Human Microbiota-Driven Mouse Model Improves Drug Metabolism Prediction 2258986

Introduction Drug—microbiome interactions are increasingly recognized as critical in pharmacology. The gut microbiome influences drug properties such as bioavailability, absorption, metabolism, excretion, toxicity, and efficacy. Mice are widely used for preclinical studies, but their gut microbiome differs from humans, which can lead to inconsistent results in drug PK/PD and efficacy. To address this limitation, we developed a humanized gut microbiota mouse model. Methods Fecal material from three healthy donors–matched for age and BMI, and with no medication for three months–was pooled and administered by oral gavage twice weekly for four weeks to antibiotic-pretreated C57BL/6 mice. After colonization, a test molecule was given orally, and blood samples were collected at multiple time points for LC-MS/MS analysis. Results At baseline, the mouse microbiome contained ∼40% Muribaculaceae and ∼20% Lachnospiraceae. After FMT, Bacteroidaceae and Lachnospiraceae dominated, while Muribaculaceae dropped to 17% versus 40% in controls. The resulting profile closely resembled the human gut microbiome (∼30% Lachnospiraceae, ∼20% Bacteroidaceae). The pharmacokinetic profile of the tested compound in humanized mice differed markedly from conventional mice, suggesting that human-derived microbes alter enzymatic activity and metabolic pathways, impacting key PK parameters such as Cmax, AUC, and clearance. Conclusion This model provides a relevant platform to study microbiome-driven variability in drug disposition and supports the development of more predictive preclinical approaches for personalized medicine.