Chung So Hyeon, Yoo Dallah, Ahn Tae-Beom, Lee Wonwoong, Hong Jongki
College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
Department of Neurology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
Pharmaceuticals (Basel). 2023 Oct 20;16(10):1495. doi: 10.3390/ph16101495.
Although Parkinson's disease (PD) is a representative neurodegenerative disorder and shows characteristic motor impediments, the pathophysiological mechanisms and treatment targets for PD have not yet been clearly identified. Since several tryptophan metabolites produced by gut microbiota could pass the blood-brain barrier and, furthermore, might influence the central nervous system, tryptophan metabolites within the indole, kynurenine, and serotonin metabolic pathways might be the most potent targets for PD development. Furthermore, most metabolites are circulated via the blood, play roles in and/or are metabolized via the host organs, and finally are excreted into the urine. Therefore, profiling the overall tryptophan metabolic pathways in urine samples of patients with PD is important to understanding the pathological mechanisms, finding biomarkers, and discovering therapeutic targets for PD. However, the development of profiling analysis based on tryptophan metabolism pathways in human urine samples is still challenging due to the wide physiological ranges, the varied signal response, and the structural diversity of tryptophan metabolites in complicated urine matrices. In this study, an LC-MS/MS method was developed to profile 21 tryptophan metabolites within the indole, kynurenine, and serotonin metabolic pathways in human urine samples using ion-pairing chromatography and multiple reaction monitoring determination. The developed method was successfully applied to urine samples of PD patients ( = 41) and controls ( = 20). Further, we investigated aberrant metabolites to find biomarkers for PD development and therapeutic targets based on the quantitative results. Unfortunately, most tryptophan metabolites in the urine samples did not present significant differences between control and PD patients, except for indole-3-acetic acid. Nonetheless, indole-3-acetic acid was reported for the first time for its aberrant urinary levels in PD patients and tentatively selected as a potential biomarker for PD. This study provides accurate quantitative results for 21 tryptophan metabolites in biological samples and will be helpful in revealing the pathological mechanisms of PD development, discovering biomarkers for PD, and further providing therapeutic targets for various PD symptoms. In the near future, to further investigate the relationship between gut microbial metabolites and PD, we will employ studies on microbial metabolites using plasma and stool samples from control and PD patients.
尽管帕金森病（PD）是一种典型的神经退行性疾病，具有特征性的运动障碍，但PD的病理生理机制和治疗靶点尚未明确。由于肠道微生物群产生的几种色氨酸代谢产物能够穿过血脑屏障，进而可能影响中枢神经系统，因此吲哚、犬尿氨酸和血清素代谢途径中的色氨酸代谢产物可能是PD发病最关键的靶点。此外，大多数代谢产物通过血液循环，在宿主器官中发挥作用和/或被代谢，最终通过尿液排出。因此，分析PD患者尿液样本中的整体色氨酸代谢途径，对于理解其病理机制、寻找生物标志物以及发现PD的治疗靶点具有重要意义。然而，由于人体尿液样本中色氨酸代谢途径的生理范围广泛、信号响应多样以及复杂尿液基质中色氨酸代谢产物的结构多样性，基于色氨酸代谢途径的谱分析方法的开发仍然具有挑战性。在本研究中，我们开发了一种液相色谱-串联质谱（LC-MS/MS）方法，采用离子对色谱和多反应监测测定法，对人体尿液样本中吲哚、犬尿氨酸和血清素代谢途径中的21种色氨酸代谢产物进行谱分析。所开发的方法成功应用于PD患者（n = 41）和对照组（n = 20）的尿液样本。此外，我们基于定量结果研究了异常代谢产物，以寻找PD发病的生物标志物和治疗靶点。遗憾的是，除吲哚-3-乙酸外，尿液样本中的大多数色氨酸代谢产物在对照组和PD患者之间没有显著差异。尽管如此，首次报道了PD患者尿液中吲哚-3-乙酸水平异常，并初步将其选为PD的潜在生物标志物。本研究为生物样本中的21种色氨酸代谢产物提供了准确的定量结果，将有助于揭示PD发病的病理机制，发现PD的生物标志物，并进一步为各种PD症状提供治疗靶点。在不久的将来，为了进一步研究肠道微生物代谢产物与PD之间的关系，我们将利用对照组和PD患者的血浆和粪便样本开展微生物代谢产物研究。
