For some time, gut microbes have been thought to metabolize and lessen the efficacy of levodopa, the primary drug treatment for Parkinson’s disease, but the species responsible have eluded detection.
One such species, however, was recently identified by scientists based at Harvard University. Combing through data from the Human Microbiome Project, the scientists homed in on Enterococcus faecalis. This bacterium absorbs levodopa, and it possesses an enzyme that can convert levodopa to dopamine. What’s more, E. faecalis has a partner of sorts, Eggerthella lenta. This bacterium converts dopamine into meta-tyramine. This compound may contribute to some of levodopa’s side effects.
“This kind of microbial metabolism can be detrimental,” said Vayu Maini Rekdal, a graduate student in the laboratory of Emily Balskus, PhD, associate professor of chemistry and chemical biology at Harvard. “Maybe the drug is not going to reach its target in the body, maybe it’s going to be toxic all of a sudden, maybe it’s going to be less helpful.”
Maini Rekdal is the first author and Balskus the senior author of a paper (“Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism”) that appeared June 14 in Science. In this paper, the authors describe how tyrosine decarboxylase (TyrDC) from E. faecalis and dopamine dehydroxylase (Dadh) from E. lenta A2 sequentially metabolized levodopa into meta-tyramine.
“We have used chemical knowledge and interdisciplinary tools to decipher the molecular mechanisms by which gut bacteria interfere with the treatment of Parkinson’s disease,” the article’s authors wrote. “The decarboxylation of levodopa by E. faecalis mirrors host drug metabolism and, together with [a dopamine-converting human enzyme], likely limits drug availability and contributes to interindividual variation in efficacy.”
These findings, the authors noted, show that gut bacterial metabolism need not be chemically distinct from host activities to alter drug efficacy, and suggest that such interactions may be underappreciated.
Since the introduction of levodopa in the late 1960s, researchers have known that the body’s enzymes (tools that perform necessary chemistry) can break down levodopa in the gut, preventing the drug from reaching the brain. So, the pharmaceutical industry introduced a new drug, carbidopa, to block unwanted levodopa metabolism. Taken together, the treatment seemed to work.
“Even so,” Maini Rekdal pointed out, “there’s a lot of metabolism that’s unexplained, and it’s very variable between people.” That variance is a problem: Not only is the drug less effective for some patients, but when levodopa is transformed into dopamine outside the brain, the compound can cause side effects, including severe gastrointestinal distress and cardiac arrhythmias. If less of the drug reaches the brain, patients are often given more to manage their symptoms, potentially exacerbating these side effects.
Although the human enzyme in the gut that converts levodopa to dopamine is stopped by carbidopa, the bacterial enzyme appears unaffected. How could this be, Balskus’ team wondered?
Even though the human and bacterial enzymes perform the exact same chemical reaction, the bacterial one looks just a little different. Maini Rekdal speculated that carbidopa may not be able to penetrate the microbial cells, or the slight structural variance could prevent the drug from interacting with the bacterial enzyme. If true, other host-targeted treatments may be just as ineffective as carbidopa against similar microbial machinations.
But the cause may not matter. Balskus and her team already discovered a molecule capable of inhibiting the bacterial enzyme.
“To identify a selective inhibitor of gut bacterial levodopa decarboxylation, we leveraged our molecular understanding of gut microbial levodopa metabolism,” the authors of the Science article indicated. “Given TyrDC’s preference for tyrosine, we examined tyrosine mimics and found that (S)-α-fluoromethyltyrosine (AFMT) prevented levodopa decarboxylation by TyrDC and E. faecalis as well as complex gut microbiota samples from Parkinson’s patients.”
“The molecule turns off this unwanted bacterial metabolism without killing the bacteria,” Maini Rekdal said. “It’s just targeting a non-essential enzyme.” This and similar compounds could provide a starting place for the development of new drugs to improve levodopa therapy for Parkinson’s patients.
Apart from the implications for Parkinson’s patients, the current study raises additional questions of more general import: Why would bacteria adapt to use dopamine, which is typically associated with the brain? What else can gut microbes do? And does this chemistry impact our health?
“All of this suggests that gut microbes may contribute to the dramatic variability that is observed in side effects and efficacy between different patients taking levodopa,” Balskus said.
But this microbial interference may not be limited to levodopa and Parkinson’s disease. The current study could shepherd additional work to discover exactly what microbes are in our gut, what they can do, and how they can impact our health, for better or worse.