Global landscape of antibiotic resistance genes in the human gut microbiome metagenome-assembled genomes

Antibiotic resistance poses a significant threat to human health, and the human gut microbiota serves as a major reservoir of antibiotic resistance genes (ARGs). In this study, we analyzed 149,515 metagenome-assembled genomes (MAGs) from human gut microbiomes and revealed marked geographic variations in the global distribution of gut-associated ARGs. Asia exhibits the highest diversity of ARGs. At the phylum level, Pseudomonadota was identified as the predominant ARG host among pathogenic bacteria, with its pathogenic strains frequently exhibiting high levels of multidrug resistant strains harboring ≥ 5 ARGs accounting for up to 88.5% and 79.1% in Africa and South America, respectively. Campylobacterota was also recognized as a potential high-risk ARG host phylum. Horizontal gene transfer (HGT) analysis revealed that ARG transmission predominantly occurred within the same phylum, with Bacillota being the most active donor, which was likely influenced by antibiotic selection pressure. Actinomycetota and Bacteroidota were identified as major recipients of interphylum HGT, indicating their greater capacity to acquire exogenous ARGs. Through the integration of deep learning and structural calculation, we also identified a potentially novel class of β-lactam resistance genes. This study provides a comprehensive global landscape of gut-associated resistomes, underscores the critical roles of public health infrastructure, antibiotic misuse, and HGT in shaping antimicrobial resistance (AMR), and offers methodological insights for the discovery of novel ARGs. Our findings highlight urgent challenges and provide a scientific basis for developing global AMR mitigation strategies.