Systems-Level Analysis of Antimicrobial Resistance Gene Transmission Networks in Human, Animal, and Environmental Compartments Across Nigeria’s Six Geopolitical Zones

The One Health framework posits that antimicrobial resistance gene (ARG) transmission occurs across human, animal, and environmental compartments in interconnected networks, yet no systems-level analysis has characterized these transmission dynamics across all of Nigeria's geopolitical zones. This study developed and applied a systems-level mixed-methods framework integrating metagenomics, network analysis, and spatial epidemiology to map ARG transmission networks in clinical, livestock, and environmental samples from representative sites in all six geopolitical zones over a 24-month longitudinal period. Rectal swabs, clinical isolates, livestock fecal samples, and water sources were collected from 360 sites. Shotgun metagenomic sequencing and resistome profiling were conducted. Network centrality analysis identified resistance gene clusters and critical transmission nodes. Bayesian source attribution modeling determined the relative contribution of animal and environmental reservoirs to human ARG burden. CTX-M-15, NDM-1, and mcr-1 constituted the most connected ARG nodes across all zones. The North West and South South zones demonstrated the highest ARG network densities, correlating with intense livestock trading and oil-related waste contamination respectively. Source attribution modeling assigned 38.4 percent of human clinical ESBL genes to livestock-associated origins. This study provides the first zonal-level, multi-compartment ARG transmission network for Nigeria and delivers a theoretical model to prioritize One Health stewardship interventions at the highest-impact transmission nodes. Keywords: antimicrobial resistance, One Health, ARG transmission, metagenomics, systems analysis.