Global soil antibiotic resistance genes are associated with increasing risk and connectivity to human resistome

Abstract Soil is a reservoir of antibiotic resistance genes (ARGs), and understanding its connection to human antibiotic resistome is crucial for the One Health framework. Rank I ARGs appear key to deciphering this relationship, but their global distribution and attribution in soil remain unclear. To fill this gap, we analyze 3965 metagenomic data (12 habitats, including soil, feces, sewage) and 8388 genomes of Escherichia coli isolates. Results show that soil ARG risk has increased over time (from 2008 to 2021). We introduce a “connectivity” metric that evaluates cross-habitat ARGs connectivity through sequence similarity and phylogenetic analysis, and reveal higher genetic overlap with clinical E. coli genomes (1985–2023) over time suggesting an increasing link between soil and human resistome. A comparison of 45 million genome pairs suggests that cross-habitat horizontal gene transfer (HGT) is crucial for the connectivity of ARGs between humans and soil. Finally, we compile clinical antibiotic resistance datasets (covering 126 countries from 1998 to 2022) and find significant correlations between soil ARG risk, potential HGT events and clinical antibiotic resistance ( R 2 = 0.40–0.89, p < 0.001). Overall, our work provides insights into the ARGs connectivity between soil and humans, and could help identify strategies to prevent dissemination of antibiotic resistance.