serve as a novel therapeutic supplement for PD by protecting against dopaminergic neuronal loss, restoring inflammatory homeostasis, and correcting gut microbiota dysbiosis in both gut-initiated and brain-initiated PD subtypes.
