Parkinson’s disease is a debilitating neurological condition affecting more than 1% of the global population aged 60 and above. The primary medication used to treat this disease is levodopa. The efficacy of the treatment is hugely variable between individuals, depending on the composition of their microbiota. Levodopa is converted into active dopamine, but if the gut microbiota metabolize levodopa before it crosses the blood-brain barrier, medication is ineffective. A research team led by Harvard University scientists has found that different species of bacteria are involved in levodopa metabolism.
This digitally-colorized scanning electron microscopic image depicts Enterococcus faecalis. Image credit: Pete Wardell / CDC.
“Gut microbes can chew up medications, too, often with hazardous side effects,” said study first author Vayu Maini Rekdal, a graduate student at Harvard University.
“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.”
Few bacterial enzymes can perform this conversion. But, a good number bind to tyrosine, an amino acid similar to levodopa. And one, from Lactobacillus brevis — a food microbe often found in milk and pickles — can accept both tyrosine and levodopa.
Using the Human Microbiome Project as a reference, Maini Rekdal and his colleagues hunted through bacterial DNA to identify which gut microbes had genes to encode a similar enzyme.
Several fit their criteria; but only one strain, Enterococcus faecalis ate all the levodopa, every time.
With this discovery, the researchers provided the first strong evidence connecting Enterococcus faecalis and the bacteria’s enzyme (PLP-dependent tyrosine decarboxylase, or TyrDC) to levodopa metabolism.
And yet, a human enzyme can and does convert levodopa to dopamine in the gut, the same reaction carbidopa is designed to stop.
Then why, the team wondered, does the Enterococcus faecalis enzyme escape carbidopa’s reach?
Even though the human and bacterial enzymes perform the exact same chemical reaction, the bacterial one looks just a little different.
When gut microbes metabolize the Parkinson’s drug levodopa, they produce dopamine; a second microbe then metabolizes dopamine, producing meta-tyramine. While levodopa metabolism likely limits drug availability and contributes to side effects, the potential ramifications of transforming dopamine into meta-tyramine are unknown. Image credit: Harvard University.
“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,” Maini Rekdal said.
“If true, other host-targeted treatments may be just as ineffective as carbidopa against similar microbial machinations.”
But the cause may not matter. The study authors already discovered a molecule capable of inhibiting the bacterial enzyme.
“The molecule turns off this unwanted bacterial metabolism without killing the bacteria; 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,” Maini Rekdal said.
The scientists might have stopped there. But instead, they pushed further to unravel a second step in the microbial metabolism of levodopa.
After Enterococcus faecalis converts the drug into dopamine, a second organism — Eggerthella lenta — converts dopamine into another compound, meta-tyramine, they found.
“Eggerthella lenta consumes dopamine, producing meta-tyramine as a by-product. This kind of reaction is challenging, even for chemists,” they said.
“There’s no way to do it on the bench top, and previously no enzymes were known that did this exact reaction,” Maini Rekdal added.
The meta-tyramine by-product may contribute to some of the noxious levodopa side effects; more research needs to be done.
But, apart from the implications for Parkinson’s patients, Eggerthella lenta’s novel chemistry raises more questions: 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,” said Harvard University’s Professor Emily Balskus, senior author of the study.
The findings were published in the journal Science.
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Vayu Maini Rekdal et al. 2019. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science 364 (6445): eaau6323; doi: 10.1126/science.aau6323
