Gut bacterial deamination of residual levodopa medication for Parkinson\u2019s disease

Sebastiaan P Van Kessel,Hiltje R De Jong,Sahar El Aidy,Simon L Winkel,Hjalmar Permentier,Ali Keshavarzian,Sieger A Nelemans,Sander S Van Leeuwen

doi:10.1186/s12915-020-00876-3

Abstract

BackgroundParkinson’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.ResultsHere, 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.ConclusionsLevodopa 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.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms
Analysis of the samples using high-pressure liquid chromatography (HPLC) coupled to an electrochemical detector (ED) revealed that levodopa is completely converted within 24 h to a new metabolite, which was identified by 1H/13C-NMR and LC-MS as 3-(3,4-dihydroxyphenyl)propionic acid, DHPPA (Fig. 1b, c; Additional File 1: Fig. S1A, 1B, 1C)
The incubations showed that the proteinogenic aromatic amino acids (PAAAs) available from the growth medium did not prevent the deamination of levodopa and that, during the incubation for 48 h, DHPPA remained stable

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Clostridium sporogenes is a key contributor to the production of these bioactive metabolites in the human gut. Gut bacteria produce a wide range of small bioactive molecules from different chemical classes, including aromatic amino acids [1]. Bacterial products from aromatic amino acid degradation have been shown to play a critical role in intestinal barrier function, immune modulation, and gut motility [2,3,4,5,6]. In the lower part of the gastrointestinal (GI) tract, where oxygen is limited, aromatic amino acid degradation by anaerobic bacteria involves reductive or oxidative deamination [7] resulting in production of aromatic metabolites [8,9,10,11].

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