Pharmacomicrobiomics: Bidirectional Drug-Microbiome Interactions, Clinical Translation and Precision Therapeutics

Abstract

Inter-individual variability in drug efficacy and toxicity is only partly explained by dose, organ function, pharmacogenomics and adherence. The intestinal microbiome adds a dynamic, environmentally responsive metabolic layer that can directly transform drugs, sequester them within microbial biomass, reactivate conjugated metabolites, alter enterohepatic cycling, and regulate host enzymes, transporters and immune pathways. Conversely, antibiotics and many non-antibiotic medicines reshape microbial community structure and function, creating bidirectional feedback that may modify subsequent pharmacological responses. This narrative review synthesizes mechanistic and clinical evidence across drug absorption, distribution, metabolism and excretion, with focused discussion of microbial bioaccumulation, sulfasalazine activation, irinotecan-associated diarrhoea, digoxin inactivation, immune-checkpoint inhibitor response, psychotropic drugs, the gut–liver axis and inflammatory bowel disease. The strongest causal examples arise from defined microbial enzymes and genes—such as bacterial β-glucuronidases and the cardiac glycoside reductase operon—whereas many taxonomic associations remain context-dependent and incompletely reproducible. Meta-analyses consistently associate peri-immunotherapy antibiotic exposure with poorer outcomes, but confounding by infection severity, cancer burden and co-medication limits causal interpretation. Translation will require standardized sampling, shotgun metagenomics and functional assays, longitudinal designs, external validation, and interventional trials of enzyme inhibitors, diet, defined microbial consortia or faecal microbiota transplantation. Pharmacomicrobiomics should therefore be viewed as a complement to pharmacogenomics and therapeutic drug monitoring rather than a replacement. A function-first, mechanism-led approach may ultimately support microbiome-informed dose selection, toxicity prevention and treatment stratification.