Samuel Ebiloma¹, Okoronkwo Christopher Uche¹, Chibundo N Okorie²

Abstract

Purpose: To evaluate current knowledge on microbiota-driven drug metabolism, focusing on microbial biotransformation mechanisms, host–microbe co-metabolism, and their clinical implications. Method: A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar for studies published between 2020 and 2026, following PRISMA guidelines. Results: Findings reveal that gut microbes influence drug metabolism through enzymatic processes including reduction, hydrolysis, and deconjugation, as well as through indirect mechanisms such as modulation of host metabolic enzymes and drug transporters. Clinically relevant examples include microbial inactivation of digoxin by Eggerthella lenta, reactivation of irinotecan via bacterial β glucuronidases leading to gastrointestinal toxicity, and microbial activation of sulfasalazine through azoreductase activity. Additionally, microbial metabolites such as short-chain fatty acids and bile acids regulate host enzyme expression, further shaping drug disposition and response. Despite these advances, substantial interindividual variability in microbiome composition remains a major challenge in predicting drug response and toxicity. Conclusion: Microbiota-driven drug metabolism represents a critical component of precision medicine. Integrating microbiome-informed strategies into clinical practice may enhance drug efficacy, reduce adverse effects, and enable more personalized therapeutic interventions. Emerging approaches, including artificial intelligence-based modeling, microbiome profiling, and gene-editing technologies, offer promising avenues for improving therapeutic precision but require further clinical validation.