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

Autor: Hiltje Riemke de Jong, Sieger Adriaan Nelemans, Ali Keshavarzian, Hjalmar P. Permentier, Sander S. van Leeuwen, Simon Laurens Winkel, Sebastiaan P van Kessel, Sahar El Aidy
Přispěvatelé: Molecular Immunology, Host-Microbe Interactions, Analytical Biochemistry
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Parkinson's disease
Physiology
Metabolite
Aminotransferase
Plant Science
Pharmacology
Gut flora
Antiparkinson Agents
Levodopa
Mice
chemistry.chemical_compound
Structural Biology
Aromatic amino acids
lcsh:QH301-705.5
media_common
Gastrointestinal tract
biology
digestive
oral
and skin physiology
Parkinson Disease
Deamination
Clostridium sporogenes
General Agricultural and Biological Sciences
Research Article
Biotechnology
medicine.drug
Drug
media_common.quotation_subject
Non-motor symptoms
General Biochemistry
Genetics and Molecular Biology
medicine
Animals
Transaminases
Ecology
Evolution
Behavior and Systematics
Clostridium
Gastrointestinal motility
business.industry
Cell Biology
biology.organism_classification
medicine.disease
Gastrointestinal Microbiome
Mice
Inbred C57BL
lcsh:Biology (General)
chemistry
Drug side effects
business
Bioactive metabolites
Drug metabolism
Ex vivo
Developmental Biology
Zdroj: BMC Biology
BMC Biology, Vol 18, Iss 1, Pp 1-14 (2020)
BMC Biology, 18(1):137. BioMed Central Ltd.
ISSN: 1741-7007
DOI: 10.1186/s12915-020-00876-3
Popis: Background 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. Results 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. Conclusions 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.
Databáze: OpenAIRE
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