Lactiplantibacillus plantarum alleviates Parkinson’s disease progression by reducing enteroendocrine α-synuclein aggregation in a rotenone-induced mouse model

Parkinson's disease (PD) is a progressive neurodegenerative disorder driven by α-synuclein (α-syn) aggregation and accumulation. Recent evidence suggests that gut dysbiosis may trigger α-syn accumulation in the enteric nervous system, which spreads to the brain via the vagus nerve. Restoring the gut microbial balance through probiotic intervention offers a promising strategy to mitigate gut-origin pathology in PD. Lactiplantibacillus plantarum PS128 (PS128), a probiotic strain with neuroprotective properties, has shown neurotherapeutic benefits in PD models and patients; however, its mechanisms remain unclear. In a rotenone-induced PD mouse model, we found that PS128 supplementation significantly improved motor deficits and gastrointestinal dysfunction, reversed enteroendocrine cell (EEC) hyperplasia in the proximal colon (PC), and reduced α-syn accumulation in both intestinal and brain tissues. Notably, phosphorylated α-syn levels were significantly elevated in EECs, the myenteric plexus, and the substantia nigra, and these elevations were reversed by PS128. Furthermore, using real-time calcium imaging in a zebrafish model, we demonstrated that PS128 directly activates EECs. Transcriptomic profiling of the PC revealed calcium signaling and vitamin D metabolism as the major pathways modulated by PS128. Consistent with the transcriptomic findings, biochemical analyses demonstrated that PS128 increased serum calcium and 25-hydroxyvitamin D levels. Moreover, 16S rRNA sequencing and correlation analysis revealed that PS128 modulated gut microbiota composition in PD-like mice, with changes in specific taxa correlating with α-syn burden and calcium regulation. Taken together, our findings suggest that PS128 alleviates PD-like pathology through modulation of the gut-brain axis and provide mechanistic insights into the neuroprotective actions of probiotics.