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

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $195,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10869308
- **Project number:** 1R21NS137244-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Jimmy Feix
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,000
- **Award type:** 1
- **Project period:** 2024-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869308

## Citation

> US National Institutes of Health, RePORTER application 10869308, Modifying the microbiome to enhance L-dopa therapy in Parkinson’s disease (1R21NS137244-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10869308. Licensed CC0.

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