Pharmacomicrobiomics in Precision Pharmacotherapy: Bidirectional Microbial-Drug Interactions as a Key Determinant of Therapeutic Response

Interindividual variability in drug efficacy and toxicity remains a major challenge in clinical pharmacotherapy. Although pharmacogenomics has substantially advanced personalized medicine, host genetic variation alone cannot fully explain differences in drug disposition, response, and adverse effects. Increasing evidence identifies the human gut microbiotaas an additional, functionally relevant metabolic layer that complements host drug-metabolizing enzymes, giving rise to the field of pharmacomicrobiomics. This discipline examines bidirectional interactions between drugs and microbial communities that influence absorption, metabolism, enterohepatic circulation, and pharmacodynamic outcomes. The gut microbiota can directly biotransform or sequester drugs through diverse enzymatic reactions, including deconjugation, reduction, and decarboxylation, thereby modifying systemic drug exposure and toxicity. In parallel, microbially derived metabolites and bile acid-mediated signaling pathways regulate host drug-metabolizing enzymes and transporters, including cytochrome P450 enzymes and ATP-binding cassette transporters. Conversely, many commonly used medications-such as antibiotics, chemotherapeutic agents, targeted therapies, immunotherapies, psychotropic drugs, and proton pump inhibitors-can substantially reshape microbial composition and function, resulting in dysbiosis that feeds back onto drug metabolism and therapeutic outcomes. This review summarizes the mechanistic basis and clinical relevance of microbiota-drug interactions across key therapeutic areas, including oncology (chemotherapy and immunotherapy), neuropsychiatric disorders, and metabolic diseases. Well-established examples, including microbial β-glucuronidase-mediated reactivation of irinotecan, microbiota-dependent modulation of levodopa and antidepressant pharmacokinetics, and microbiota-driven variability in immune checkpoint inhibitor efficacy, are discussed to illustrate causality. Emerging microbiome-informed strategies-such as selective inhibition of microbial enzymes, microbiota modulation, and microbial biomarker-based patient stratification-are highlighted. Finally, we examine integration of pharmacomicrobiomics with pharmacogenomics within multi-omic and systems pharmacology frameworks, emphasizing implications for predictive modeling and precision drug metabolism.