Gut bacterial O-demethylation in microbiome-dependent drug response

The gut microbiota is recognized as an important contributor to drug metabolism and therapeutic variability. By directly transforming orally administered drugs, gut microbes can influence drug exposure, efficacy, and toxicity. Among these microbial reactions, O-demethylation of methoxy-containing drugs remains relatively underexplored, despite the prevalence of this structural motif in many therapeutic agents. Recent studies suggest that gut bacterial O-demethylation can alter parent-drug exposure and generate metabolites with distinct biological activities, with potential consequences for therapeutic efficacy and toxicity across clinical settings. In this mini-review, we discuss gut bacterial O-demethylation as a distinct mechanism in microbiome-dependent pharmacology, with emphasis on its chemical logic, microbial basis, pharmacokinetic and toxicologic consequences, and translational potential for microbiome-targeted interventions and biomarker development.