Bioengineered gut bacterium synthesizing levodopa alleviates motor deficits in models of Parkinson’s disease

L-3,4-Dihydroxyphenylalanine (L-DOPA), synthesized from L-tyrosine, is a direct precursor to dopamine. L-DOPA is the gold-standard treatment for Parkinson’s disease (PD), given orally alongside decarboxylase inhibitors (e.g., benserazide) to enhance bioavailability. However, its chronic daily pulsatile-like delivery is associated with complications. Herein, we show the construction and in vivo efficacy of a programmable, titratable, genetically engineered E. coli Nissle 1917 system (EcN L-DOPA ) that continuously synthesizes L-DOPA from L-tyrosine for systemic distribution. Oral administration of EcN L-DOPA with benserazide maintains therapeutic plasma L-DOPA concentrations and increases brain dopamine levels. EcN L-DOPA improves motor performance and limits depressive-like behaviors without adverse side effects in healthy mice, Parkinsonian mice, and canine models. Simulated physiological models from pharmacokinetic and pharmacodynamic studies in canines demonstrate the translational feasibility of this biotherapeutic system for potential human studies. This work lays the groundwork for EcN L-DOPA as a continuous, non-invasive microbial drug delivery platform for PD and chronic neurological diseases. • Oral EcN L-DOPA 2 delivers non-pulsatile L-DOPA while transiently residing in the gut • Low plasma fluctuations and elevated brain dopamine levels in mice and dogs • Reduces motor and depressive-like deficits in two complementary models of PD • EcN L-DOPA 2 is safe, well tolerated, with consistent pharmacology across all models Padhi et al. bioengineered a gut-beneficial microbe to continuously produce and deliver L-DOPA, the gold-standard treatment for Parkinson’s disease, in a non-pulsatile manner. This biotherapeutic approach reduces the drug fluctuations that cause debilitating motor and non-motor symptoms, offering steady therapeutic benefits in animal models while maintaining safety and tolerability.