Association Between Microbial Tyrosine Decarboxylase Gene and Levodopa Responsiveness in Patients With Parkinson Disease.

Abstract

Interindividual variability in levodopa efficacy is a challenge for the personalized treatment of Parkinson disease (PD). Gut microbiota might represent a new approach for personalized medicine. Recently, a novel microbial levodopa metabolism pathway was identified, which is mediated by tyrosine decarboxylase mainly encoded by tyrosine decarboxylase gene (<i>tyrDC</i>) in <i>Enterococcus faecalis</i>. In this study, we aimed to identify whether the abundance of microbial <i>tyrDC</i> gene and <i>E faecalis</i> is associated with levodopa responsiveness and could predict the drug response. This cross-sectional study enrolled patients with PD between December 2019 and January 2022 and evaluated levodopa responsiveness using a levodopa challenge test. Patients were stratified into moderate and good responders based on levodopa responsiveness. The <i>tyrDC</i> gene and <i>E. faecalis</i> abundance in fecal samples were measured using quantitative real-time PCR. Plasma levodopa concentrations were measured using liquid chromatography-tandem mass spectrometry analysis. The predictive models for levodopa responsiveness were constructed and verified through cross-validation and external validation. A total of 101 patients with PD were enrolled in the primary cohort and 43 were enrolled in the external validation cohort. Moderate responders had higher abundances of the <i>tyrDC</i> gene (3.6 [3.1-4.3] vs 2.6 [2.1-2.9], <i>p</i> < 0.001) and <i>E faecalis</i> (3.2 [2.5-4.4] vs 2.6 [2.1-3.6], <i>p</i> = 0.010) than good responders. The <i>tyrDC</i> gene abundance was independently associated with levodopa responsiveness (OR: 5.848; 95% CI: 2.664-12.838; <i>p</i> < 0.001). Notably, <i>tyrDC</i> gene abundance showed certain discriminative power for levodopa responsiveness in primary cohort (sensitivity: 80.0%; specificity: 84.3%; area under the curve [AUC]: 0.85; 95% CI: 0.77-0.93; <i>p</i> < 0.001) and external validation cohort (sensitivity: 85.0%; specificity: 95.7%; AUC: 0.95; 95% CI: 0.89-1.02; <i>p</i> < 0.001). The prediction of levodopa responsiveness based on <i>tyrDC</i> gene abundance had good calibration and discrimination in cross-validation (C-index in training and test sets: 0.856 and 0.851, respectively) and external validation (C-index: 0.952). The microbial <i>tyrDC</i> gene abundance could serve as a potential biomarker of levodopa responsiveness. Novel strategies targeting the <i>tyrDC</i> gene may provide new approaches for personalized levodopa treatment.