Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Current Address: Department of Laboratory Medicine, Cluster Human Nutrition & Health, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
BMC Biol. 2020 Oct 20;18(1):137. doi: 10.1186/s12915-020-00876-3.
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.
帕金森病（PD）是一种进行性神经退行性疾病，其特征既有运动症状，也有非运动症状。胃肠道功能障碍是其非运动特征之一，其中便秘被报道为最常见的胃肠道症状。芳香族细菌代谢物因其对肠道稳态和宿主生理的影响而受到广泛关注。特别是，凝结芽孢杆菌是产生这些生物活性代谢物的关键因素。
在这里，我们表明凝结芽孢杆菌能够脱氨基左旋多巴，这是治疗帕金森病的主要药物，并确定了负责脱氨途径起始的芳香族转氨酶。来自左旋多巴的脱氨代谢物 3-(3,4-二羟基苯基)丙酸，在离体模型中对回肠运动产生抑制作用。我们在服用左旋多巴的帕金森病患者的粪便样本中检测到 3-(3,4-二羟基苯基)丙酸，并发现这种代谢物在这些粪便样本中由肠道微生物群积极产生。
左旋多巴被肠道细菌凝结芽孢杆菌脱氨基生成一种代谢物，该代谢物在体外抑制回肠运动。总的来说，这项研究强调了肠道微生物群代谢途径在药物代谢中的重要性，不仅可以保持药物的有效性，还可以避免药物未被吸收部分的细菌分解产物的潜在副作用。
