Gut Microbiota-Associated Molecules in Plasma-Derived Extracellular Vesicle-Enriched Fractions of Patients with Parkinson’s Disease

Background: Microbiota-related metabolites and innate immune signaling molecules transported via plasma-derived extracellular vesicle (EV)-enriched fractions through the gut–brain axis may contribute to neuroinflammation and disease progression in Parkinson’s disease (PD). Therefore, this study aimed to investigate the levels of microbiota-associated molecules in plasma-derived EV-enriched fractions and their relationship with clinical parameters in patients with PD. Methods: This study included 38 patients with PD and 38 age-matched healthy spouses. Clinical evaluations, disease staging (Hoehn & Yahr, UPDRS), and cognitive/psychiatric tests (MMSE, BDI, BAI) were conducted. Uncorrected spot urinary indoxyl sulfate concentration and routine serum biochemical markers were analyzed. Plasma-derived EV-enriched fractions were isolated and analyzed for microbiota-related molecules (acetate, TLR2, TLR4, TLR5, LPS, and EGF) using ELISA and functional assays. Results: Clinical evaluations indicated mild-to-moderate disease severity in PD patients. Systemic analyses revealed elevated uncorrected spot urinary indoxyl sulfate alongside reduced serum folate, vitamin B12, and free T4, together with increased copper, iron, and zinc levels in PD. Acetate, LPS, TLR2, and TLR5 levels in the plasma-derived EV-enriched fractions were significantly upregulated. Exploratory correlation analyses (none significant after FDR correction) suggested that lower serum folate and TLR4 levels in the plasma-derived EV-enriched fractions were associated with higher motor symptom severity and treatment complications. ROC analyses showed that TLR2 levels in the plasma-derived EV-enriched fractions had the highest observed AUC among the evaluated markers for PD. Conclusions: In this exploratory cross-sectional study, patients with PD showed differences in microbiota-related molecules (acetate, LPS; urinary indoxyl sulfate as an uncorrected spot concentration) and host-associated innate immune markers (TLR2, TLR5) in plasma-derived EV-enriched fractions, and TLR2 had the highest observed AUC among the evaluated markers. These findings are compatible with, but do not demonstrate, a contribution of the gut microbiota to PD; vesicular association, microbial origin, and causality were not established. Whether dietary or other microbiota-targeted interventions could be beneficial remains an open question for future longitudinal and interventional studies.