Ligilactobacillus salivarius NCU-41 reduces oxidative stress to ameliorate Parkinson's disease by regulating the AKT/Nrf2 signaling pathway.

A growing body of evidence suggests that the gut microbiota influences the onset and progression of Parkinson's disease (PD) by regulating oxidative stress pathways. However, existing evidence remains the phenotypic level, and high-quality research is still lacking regarding specific probiotic strains with clearly defined ameliorative functions and their precise underlying molecular mechanisms. In this study, high-throughput sequencing confirmed significant differences in the gut microbiota between PD patients and healthy individuals. Furthermore, fecal microbiota transplantation (FMT) from healthy individuals significantly improved motor dysfunction in PD mice, reduced α-syn aggregation (MP vs. M = 319.61 ng/ML vs. 507.84 ng/ML), alleviated neuroinflammation (reduced GFAP and IBA1 positive areas), protected dopaminergic neurons (increased TH expression), and optimized the structure of the gut microbiota, whereas FMT from PD patients exacerbated PD progression. Additionally, through correlation analysis, culturomics, and tryptophan metabolite analysis, Ligilactobacillus salivarius NCU-41 may improve PD by producing indole-3-lactic acid (ILA). Further validation through animal experiments demonstrating that supplementation with either NCU-41 or ILA alone significantly improved PD symptoms, though not as effectively as FMT from healthy individuals. Mechanistically, NCU-41 might activate the AKT/Nrf2 signaling pathway through its tryptophan metabolite (ILA), thereby enhancing the body's antioxidant capacity and ultimately alleviating PD. In summary, this study revealed that L. salivarius NCU-41 to activate the AKT/Nrf2 signaling pathway, thereby exerting a therapeutic effect on PD. These findings provide a deeper mechanistic basis for the potential application of this strain in the future treatment of PD.