The Microbiome–Drug Interface: Decoding Bidirectional Interactions, Therapeutic Outcomes and Precision Medicine

The human gut microbiome plays a significant role in drug metabolism, therapeutic efficacy, safety, and individual variability in treatment response. The bidirectional interactions between gut microorganisms and pharmaceutical agents form the basis of pharmacomicrobiomics, an emerging field that investigates how microbial composition and activity influence drug absorption, distribution, metabolism, and excretion (ADME). Certain microorganisms can activate, inactivate, or chemically modify drugs through enzymatic processes, while pharmaceutical agents can alter microbial composition and function, potentially leading to dysbiosis and adverse effects. This review discusses the mechanisms underlying microbiome–drug interactions, their influence on pharmacokinetics and pharmacodynamics, and their clinical significance in various diseases, including diabetes, inflammatory bowel disease, and cancer. It also highlights microbiome-triggered drug delivery systems using polysaccharides, microbial enzymes, and bacteria-responsive formulations for targeted colonic drug delivery. These approaches offer potential advantages, including improved site-specific drug release, enhanced therapeutic efficacy, and reduced systemic toxicity. However, interindividual microbiome variability, antibiotic-associated disturbances, formulation challenges, and limited clinical evidence remain significant barriers to clinical translation. Understanding these interactions may support the development of personalized therapeutic strategies, microbiome-targeted interventions, and more effective drug delivery systems. Further multidisciplinary research and well-designed clinical studies are required to establish standardized approaches and translate pharmacomicrobiomics into routine clinical practice.