Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder associated with gut dysbiosis and tryptophan metabolism disturbance, but the mechanisms of probiotic action are unclear. We orally administered Lactobacillus reuteri DSM 17938 live bacteria (1.0 × 109 CFU/mL, 0.2 mL) or its fermentation supernatant lyophilized powder at three concentrations to MPTP-induced PD male C57BL/6J mice. Treatments increased locomotor distance and speed, elevated serum SOD and GSH, reduced MDA, TNF-α, IL-6, and IL-1β, promoted neuronal survival, and tended to increase TH expression in the substantia nigra. 16S rRNA sequencing showed that treatments altered gut microbiota composition. PD mice had increased Lactobacillus and Allobaculum but decreased Oscillospira and Helicobacter; treatments restored Oscillospira. Fecal untargeted metabolomics revealed disturbed tryptophan metabolism in PD, with elevated indoleacetic acid and reduced kynurenic acid, xanthurenic acid, indole-3-ethanol, and α-oxo-1H-indole-3-propanoic acid. Treatments significantly restored neuroprotective metabolites including kynurenic acid, xanthurenic acid, and serotonin. PICRUSt2 predicted tryptophan synthesis pathway-associated microbes (Oscillospira, Ruminococcus, Coprococcus). Treatments ameliorated motor deficits, oxidative stress, inflammation, and dopaminergic neuron death, correlating with gut microbiota modulation and accumulation of microbiota-derived tryptophan metabolites. Live bacteria showed superior antioxidant and neuroprotective efficacy compared to supernatant, likely due to sustained colonization and continuous metabolic activity. These findings suggest that targeting key tryptophan-metabolizing bacteria or their metabolites may be a potential PD therapy.

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