Engineering human Gut-on-a-Chip culturomics for predictive pharmacomicrobiomics of first-pass metabolism

For orally administered drugs, intestinal first-pass metabolism influences systemic exposure and accounts for inter-individual pharmacokinetic differences. However, the mechanistic roles of gut microbiome-mediated biotransformation and patient-specific intestinal variability remain underrepresented in current regulatory frameworks. This Perspective explores how human-relevant culturomics platforms, including Gut-on-a-Chip microphysiological systems, allow for quantitative analysis of host-microbiome-drug interactions. We also discuss the potential of predictive intestinal ecosystem models for personalized pharmacomicrobiomics and next-generation translational drug development.