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Ability of gut microbiota to influence the bioavailability of levodopa in Parkinson’s disease – The presence of more bacteria producing the tyrosine decarboxylase (TDC) enzyme means less levodopa in the bloodstream

Reporter: Aviva Lev-Ari, PhD, RN

Decarboxylase enzymes can convert levodopa into dopamine. In contrast to levodopa, dopamine cannot cross the blood-brain barrier, so patients are also given a decarboxylase inhibitor. “But the levels of levodopa that will reach the brain vary strongly among Parkinson’s disease patients.

The bacterial tyrosine decarboxylase enzyme, which normally converts tyrosine into tyramine, but was found to also convert levodopa into 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 the amino acid tyrosine, the main substrate of the bacterial tyrosine decarboxylase enzyme.

• Carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,
• the higher abundance of bacterial enzyme in the small intestines of rats reduced levels of levodopa in the bloodstream,

• positive correlation between disease duration and levels of bacterial tyrosine decarboxylase.
• Some Parkinson’s disease patients develop an overgrowth of small intestinal bacteria including Enterococci due to frequent uptake of proton pump inhibitors, which they use to treat gastrointestinal symptoms associated with the disease.
• Altogether, these factors result in a vicious circle leading to an increased levodopa/decarboxylase inhibitor dosage requirement in a subset of patients.El Aidy concludes that
• the presence of the bacterial tyrosine decarboxylase enzyme can explain why some patients need more frequent dosages of levodopa to treat their motor fluctuations. “This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment.“

SOURCE

https://www.rdmag.com/news/2019/01/how-gut-bacteria-affect-treatment-parkinsons-disease?type=cta&et_cid=6585419&et_rid=461755519&linkid=Mobius_Link

Article | OPEN | Published: 18 January 2019

Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease

• Sebastiaan P. van Kessel,
• Alexandra K. Frye,
• Ahmed O. El-Gendy,
• Maria Castejon,
• Ali Keshavarzian,
• Gertjan van Dijk &
• Sahar El Aidy

Nature Communications volume 10, Article number: 310 (2019) | Download Citation

Abstract

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients.

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SOURCE

https://www.rdmag.com/news/2019/01/how-gut-bacteria-affect-treatment-parkinsons-disease?type=cta&et_cid=6585419&et_rid=461755519&linkid=Mobius_Link