Geographical variation and antibiotic exposure-associated perturbation of the early-life children’s gut resistome

The gut microbiome of infants and young children (0–24 months) represents a critical interface for investigating the drivers of early-life resistome establishment. Therefore, this study investigated the factors driving resistome acquisition and profiles in early life. Here, we analyzed fecal metagenomes from infants and young children across six countries, including the United States, Norway, Spain, the United Kingdom, Denmark, and Nicaragua. This study showed that, rather than inducing uniform ARG enrichment, early-life antibiotic exposure was associated with pronounced restructuring of the gut microbial community, characterized by a decreased microbial and resistome abundance. Multidrug resistance (MDR) genes (often via efflux pumps) predominated in the gut resistomes of infants and young children, followed by genes conferring resistance to peptide antibiotics and glycopeptides, with substantial contributions from tetracycline, macrolide, and fluoroquinolone resistance genes. Geographic context, feeding practices, and age emerged as significant determinants of resistome diversity and structure. Collectively, these findings indicate that the infants and young children’s gut resistome is developmentally sensitive to antibiotic perturbation, while a substantial fraction of resistance genes appears to be structured by early-life ecological and dietary factors. This highlights infancy as a critical window during which resistome composition is shaped by multiple non-exclusive forces, with implications for understanding the origins of antimicrobial resistance trajectories later in life.