Targeted Gut Microbiota Modulation Enhances Levodopa Bioavailability and Motor Recovery in MPTP Parkinson’s Disease Models

Emerging evidence highlights the gut microbiota as a pivotal determinant of pharmacological efficacy. While <i>Enterococcus faecalis</i> (<i>E. faecalis</i>)-derived tyrosine decarboxylases (<i>tyrDCs</i>) are known to decarboxylate levodopa (L-dopa), compromising systemic bioavailability, the causal mechanisms underlying microbiota-mediated pharmacodynamic variability remain unresolved. In our study, we employed antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) to interrogate microbiota-L-dopa interactions in MPTP-induced Parkinson's disease (PD) mice. The study demonstrated that antibiotic-mediated microbiota depletion enhances L-dopa bioavailability and striatal dopamine (DA) level, correlating with improved motor function. To dissect clinical heterogeneity in the L-dopa response, PD patients were stratified into moderate responders and good responders following standardized L-dopa challenges. In vitro bioconversion assays revealed greater L-dopa-to-DA conversion in fecal samples from moderate responders versus good responders. FMT experiments confirmed mice receiving good-responder microbiota exhibited enhanced L-dopa bioavailability, higher striatal DA concentrations, and a heightened therapeutic effect of L-dopa relative to moderate-responder recipients. Collectively, our study provided evidence that the gut microbiota directly modulates L-dopa metabolism and microbial composition determines interindividual therapeutic heterogeneity. Targeted microbial modulation-through precision antibiotics or donor-matched FMT-is a viable strategy to optimize PD pharmacotherapy, supporting the potential for microbiota-targeted adjuvant therapies in PD management.