BACKGROUND: Parkinson's disease (PD) exhibits a distinct gut microbiota and microbial metabolites, with specific enterotypes potentially influencing disease susceptibility. Current research lacks systematic comparisons of different enterotypes in PD susceptibility and targeted intervention efficacy. This study identifies their gut microbiota-metabolite biomarkers and validates a "probiotic plus herbal medicine" intervention in vitro to explore enterotype-stratified precision strategies for PD prevention and treatment.
PURPOSE: This study aimed to identify a high-risk enterotype for PD and its associated microbial and metabolic signatures using public metagenomic data. Furthermore, we evaluated the therapeutic efficacy of a combination therapy, comprising Patrinia scabiosaefolia Fisch (Herba Patriniae; HP) extract and the probiotics, Faecalibacterium prausnitzii and Lactiplantibacillus plantarum (F.l-HP), in a PD-relevant in vitro model.
METHODS: Public metagenomic data from PD patients and healthy controls (HC) were analyzed to characterize enterotypes. An in vitro gut-brain axis (GBA) model was established by co-culturing PC12 neuronal cells and Caco-2 intestinal epithelial cells to validate the pathogenic role of Escherichia fergusonii. The effects of the F.l-HP combination therapy were then assessed on bacterial growth, key metabolites (5-hydroxytryptophan (5-HTP), trimethylamine N-oxide (TMAO), butyrate), neuroinflammation, oxidative stress, mitochondrial function, and gut barrier integrity, with a focus on the underlying p-Akt and p-AMPKα signaling pathways.
RESULTS: The Bacteroidaceae enterotype (ET-B) was identified as a high-risk enterotype for PD, characterized by an enrichment of E. fergusonii. This bacterium was associated with the consumption of neuroprotective 5-HTP and the production of pro-inflammatory TMAO. The F.l-HP combination therapy significantly suppressed the growth of E. fergusonii while promoting the proliferation of beneficial probiotics. This intervention restored metabolic balance by reducing 5-HTP consumption and TMAO production and increasing butyrate levels. Consequently, F.l-HP treatment alleviated neuroinflammation and oxidative stress in neuronal cells, restoring mitochondrial function via the p-Akt pathway. In intestinal cells, it enhanced gut barrier integrity by upregulating zonula occludens-1 expression and activating p-AMPKα signaling.
CONCLUSION: E. fergusonii may participate in a 5-HTP-TMAO metabolic axis potentially linked to PD risk. F.l-HP intervention suppressed E. fergusonii activity, reduced 5-HTP consumption and TMAO production, modulated Akt and AMPKα signaling pathway, and alleviated neuroinflammation while enhancing intestinal barrier integrity.
