Insights into the dynamics of antibiotic resistance genes in the human gut microbiome across populations

Abstract The human microbiome serves as a reservoir of antibiotic resistance genes (ARGs), collectively known as the resistome, which has crucial implications for human health. However, the distribution of ARGs across diverse bacterial taxa and their variation across populations, disease states, and body sites remain less well understood. Here, we comprehensively profiled the human resistome using genomic and metagenomic data. Our analysis included 4,744 species-representative gut bacterial genomes and 452 oral bacterial genomes, along with gut metagenomic data from 10,230 individuals across 58 studies encompassing 5,388 healthy and 4,842 disease-associated samples, including underexplored non-Western cohorts. Our analysis revealed variation in the gut resistome across population groups and countries. The oral microbiome exhibited a distinct resistome profile with lower ARG prevalence compared to the gut. Across multiple datasets, ARG abundance was generally higher in inflammatory bowel disease samples compared to healthy samples. Pathogenic taxa such as Enterobacter , Citrobacter , Escherichia , and Klebsiella carried the highest number of ARGs, including clinically relevant ARGs, whereas abundant commensals like Bacteroides and Prevotella contributed to the baseline resistome. Notably, population-level differences in ARG composition appeared to be linked to microbial community structure. Shared ARGs between commensal and pathogenic bacteria provided clues to horizontal gene transfer. These findings provide crucial insights into the ecological and population-level factors shaping the gut resistome, highlighting the roles of both pathogens and commensals in the maintenance and dissemination of antimicrobial resistance.