Global population genomics reveals the lineage-dependent distribution of the YeaWX trimethylamine-associated module in Escherichia coli

Trimethylamine (TMA) and trimethylamine N-oxide (TMAO) have attracted increasing attention due to their potential involvement in host–microbiome interactions and cardiometabolic processes. In Escherichia coli , the YeaWX system has been proposed to participate in trimethylamine-associated metabolic pathways; however, its population-level distribution and population genomic organization remain poorly understood. In this study, we performed a large-scale population genomics analysis of the YeaWX module across 9700 quality-filtered E. coli genomes. Genome-wide detection of yeaX and yeaW was conducted using TBLASTN-based comparative genomics approaches, followed by integrated analyses of phylogroup distribution, sequence type (ST) composition, antimicrobial resistance (AMR) profiles, multidrug resistance (MDR) prevalence, plasmidome structure, and resistance gene localization patterns. The YeaWX module displayed near-complete co-occurrence across the global E. coli population, with 3798 genomes (39.2%) carrying both genes simultaneously, whereas only nine genomes exhibited dissociation between yeaX and yeaW . The module displayed a strongly lineage-dependent distribution across phylogroups and sequence types. YeaWX carriage was almost completely absent from phylogroup B2 and major extraintestinal pathogenic E. coli (ExPEC)-associated lineages including ST131, ST95, ST73, ST127, and ST12, while significant enrichment was observed in phylogroups B1, D, A, F, and G as well as in ST69, ST101, ST10, and ST393. YeaWX-positive genomes displayed modest differences in AMR profiles and plasmid-associated characteristics compared with YeaWX-negative populations. However, adjusted multivariable analyses demonstrated that these apparent enrichments were largely explained by underlying lineage-associated population structure. Overall, these findings demonstrate that the YeaWX trimethylamine-associated module exhibits a strongly lineage-dependent population structure within global E. coli populations and provide new insight into the population genomic organization of bacterial trimethylamine-associated metabolic pathways.