Abstract：
The human microbiome significantly influences drug metabolism through the gut-liver axis, leading to modified drug responses and potential toxicity. Due to the complex nature of the human gut environment, the understanding of microbiome-driven impacts on these processes is limited. To address this, a multiorgan-on-a-chip (MOoC) platform that combines the human microbial-crosstalk (HuMiX) gut-on-chip (GoC) and the Dynamic42 liver-on-chip (LoC), mimicking the bidirectional interconnection between the gut and liver known as the gut-liver axis, is introduced. This platform supports the viability and functionality of intestinal and liver cells. In a proof-of-concept study, the metabolism of irinotecan, a widely used colorectal cancer drug, is imitated within the MOoC. Utilizing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), irinotecan metabolites are tracked, confirming the platform\'s ability to represent drug metabolism along the gut-liver axis. Further, using the authors\' gut-liver platform, it is shown that the colorectal cancer-associated gut bacterium, Escherichia coli, modifies irinotecan metabolism through the transformation of its inactive metabolite SN-38G into its toxic metabolite SN-38. This platform serves as a robust tool for investigating the intricate interplay between gut microbes and pharmaceuticals, offering a representative alternative to animal models and providing novel drug development strategies.
摘要：
人体微生物组显着影响通过肠-肝轴的药物代谢，导致改变的药物反应和潜在的毒性。由于人类肠道环境的复杂性，我们对微生物群对这些过程的影响的理解是有限的。为了解决这个问题，我们引入了一个多器官芯片（MOoC）平台，该平台结合了人类微生物串扰（HuMiX）芯片上肠道（GoC）和Dynamic42芯片上肝脏（LoC），模拟肠道和肝脏之间的双向互连，称为肠-肝轴。该平台支持肠和肝细胞的活力和功能。在概念验证研究中,我们复制了伊立替康的代谢,一种广泛使用的结直肠癌药物，在我们的MOOC内。利用液相色谱与串联质谱联用(LC-MS/MS)，我们追踪了伊立替康代谢物,确认平台代表沿着肠-肝轴的药物代谢的能力。此外，使用我们的肠道-肝脏平台，我们发现结直肠癌相关的肠道细菌，大肠杆菌,通过将其非活性代谢物SN-38G转化为毒性代谢物SN-38来修饰伊立替康的代谢。这个平台是一个强大的工具，用于研究肠道微生物和药物之间的复杂相互作用。提供动物模型的代表性替代方案，并提供新的药物开发策略。本文受版权保护。保留所有权利。
