Generation-scale evolution of the gut resistome under selective antibiotic pressure

The emergence and spread of antimicrobial resistance (AMR) represent an ever-growing healthcare challenge worldwide. Nevertheless, the mechanisms and time-scales shaping this resistome remain elusive. Here, using a cocktail of antibiotics administered to a murine model over a single generation along with a detailed, longitudinal sampling strategy, we identify the mechanisms by which gut commensals acquire AMR within a single generation. While the majority of the resident bacterial populations are depleted due to the treatment, Akkermansia muciniphila and members of the Lachnospiraceae family develop resistance and remain recalcitrant. We identify specific genes conferring resistance against the antibiotic cocktail in the corresponding metagenome-assembled genomes (MAGs), and trace their origins within each genome. While mobile genetic elements (MGEs), including plasmids and phages, contribute to the spread of AMR, we observe that integrons represent the primary factors mediating AMR in the antibiotic-treated mice. Our findings suggest that antibiotic treatment alone may act as the selective pressure driving AMR acquisition and incidence in gut commensals on a generational timescale.