Farming practices exert selection pressures on the resistome of natural populations of house mice.

The factors maintaining antimicrobial resistance genes (ARGs) in non-domesticated animal microbiomes remain unclear for species inhabiting human-dominated or less human-impacted landscapes. We analysed 875 gut metagenomes from natural populations of house mice (Mus musculus) on German farms between 2016 and 2022 to identify environmental and host determinants of ARG occurrence. Using joint species distribution models, we quantified the influence of landscape, climate and mouse associated characteristics on the occurrence of individual ARGs and on trait dependence among genes. Environmental variables and livestock farming intensity explained 27% of ARG variation, whereas host characteristics accounted for 8%. Analysis of ARG traits revealed that agricultural land use and exposure to livestock increased the occurrence of potentially mobile ARGs. Pig density was strongly associated with an integron-encoded sulfonamide resistance gene (sul1) and genes conferring tetracycline (tet) and beta-lactam resistance (cblA-1) (posterior probability 0.75). Consistently, mouse resistomes have a distinctive resistome, but share more than 50% of ARGs with livestock manure, including widespread genes and those promoted in livestock. Here, we show that landscape conditions, particularly farming intensity, shape the distribution of specific ARGs and potentially mobile ARGs in house mice microbiomes.