One Health Genomics Reveals Niche-Specific Lineage Replacement in <i>Salmonella</i> Enteritidis

Abstract Salmonella enterica serovar Enteritidis is a broad-host-range pathogen posing global challenges to livestock production and public health. However, nation-scale evolutionary dynamics of Enteritidis remain unexplored, considering emerging evidence of human-adaptive traits. Here, we employed a transdisciplinary One Health approach to compile and analyze the largest genomic dataset of S. Enteritidis in China, integrating isolates across human, animal, food, and environmental sectors. Our analyses reveal an alarming escalation in antimicrobial resistance (AMR), with multidrug resistance rates tripling over the two decades. This surge in AMR coincides with the divergent evolution of three major Chinese mainland lineages: Global-b1, Global-b2, and Global-c. Crucially, we demonstrate that the Global-c lineage has achieved proportional dominance through a process of resistance-driven lineage replacement. This success is fueled by mobile genetic elements and supported by enhanced environmental stress tolerance and metabolic plasticity. Additional SNP-distance mapping uncovered evidence of human-centric dissemination. Collectively, we elucidate the complex, localized adaptation and competitive dynamics of S. Enteritidis lineages.