Multi-omics analysis reveals the genetic and environmental factors in shaping the gut resistome of a keystone rodent species.

Understanding the emergence and spread of antibiotic resistance genes (ARGs) in wildlife is critical for the health of humans and animals from a "One Health" perspective. The gut microbiota serve as a reservoir for ARGs; however, it remains poorly understood how environmental and host genetic factors influence ARGs by affecting the gut microbiota. To elucidate this, we analyzed whole-genome resequencing data from 79 individuals of Brandt's vole in two geographic locations with different antibiotics usage, together with metabolomic data and shotgun sequencing data. A high diversity of ARGs (851 subtypes) was observed in vole's gut, with a large variation in ARG composition between individuals from Xilingol and Hulunbuir in China. The diversity and composition of ARGs were strongly correlated with variations in gut microbiota community structure. Genome-wide association studies revealed that 803 loci were significantly associated (P<5.05×10^-9) with 31 bacterial species, and bipartite networks identified 906 bacterial species-ARGs associations. Structural equation modeling analysis showed that host genetic factors, air temperature, and presence of pollutants (Bisphenol A) significantly affected gut microbiota community structure, which eventually regulated the diversity of ARGs. The present study advances our understanding of the complex host-environment interactions that underlie the spread of ARGs in the natural environments.