<p>We hypothesize that intestinal microbiome dysbiosis may contribute to Parkinson’s disease (PD) pathogenesis. Our prior proof-of-concept clinical trial demonstrated that a precision prebiotic intervention improved microbiota dysbiosis and alleviated gastrointestinal and motor symptoms in PD patients. Building on this, we analyzed plasma extracellular vesicles (EVs) from participants to explore EVs as a dynamic PD biomarker and to assess the systemic effects of a microbiota-directed intervention. Using mass spectrometry-based proteomics of EVs from PD and healthy control (HC) participants, we identified distinct human and bacterial proteins in plasma-derived EV. Crucially, this offers a holistic systemic readout of the microbiota-gut-brain axis by quantifying both host and microbial components. We found that EV proteomic profiles differed between PD and HC samples as well as between unmedicated/mild and medicated/moderate PD participants. Furthermore, the microbiota-directed prebiotic intervention induced an acutely modifiable PD signature, shifting host and microbial EV proteomic profiles toward the HC profile. Using a combined 16-feature host-microbe signature, we built a multiple linear regression model that accurately distinguishes PD status from HC (<i>R</i>^<i>2</i> = 0.88) and successfully stratified disease severity (<i>R</i>^<i>2</i> = 0.72). Based on these findings, we suggest that: (1) a precision prebiotic mixture can modulate PD-associated proteomic signatures and (2) plasma EV proteomics may be a platform to capture these biological responses and to explore potential diagnostic and staging biomarkers in the context of microbiome-targeted interventions.</p>