Limosilactobacillus reuteri Alleviates Parkinson's Disease by Regulating CDCA Secretion

To explore potential therapeutic agents for Parkinson's disease (PD), we investigated the impact of Limosilactobacillus reuteri (L. reuteri), a probiotic found to be significantly depleted in 6-hydroxydopamine (6-OHDA)-induced PD rat model. Despite its known benefits, the specific effects and underlying mechanisms of L. reuteri in PD remain poorly understood. In this study, we demonstrated that supplementation with L. reuteri alleviated motor deficits and attenuated dopamine (DA) neuron damage in 6-OHDA-induced PD rats. 16 S rRNA sequencing and untargeted metabolomics revealed that L. reuteri modulated gut microbiota composition and partially restored Chenodeoxycholic acid (CDCA) levels, which were reduced in PD model rats. CDCA treatment also attenuated 6-OHDA-induced neurotoxicity in vivo. To elucidate the underlying mechanisms, a Transwell co-culture system consisting of enteroendocrine and neuronal cells was established. While CDCA did not exert a direct neuroprotective effect on neurons, it significantly stimulated glucagon-like peptide-1 (GLP-1) secretion. This effect was markedly suppressed by the TGR5 inhibitor (Triamterene). Importantly, the neuroprotective benefits of CDCA were abolished by the GLP-1 receptor (GLP-1R) antagonist Exendin (9-39), confirming the necessity of the TGR5-GLP-1-GLP-1R signaling cascade. Collectively, these findings suggest that L. reuteri may exert neuroprotective effects by modulating bile acid metabolism, particularly CDCA, and potentially involving the TGR5-GLP-1R axis. This study highlights a possible gut microbiota-bile acid-brain axis and provides a basis for microbiota-based therapeutic strategies in PD.