How intestinal bacteria affect the treatment of Parkinson's disease

Patients with Parkinson's disease are treated with levodopa, which is converted to dopamine, a neurotransmitter in the brain. In a study published January 18 in the journal Nature CommunicationsScientists at the University of Groningen have shown that intestinal bacteria can metabolize levodopa to dopamine. And since dopamine can not cross the blood-brain barrier, the drug is therefore 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," says microbiology badistant professor Sahar El Aidy, a senior researcher of the study. "There is a continuous chemical dialogue between intestinal bacteria and the brain, the so-called intestine-brain axis." El Aidy and his team have studied the ability of the gut microbiota to influence the bioavailability of levodopa, a drug used to treat Parkinson's disease.

Blood-brain barrier

The drug is usually taken orally and levodopa is absorbed into the small intestine and then transported by the blood to the brain. However, decarboxylase enzymes can convert levodopa to dopamine. Unlike levodopa, dopamine can not cross the blood-brain barrier; patients therefore also receive a decarboxylase inhibitor. "But the levels of levodopa that will reach the brain vary greatly between patients with Parkinson's disease, and we wondered if the gut microbiota played a role in this difference," El Aidy said.

In bacterial samples of the small intestine of rats, Ph.D. Sebastiaan van Kessel, student, discovered an activity of the bacterial enzyme tyrosine decarboxylase, which normally converts tyrosine into tyramine, but which also converted levodopa in dopamine. "We then determined that the source of this decarboxylase was Enterococcus bacteria." The researchers also showed that the conversion of levodopa was not inhibited by a high concentration of amino acid, tyrosine, the main substrate of the bacterial enzyme tyrosine decarboxylase.

bioavailability

Parkinson's patients receiving a decarboxylase inhibitor, the next step was to test the effect of several inhibitors of human decarboxylase on the bacterial enzyme. "It appeared that, for example, the carbidopa inhibitor inhibited human decarboxylase more than 10,000 times," said El Aidy.

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

Vicious circle

Another important discovery in the study is the positive correlation between the duration of the disease and the levels of bacterial tyrosine decarboxylase. Some patients with Parkinson 's disease develop a proliferation of small intestine bacteria, including enterococci, due to the frequent absorption of proton pump inhibitors, which they use to treat the gastrointestinal symptoms badociated with the disease. Overall, these factors lead to a vicious circle leading to an increase in levodopa / decarboxylase inhibitor dosage in a subset of patients.

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

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University of Groningen