Unexpected effects of antibiotics on microbiota-mediated drug metabolism in a fistulated dog model

The human gut microbiome plays a crucial role in the metabolism of drugs, with various bacterial species catalysing the biotransformation of pharmaceutical compounds. In vitro microbiota models, typically derived from faecal material, have been employed to study this phenomenon. However, they often do not fully capture the complex and dynamic environment of the living colon. This study aimed to evaluate whether in vitro models accurately reflect in vivo microbiota-drug interactions by comparing both approaches within the same individual animal via a fistulated dog model, with the fistula located in the ascending colon. We investigated the metabolism of metronidazole and sulindac, two structurally and pharmacologically distinct drugs, before and after broad-spectrum antibiotic treatment. Prior to antibiotics, in vitro biotransformation in faecal material was observed for both drugs: metronidazole (t₁/₂ = 22.9 ± 1.2 min) and sulindac (t₁/₂ = 104.2 ± 1.0 min). Following antibiotic treatment, no measurable degradation occurred in vitro. However, in the fistulated dog model plasma concentrations decreased following antibiotic treatment compared to pre-treatment levels, indicating a lack of correlation between microbiota metabolism observed in vitro and systemic drug levels in vivo. These findings underscore the complexity of microbiota-host-drug interactions and provide important insights for the development of translational microbiome-pharmacology models. Additionally, the drawbacks over the use of antibiotic-treated animal models to study microbiota-drug interactions are discussed due to antibiotic-induced changes in intestinal permeability and efflux that may influence drug absorption and metabolism.