Gut bacterial deamination of residual levodopa medication for Parkinson’s disease

Gut bacterial deamination of residual levodopa medication for Parkinson’s disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Gastrointestinal tract dysfunction is one of the non-motor features, where constipation is reported as the most common gastrointestinal symptom. Aromatic bacterial metabolite...

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Bibliographic Details
Published in:BMC biology Vol. 18; no. 1; pp. 1 - 137
Main Authors: van Kessel, Sebastiaan P, de Jong, Hiltje R, Winkel, Simon L, van Leeuwen, Sander S, Nelemans, Sieger A, Permentier, Hjalmar, Keshavarzian, Ali, El Aidy, Sahar
Format: Journal Article
Language:English
Published: London BioMed Central Ltd 20-10-2020
BioMed Central
BMC
Subjects:
Amino acids
Aminotransferase
Analysis
Bacteria
Bioactive compounds
Bioactive metabolites
Clostridium sporogenes
Constipation
Deamination
Digestive system
Drug metabolism
Drug side effects
Enzymes
Gastric motility
Gastrointestinal motility
Gastrointestinal symptoms
Gastrointestinal system
Gastrointestinal tract
Homeostasis
Intestinal microflora
L-dopa
Levodopa
Medical treatment
Metabolic pathways
Metabolites
Microbiomes
Microbiota
Microbiota (Symbiotic organisms)
Motility
Movement disorders
Neurodegenerative diseases
Non-motor symptoms
Ostomy
Parkinson's disease
Physiological aspects
Polyphenols
Propionic acid
Resveratrol
Side effects
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Summary:Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Gastrointestinal tract dysfunction is one of the non-motor features, where constipation is reported as the most common gastrointestinal symptom. Aromatic bacterial metabolites are attracting considerable attention due to their impact on gut homeostasis and host's physiology. In particular, Clostridium sporogenes is a key contributor to the production of these bioactive metabolites in the human gut. Here, we show that C. sporogenes deaminates levodopa, the main treatment in Parkinson's disease, and identify the aromatic aminotransferase responsible for the initiation of the deamination pathway. The deaminated metabolite from levodopa, 3-(3,4-dihydroxyphenyl)propionic acid, elicits an inhibitory effect on ileal motility in an ex vivo model. We detected 3-(3,4-dihydroxyphenyl)propionic acid in fecal samples of Parkinson's disease patients on levodopa medication and found that this metabolite is actively produced by the gut microbiota in those stool samples. Levodopa is deaminated by the gut bacterium C. sporogenes producing a metabolite that inhibits ileal motility ex vivo. Overall, this study underpins the importance of the metabolic pathways of the gut microbiome involved in drug metabolism not only to preserve drug effectiveness, but also to avoid potential side effects of bacterial breakdown products of the unabsorbed residue of medication.
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ISSN:1741-7007
1741-7007
DOI:10.1186/s12915-020-00876-3