Infant age negatively correlates with the overall load of gut resistome reflecting modifications of carbohydrate metabolism during early life

Background: The infant gut microbiome is increasingly recognized as a reservoir of antibiotic resistance genes, yet the assembly of gut resistome in infants and its influencing factors remain largely unknown. Results: We characterized resistome in 4132 metagenomes from 963 infants in six countries, and 4285 resistance genes were observed. In healthy infants (N = 272), the summed abundance of resistance genes significantly decreased over the first 14 months with two distinct stages: a multi-compound resistance phase (month 0–7) and a tetracycline-mupirocin-β-lactam dominant phase (month 8–14). Microbial taxonomy explained 43.9% of the gut resistome of healthy infants with Escherichia (25.5%) harboring the most resistance genes. Leveraging metagenomes from all infants (N = 963), we found that age negatively correlated with the overall resistance within three years ( P  < 0.001). This was due to that the age-dependent reduction of resistance genes (e.g., drug-biocide resistance), which were often intrinsic, from Pseudomonadota outweighed the gradual increase of genes (e.g., β-lactams), most of which were transferrable, from Actinomycetota, Bacillota, and Bacteroidota. Our functional profiling analysis further indicated that the maturation of gut resistome was likely driven by infants’changing carbohydrate metabolism, which demonstrated an increasing need for carbohydrate-active enzymes from Bacteroidota and decreasing involvements from Pseudomonadota during infancy. Importantly, we observed an elevated contribution of acquired resistance genes in the resistome over time which was interrelated with increased lateral gene transfer in the developing infant gut microbiome. Conclusions: Infant age negatively correlated with the overall load of gut resistome reflecting programmed modification in the gut microbiome, which was likely driven by the changing carbohydrate metabolism during early life.