Levodopa (top right) is converted to DHPPA (middle right) by gut bacteria, which inhibits acetylcholine-induced intestinal motility (see bottom right). These results are important for Parkinson’s patients, who experience frequent gastrointestinal problems such as constipation, and they show the possible side effects of unabsorbed drugs such as levodopa. Photo credit: University of Groningen
Bacteria in the small intestine can deaminate levodopa, the main drug used to treat Parkinson’s disease. The bacterial processing of the unabsorbed fractions of the drug results in a metabolite that decreases intestinal motility. These results were reported on October 20 in the journal BMC Biology by scientists from the University of Groningen. Since the disease is already linked to constipation, intestinal bacteria processing the drug can worsen gastrointestinal complications.
Parkinson’s disease patients are treated with levodopa, which is converted into the neurotransmitter dopamine in the brain. Levodopa is absorbed in the small intestine, although not completely. Eight to ten percent continue to migrate to a more distal part of the intestine, and that percentage increases with age and the dose of drug administered. In this distal part of the intestine, bacteria such as Clostridium sporogenes can be found, which can deaminate aromatic amino acids (remove an NH2 group).
“Last year, other scientists demonstrated the deamination activity of this bacterium on aromatic amino acids,” says Sahar El Aidy, Assistant Professor of Microbiology at the University of Groningen. El Aidy knew that the chemical structure of levodopa was similar to that of the aromatic amino acid tyrosine. “This suggested that the bacterium could metabolize levodopa, which could affect bowel motility in people with Parkinson’s disease.”
Studies by El Aidy and her research team showed that the bacterium C. sporogenes actually breaks down levodopa into 3- (3,4-dihydroxyphenyl) propionic acid (DHPPA). “There are four steps in this process, three of which were already known. However, we have discovered the first step, which is mediated by a transaminase enzyme.”
The team then used an ex vivo model system for intestinal motility to investigate whether DHPPA has an influence on the motility of the distal small intestine. Intestinal motility was induced by the addition of acetylcholine, after which DHPPA was added. “In five minutes this reduced motility by 69 percent and increased to 73 percent in ten to fifteen minutes.” This clearly demonstrated that the levodopa metabolite can reduce bowel contractions that can lead to constipation.
To test whether these results are relevant for Parkinson’s patients, Sebastiaan van Kessel, Ph.D. The student on El Aidy’s research team tested patient stool samples for the presence of DHPPA. “Since it is also produced as a breakdown product from coffee and fruit, we compared samples from patients with those from healthy control persons on a comparable diet,” explains El Aidy. The result showed significantly higher DHPPA levels in stool samples from Parkinson’s patients treated with levodopa. To confirm that this metabolite resulted from the presence and activity of the intestinal bacterium C. sporogenes or other intestinal bacteria capable of anaerobic deamination, bacteria were cultured from stool samples and fed the precursor of DHPPA. This experiment showed that the bacteria can actually metabolize levodopa to produce DHPPA.
All of these results suggest that any remainder of the drug levodopa that is not absorbed early in the intestine can be metabolized to DHPPA by intestinal bacteria, which then decreases distal intestinal motility. Since constipation is already one of the symptoms of Parkinson’s disease, it is unfortunate that the drug used to treat the symptoms itself may further decrease intestinal motility due to the bacterial metabolism of the gut. “However, now that we know, it is possible to look for inhibitors of the enzymes in the deamination pathway identified in our study.”
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Sebastiaan P. van Kessel, Hiltje R. de Jong, Simon L. Winkel, Sander S. van Leeuwen, Sieger A. Nelemans, Hjalmar Permentier, Ali Keshavarzian and Sahar El Aidy: Intestinal bacterial deamination of residual levodopa drugs for Parkinson’s disease BMC Biology, October 20, 2020. DOI: 10.1186 / s12915-020-00876-3 Provided by the University of Groningen
Quote: Gut bacteria could be responsible for the side effect of the Parkinson’s drug (2020, October 19), which was released on October 20, 2020 at https://medicalxpress.com/news/2020-10-gut-bacteria-responsible-side-effect .html was obtained
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