Global transmission dynamics of antibiotic resistance genes: Foodborne pathways as the critical link to humans.

The global spread of antimicrobial resistance (AMR) poses a major challenge to food safety and public health. To evaluate foodborne transmission as a critical pathway, we analyzed 713,343 Salmonella enterica genomes from the NCBI Pathogen Detection database across 164 countries. A total of 363,409 ARGs conferring resistance to aminoglycosides, tetracyclines, and β-lactams were identified. Source-specific resistome signatures were evident, with primary sources (human feces, animal waste) exhibiting the highest ARG abundance and diversity, followed by secondary sources (food products) and tertiary sources (environmental matrices). Structural equation modeling (SEM) demonstrated that the food chain is a key transmission pathway for ARGs to humans, with strong positive associations from environment to food (β = 5.320) and food to humans (β = 11.334), while the direct environment-to-human pathway showed a significant negative effect (β = -34.809). Additionally, strong interclass correlations (r ≥ 0.96) among ARGs suggest co-selection and horizontal gene transfer as major drivers of resistance propagation. Our findings further reveal pronounced geographic and ecological variability in ARG prevalence, with the United States, United Kingdom, and China accounting for the highest ARG burdens. These findings highlight the central role of foodborne transmission in AMR dissemination and highlight the need for integrated surveillance and interventions targeting agricultural practices, food production, and environmental contamination. Overall, our work provides insights into the ARGs connectivity between environment, food and humans, and could help identify strategies to prevent dissemination of antibiotic resistance.