Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of alpha-synuclein. Growing evidence implicates the gut-brain axis in PD pathogenesis, with dysbiosis potentially influencing alpha-synuclein homeostasis and serving as a disease biomarker. Methods: We established substrate-specific bacterial enrichment cultures from a pooled fecal inoculum of 15 treatment-naïve PD patients. 16S rRNA gene sequencing defined the taxonomic profiles of five consortia (PLactate, MTryptone, MPeptone/Sucrose, MFat, MStarch). The impact of bacterial lysates on a human neuronal model was assessed using SH-SY5Y neuroblastoma cells. Gene expression of SNCA, HSPA8, SNAP25, STX1A, and APP was quantified via qRT-PCR, and cytotoxicity was measured by MTT assay. Results: The choice of carbon source selected for communities with distinct taxonomic profiles. Lysates from the MTryptone consortium, dominated by Clostridium, Coprococcus, and Eggerthella, significantly upregulated APP, SNAP25, and HSPA8 expression and increased cytotoxicity in live co-culture. Conversely, lysates from the MPeptone/Sucrose consortium, enriched in Lactobacillus, Bifidobacterium, Peptoniphilus, Ruminococcus, and Bacteroides, downregulated SNAP25, HSPA8, and STX1A and exhibited a protective effect on viability. SNCA expression remained unchanged across all treatments. Conclusions: Our findings demonstrate that specific gut bacterial consortia derived from PD patients can directly and differentially modulate the expression of key neuronal genes linked to synaptic function and protein processing. This work provides direct in vitro evidence supporting the hypothesis that a shift in gut microbial ecology may contribute to neuronal dysfunction in PD, highlighting specific microbial guilds as potential targets for therapeutic intervention.
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