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While we usually blame the liver for drug interactions, the gut microbiome is often the true mediator. Credit: Neuroscience News<\/p>\nSummary: Levodopa is the primary weapon against Parkinson\u2019s disease, and COMT inhibitors (COMT-Is) are designed to be its ultimate backup, preventing the body from breaking down the drug before it hits the brain. However, a \u201ccounterproductive\u201d discovery reveals a hidden drug-drug interaction occurring in the gut.<\/p>\n
Researchers found that COMT-Is have unintended antibacterial properties that kill off beneficial gut microbes, allowing a specific bacterium, Enterococcus faecalis\u2014to flourish. This \u201cbad\u201d bacterium then proceeds to metabolize and destroy levodopa in the gut, effectively sabotaging the very treatment the COMT-Is were supposed to protect.<\/p>\n
Key Facts<\/p>\n
The Microbiome Middleman: While drug interactions are usually managed by the liver, this study proves the gut microbiome can mediate interactions between co-prescribed medications.The \u201cAccidental\u201d Antibiotic: COMT-Is were found to kill susceptible gut bacteria, which acts like \u201cweeding a garden\u201d to let the levodopa-eating E. faecalis take over.Treatment Sabotage: E. faecalis contains enzymes that chemically modify levodopa, preventing it from crossing the blood-brain barrier. This leaves patients with less dopamine in the brain despite taking more medication.Explaining Patient Variance: The research helps explain why the same dose of Parkinson\u2019s medication works well for some but fails for others, depending on their unique \u201cmicrobiome fingerprint.\u201dBroader Implications: Lead author Andrew Verdegaal suggests this mechanism may be common in other diseases where multiple drugs are prescribed simultaneously, calling for a closer look at \u201cmicrobiome-mediated\u201d drug interactions.<\/p>\n
Source: Yale<\/p>\n
Levodopa\u2014the gold-standard treatment for Parkinson\u2019s disease\u2014increases dopamine in the brain. But as the disease progresses in severity, patients often need to take additional drugs to manage their symptoms.<\/p>\n
One class of drugs, called catechol-O-methyltransferase inhibitors (COMT-Is), can help increase the amount of levodopa that reaches the brain.<\/p>\n
While we usually blame the liver for drug interactions, the gut microbiome is often the true mediator. Credit: Neuroscience News<\/p>\n
But a new study finds that COMT-Is can interact with the microbiome in a way that hinders levodopa\u2019s efficacy.<\/p>\n
Yale School of Medicine (YSM) research, published April 6 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.<\/p>\n
\u201cWe found a counterproductive effect of this drug that\u2019s meant to increase levodopa efficacy,\u201d says lead author Andrew Verdegaal, PhD, a postdoctoral associate in the lab of senior author Andrew Goodman, PhD, chair and C.N.H. Long Professor of Microbial Pathogenesis and director of the Microbial Sciences Institute. \u201cWhile we generally think of the liver as the mediator for drug-drug interactions, this interaction occurs instead through the gut microbiome.\u201d<\/p>\n
Bacteria disruption hinders levodopa<\/p>\n
Parkinson\u2019s 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.<\/p>\n
\u201cThis drug is a way for the body to externally receive dopamine,\u201d says Verdegaal. \u201cBut it has to get into the brain to have an effect.\u201d<\/p>\n
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\u2019s efficacy.<\/p>\n
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.<\/p>\n
The findings support previous research indicating that patients with higher levels of E. faecalis in their gut experience reduced benefit from levodopa.<\/p>\n
\u201cPeople often require co-prescription of multiple drugs,\u201d says Verdegaal. \u201cWhile Parkinson\u2019s 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.\u201d<\/p>\n
The study also adds to growing evidence that differences in microbiomes can help explain why patients experience different effects from the same drug. \u201cI hope our research is a stepping stone to understand this in a wider context,\u201d Verdegaal says.<\/p>\n
Key Questions Answered:Q: Why would a Parkinson\u2019s drug act like an antibiotic?<\/p>\n
A: Many drugs have \u201coff-target\u201d effects. In this case, the chemical structure of COMT-Is happens to be toxic to certain beneficial bacteria. This clears \u201cliving space\u201d in your gut for E. faecalis, which is much hardier and has the specific enzymes needed to eat your medication for breakfast.<\/p>\n
Q: Can I just take a probiotic to fix this?<\/p>\n
A: It\u2019s not that simple yet. While the study identifies E. faecalis as the culprit, simply adding more bacteria might not work if the COMT-Is are still killing them off. The goal of this research is to eventually design \u201csmart\u201d treatments or diets that prevent E. faecalis from blooming in the first place.<\/p>\n
Q: Does this mean COMT inhibitors are bad for Parkinson\u2019s patients?<\/p>\n
A: No, they are still a \u201cgold standard\u201d for a reason and help many people. However, this study gives doctors a new \u201cdiagnostic lens.\u201d If a patient isn\u2019t responding to the drug, the issue might not be their brain or their liver, it might be their gut bacteria \u201cstealing\u201d the medicine.<\/p>\n
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this neuropharmacology and Parkinson\u2019s disease research news<\/p>\n
Author:\u00a0Colleen Moriarty<\/a>
Source:\u00a0Yale<\/a>
Contact:\u00a0Colleen Moriarty \u2013 Yale
Image:\u00a0The image is credited to Neuroscience News<\/p>\n