Gut microbiota-mediated drug metabolism and personalized pharmacotherapy: from mechanisms to clinical translation

Individual variability in drug efficacy and adverse reactions has long been a core challenge in clinical pharmacotherapy. Emerging evidence indicates that gut microbiota, as a critical metabolic organ outside the host, participates extensively in the biotransformation of numerous drugs, thereby reshaping pharmacological activity, toxicity, and interindividual therapeutic responses. This review summarizes the molecular mechanisms underlying gut microbiota-mediated drug metabolism, including enzymatic hydrolysis, reduction, dehydroxylation, and decarboxylation, as well as downstream signaling pathways such as bile acid metabolism, tryptophan metabolism, and short-chain fatty acid regulation. It further analyzes the associations between gut microbial dysbiosis and variable drug responses in metabolic diseases, neurological disorders, cancer, and inflammatory conditions. By integrating multi-omics evidence and translational research findings, this review discusses the translational prospects of microbiota-targeted interventions, including probiotic supplementation, prebiotic administration, fecal microbiota transplantation, and precision drug design tailored to microbial phenotypes. Current limitations, such as insufficient clinical validation, interindividual microbial heterogeneity, and challenges in mechanism standardization, are also highlighted. This narrative review aims to provide a theoretical and clinical framework for advancing personalized pharmacotherapy mediated by gut microbiota, promoting the translation of basic research into precise and safe clinical medication strategies.