An Organ-on-chip Platform for Simulating Drug Metabolism along the Gut-liver Axis.

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, our understanding of microbiome-driven impacts on these processes is limited. To address this, we introduce 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. This platform supports the viability and functionality of intestinal and liver cells. In a proof-of-concept study, we replicated the metabolism of irinotecan, a widely used colorectal cancer drug, within our MOoC. Utilizing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we tracked irinotecan metabolites, confirming the platform's ability to represent drug metabolism along the gut-liver axis. Furthermore, using our gut-liver platform, we show 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. This article is protected by copyright. All rights reserved.