Limosilactobacillus reuteri alleviates Parkinson's motor deficits and neurodegeneration via CDCA-GLP-1R axis

Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and debilitating motor symptoms. Current treatments primarily manage symptoms but do not halt disease progression. Emerging research highlights the critical role of the gut-brain axis in PD pathogenesis, with alterations in gut microbiota frequently observed. Specifically, Limosilactobacillus reuteri (L. reuteri), a probiotic, has been found significantly depleted in PD models, suggesting its potential as a therapeutic target to address this critical gap in disease modification.

Researchers investigated the effects of L. reuteri supplementation in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. They assessed motor deficits and dopamine neuron damage. Gut microbiota composition was analyzed using 16S rRNA sequencing, and metabolic changes were profiled via untargeted metabolomics. To dissect mechanisms, a Transwell co-culture system of enteroendocrine and neuronal cells was established. The study also evaluated direct effects of Chenodeoxycholic acid (CDCA) treatment in vivo and in vitro, and utilized the TGR5 inhibitor Triamterene and the GLP-1 receptor (GLP-1R) antagonist Exendin (9-39) to confirm pathway involvement.

Supplementation with L. reuteri significantly alleviated motor deficits and attenuated dopamine (DA) neuron damage in 6-OHDA-induced PD rats. 16S rRNA sequencing confirmed that L. reuteri modulated gut microbiota composition, while untargeted metabolomics revealed a partial restoration of Chenodeoxycholic acid (CDCA) levels, which were reduced in PD model rats. CDCA treatment alone also attenuated 6-OHDA-induced neurotoxicity in vivo. In the Transwell co-culture system, CDCA did not directly protect neurons but significantly stimulated glucagon-like peptide-1 (GLP-1) secretion. This GLP-1 stimulation was markedly suppressed by the TGR5 inhibitor Triamterene. Importantly, the neuroprotective benefits of CDCA were completely abolished by the GLP-1R antagonist Exendin (9-39), confirming the necessity of the TGR5-GLP-1-GLP-1R signaling cascade. These findings suggest a novel gut microbiota-bile acid-brain axis in PD. > L. reuteri supplementation significantly alleviated motor deficits and attenuated dopamine neuron damage in PD rats by restoring CDCA levels and activating the TGR5-GLP-1R axis.