Modifying the microbiome to enhance L-dopa therapy in Parkinson’s disease

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is a progressive neurodegenerative disease resulting from the loss of dopaminergic neurons in the substantia nigra. It is the second-leading neurodegenerative disease associated with aging. For over fifty years, treatment with levodopa (L-dopa), which crosses the blood-brain barrier and is converted to dopamine (DA), has been used to mitigate the debilitating motor symptoms associated with PD. However, there are several caveats associated with L-dopa therapy including erratic, “on-off” cyclical relief from motor symptoms, large individual variability in effective dose, and a loss of efficacy over time. This loss of efficacy necessitates escalation of L-dopa dosage, with an increased risk of L-dopa induced dyskinesia. One confounding factor in L- dopa treatment is its metabolism to DA by gut microbiota. DA produced systemically is unable to cross the blood- brain barrier and is associated with adverse physiological effects. Although aromatic amino acid decarboxylase inhibitors (e.g., carbidopa) are typically co-administered with L-dopa, they are ineffective against microbial metabolism. Enterococcus faecalis, a ubiquitous member of the gut microbiome that is primarily responsible for the bacterial metabolism of L-dopa, expresses a tyrosine decarboxylase (TyrDC) that avidly converts L-dopa to DA and is only weakly inhibited by carbidopa. In the proposed studies, we will test the hypothesis that deletion of the TyrDC gene from a previously engineered, bacteriocin-expressing strain of E. faecalis will abrogate L- dopa metabolism, leading to increased L-dopa and decreased DA in the serum, and elevated DA levels in the brain following oral L-dopa administration. In Aim 1, we will investigate colonization of the mouse gastrointestinal tract with the newly constructed ΔtyrDC mutant and determine the impact of colonization on L-dopa and DA concentrations in the blood and brain following oral administration of L-dopa. In Aim 2, we will address the impact of colonization with the ΔtyrDC mutant on the efficacy of oral L-dopa therapy in alleviating motor deficits and the development of L-dopa induced dyskinesia in a mouse model of PD. The scientific impact of these studies will be to further elucidate the effects of gut microbial metabolism on the efficacy of oral L-dopa therapy. There is a clear unmet need for novel approaches that enhance or extend the usefulness of L-dopa in PD treatment, and the development of a probiotic that effectively prevents decarboxylation of L-dopa in the gastrointestinal tract may have significant potential as an adjunct to L-dopa in the management of PD.