PDF(Pubmed)
Abstract：
Interspecies pathways in the gut microbiome have been shown to metabolize levodopa, the primary treatment for Parkinson\'s disease, and reduce its bioavailability. While the enzymatic reactions have been identified, the ability to establish the resulting macromolecules as biomarkers of microbial metabolism remains technically challenging. In this study, we leveraged an untargeted mass spectrometry-based approach to investigate volatile organic compounds (VOCs) produced during levodopa metabolism by Enterococcus faecalis, Clostridium sporogenes, and Eggerthella lenta. We cultured these organisms with and without their respective bioactive metabolites and detected levodopa-induced shifts in VOC profiles. We then utilized bioinformatics to identify significant differences in 2,6-dimethylpyrazine, 4,6-dimethylpyrimidine, and 4,5-dimethylpyrimidine associated with its biotransformation. Supplementing cultures with inhibitors of levodopa-metabolizing enzymes revealed specific modulation of levodopa-associated diazines, verifying their relationship to its metabolism. Furthermore, functional group analysis depicts strain-specific VOC profiles that reflect interspecies differences in metabolic activity that can be leveraged to assess microbiome functionality in individual patients. Collectively, this work identifies previously uncharacterized metabolites of microbe-mediated levodopa metabolism to determine potential indicators of this activity and further elucidate the metabolic capabilities of different gut bacteria.
摘要：
肠道微生物组中的种间途径已被证明可以代谢左旋多巴，帕金森病的主要治疗方法，并降低其生物利用度。虽然已经确定了酶促反应，建立所产生的大分子作为微生物代谢生物标志物的能力在技术上仍然具有挑战性。在这项研究中,我们利用基于非目标质谱的方法来研究粪肠球菌在左旋多巴代谢过程中产生的挥发性有机化合物（VOCs），产孢梭菌,还有LentaEggerthella.我们在有和没有它们各自的生物活性代谢物的情况下培养了这些生物，并检测到左旋多巴诱导的VOC谱变化。然后，我们利用生物信息学来确定2,6-二甲基吡嗪的显着差异，4,6-二甲基嘧啶,和4,5-二甲基嘧啶与其生物转化有关。用左旋多巴代谢酶抑制剂补充培养物显示出左旋多巴相关二嗪的特定调节，验证它们与新陈代谢的关系。此外，功能组分析描述了菌株特异性VOC谱,反映了代谢活性的种间差异,可用于评估个体患者的微生物组功能.总的来说，这项工作鉴定了微生物介导的左旋多巴代谢的先前未表征的代谢物，以确定该活性的潜在指标，并进一步阐明不同肠道细菌的代谢能力。
