HMN 2026: How Parkinson’s add-on drugs may spur gut bacteria that break down levodopa,

Levodopa—the gold-standard treatment for Parkinson’s disease—increases dopamine in the brain. But as the disease progresses in severity, patients often need to take additional drugs to manage their symptoms. One class of drugs, called catechol-O-methyltransferase inhibitors (COMT-Is), can help increase the amount of levodopa that reaches the brain.

But a new study finds that COMT-Is can interact with the microbiome in a way that hinders levodopa’s efficacy.

Yale School of Medicine (YSM) research, published in Nature Microbiology, has found that COMT-Is can trigger compositional changes in the gut microbiome that promote the growth of bacteria that break down levodopa before it can reach the brain.

“We found a counterproductive effect of this drug that’s meant to increase levodopa efficacy,” says lead author Andrew Verdegaal, Ph.D., a postdoctoral associate in the lab of senior author Andrew Goodman, Ph.D., chair and C.N.H. Long Professor of Microbial Pathogenesis and director of the Microbial Sciences Institute.

“While we generally think of the liver as the mediator for drug-drug interactions, this interaction occurs instead through the gut microbiome.”

Parkinson’s disease is caused by a decrease in dopamine production. Levodopa is an oral medication that is absorbed and crosses the blood-brain barrier, where it is converted into dopamine.

“This drug is a way for the body to externally receive dopamine,” says Verdegaal. “But it has to get into the brain to have an effect.”

Some enzymes in the body can interact with the drug before it reaches the brain and convert it into a different compound that cannot cross the blood-brain barrier. COMT-Is work by blocking these enzymes before they can chemically modify levodopa, boosting the drug’s efficacy.

In the new study, however, the researchers discovered that COMT-Is have antibacterial properties that alter the microbiome. When COMT-Is kill off susceptible gut bacteria, other bacteria thrive, the researchers found. This includes Enterococcus faecalis, which contains an enzyme that can also metabolize levodopa and prevent it from reaching the brain.

The findings support previous research indicating that patients with higher levels of E. faecalis in their gut experience reduced benefit from levodopa.

“People often require coprescription of multiple drugs,” says Verdegaal. “While Parkinson’s disease is one example, this study suggests that we should look more closely at the role of the microbiome in response to other co-prescribed drugs.”

The study also adds to growing evidence that differences in microbiomes can help explain why patients experience different effects from the same drug. “I hope our research is a stepping stone to understand this in a wider context,” Verdegaal says.

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NeurologyClinical pharmacology