Drug–gut Microbiome Interactions in Modern Pharmacotherapy: From Microbial Biotransformation and Host–microbe Signaling to Drug Efficacy, Toxicity, Pharmacokinetics, and Microbiome-Integrated Precision Medicine—a Comprehensive Review

The gut microbiome has emerged as an important biological determinant of drug disposition and therapeutic response, challenging the conventional host-centered view of pharmacotherapy. The extensive metabolic capacity of intestinal microorganisms enables direct transformation of pharmaceutical compounds through diverse enzymatic pathways, including hydrolysis, reduction, deconjugation, and other biotransformation reactions. These processes can activate prodrugs, inactivate therapeutic agents, regenerate host-conjugated metabolites, or generate biologically active and potentially toxic products. In parallel, drugs can alter microbial composition, diversity, and metabolic activity, establishing a dynamic bidirectional relationship between pharmaceutical agents and the intestinal ecosystem. This review comprehensively examines drug–gut microbiome interactions, with particular emphasis on microbial drug biotransformation and its consequences for absorption, distribution, metabolism, excretion, pharmacokinetics, pharmacodynamics, therapeutic efficacy, and drug toxicity. The role of microbial metabolites in host–microbe signaling, immune regulation, gut–liver and gut–brain communication, and treatment response is also discussed. Furthermore, disease-associated microbiome alterations, drug-induced dysbiosis, pharmacometagenomics, multi-omics technologies, computational approaches, and microbiome-integrated precision medicine are considered. The review highlights how interindividual variation in microbial composition and metabolic capacity may contribute to differences in drug exposure, efficacy, and adverse drug reactions. Finally, emerging strategies involving selective microbial enzyme modulation, microbiome-targeted interventions, and microbiome-informed treatment optimization are discussed. Integrating microbiome biology with conventional pharmacology may provide a more comprehensive framework for understanding therapeutic variability and advancing individualized pharmacotherapy.