How intestinal bacteria affect the treatment of Parkinson's disease



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IMAGE: The presence of more bacteria that produce the enzyme tyrosine decarboxylase (TDC) means less levodopa in the bloodstream.
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Credit: S. El Aidy, University of Groningen.

Patients with Parkinson's disease are treated with levodopa, which is converted to dopamine, a neurotransmitter in the brain. In a study published on January 18 in the magazine. Communications of nature, scientists from the University of Groningen show that intestinal bacteria can metabolize levodopa into dopamine. Since dopamine can not cross the blood-brain barrier, this makes the drug less effective, even in the presence of inhibitors that should prevent the conversion of levodopa.

"It is well established that intestinal bacteria can affect the brain," explains Assistant Professor of Microbiology Sahar El Aidy, principal investigator of the study. "There is a continuous chemical dialogue between the intestinal bacteria and the brain, the so-called brain-guts axis." Aidy and his team investigated the ability of the gut microbiota to influence the bioavailability of levodopa, a medication used in the treatment of Parkinson's disease.

Blood-brain barrier

The medication is usually taken orally, and levodopa is absorbed in the small intestine and then transported through the bloodstream to the brain. However, decarboxylase enzymes can convert levodopa to dopamine. Unlike levodopa, dopamine can not cross the blood-brain barrier, so patients also receive a decarboxylase inhibitor. "But the levels of levodopa that will reach the brain vary strongly among patients with Parkinson's disease, and we question whether the gut microbiota was playing a role in this difference," says El Aidy.

In bacterial samples from the small intestine of rats, Aidy Ph.D. student Sebastiaan van Kessel found activity of the bacterial enzyme tyrosine decarboxylase, which normally converts tyrosine to tyramine, but was found to also convert levodopa into dopamine. "Then we determined that the source of this decarboxylase was the Enterococcus bacteria." The researchers also showed that the conversion of levodopa was not inhibited by a high concentration of the amino acid tyrosine, the main substrate of the bacterial enzyme tyrosine decarboxylase.

Bioavailability

As Parkinson's patients receive a decarboxylase inhibitor, the next step was to test the effect of several human decarboxylase inhibitors on the bacterial enzyme. "It turned out that, for example, the carbidopa inhibitor is more than 10,000 times more potent than the inhibition of human decarboxylase," says El Aidy.

These findings led the team to the hypothesis that the presence of bacterial tyrosine decarboxylase would reduce the bioavailability of levodopa in Parkinson's patients. To confirm this, they badyzed stool samples from patients who were in a normal or high dose of levodopa. The relative abundance of the bacterial gene encoding tyrosine decarboxylase correlates with the need for a higher dose of the drug. "As these were stool samples, and levodopa is absorbed in the small intestine, this was not yet a solid test, however, we confirmed our observation by showing that the greater abundance of bacterial enzymes in the small intestine of rats reduced the levels of levodopa in the bloodstream, "explains El Aidy.

Vicious circle

Another important finding in the study is the positive correlation between the duration of the disease and bacterial tyrosine decarboxylase levels. Some patients with Parkinson's disease develop an overgrowth of small intestinal bacteria, including enterococci, due to the frequent uptake of proton pump inhibitors, which they use to treat gastrointestinal symptoms badociated with the disease. Taken together, these factors result in a vicious circle that leads to an increase in levodopa / decarboxylase inhibitor dose requirements in a subset of patients.

The Aidy concludes that the presence of the bacterial tyrosine decarboxylase enzyme may explain why some patients need more frequent doses of levodopa to treat their motor fluctuations. "This is considered to be a problem for patients with Parkinson's disease, because a higher dose will result in dyskinesia, one of the main side effects of levodopa treatment."

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Reference: Sebastiaan van Kessel, Alexandra Frye, Ahmed El-Gendy, Maria Castejon, Ali Keshavarzian, Gertjan van Dijk and Sahar El Aidy: Bacterial intestinal tyrosine decarboxylases restrict levodopa levels in the treatment of Parkinson's disease. Communications of natureJanuary 18, 2019

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