Human microbiome-driven antimicrobial resistance: Biological mechanisms, pharmacological considerations and next-generation therapeutic prospects

Antimicrobial resistance (AMR) remains a serious global health challenge, threatening the effectiveness of existing antimicrobial therapies. Although resistance has traditionally been linked to antibiotic misuse and pathogen evolution, increasing evidence points to the human microbiome as a central driver of resistance development. This review examines the contribution of the human microbiome to the emergence and maintenance of antimicrobial resistance and discusses microbiome-focused therapeutic strategies as emerging tools for sustainable AMR control. A narrative literature review was conducted using peer-reviewed studies sourced from PubMed, Scopus, Web of Science, Google Scholar, and selected global health databases. Publications from 2000 to 2026 were evaluated, with emphasis on human studies, relevant animal models, metagenomic analyses, and translational research addressing microbiome-AMR interactions and therapeutic innovations. Finding shows that the gut, skin, and respiratory microbiomes act as important reservoirs of antimicrobial resistance genes. Antibiotic-induced dysbiosis weakens colonization resistance, enhances horizontal gene transfer, and favors the expansion of multidrug-resistant organisms, including ESBL-producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus , and vancomycin-resistant Enterococcus . Asymptomatic carriage within these microbial niches increases future infection risk and complicates infection control. Emerging interventions such as fecal microbiota transplantation, live biotherapeutics, bacteriophage therapy, targeted antimicrobials, microbiome-preserving stewardship, and CRISPR-Cas9-based gene silencing targeting resistance determinants demonstrate potential to restore microbial balance and reduce resistance burden. Viewing antimicrobial resistance through a microbiome-centered lens supports a shift from indiscriminate microbial eradication toward microbial stewardship. Integrating microbiome science into clinical practice, antimicrobial policy, and surveillance systems is critical for achieving durable and effective AMR mitigation.