Escherichia marmotae Dominates the Global Distribution of cdtABC Carriers in the Human Gut

Abstract

The gut microbiota can influence colorectal cancer through microbial metabolism, immune regulation and direct damage to host DNA. Previous experimental studies have shown that cytolethal distending toxin (CDT) can damage host DNA and promote colorectal tumorigenesis in model systems. However, the distribution of bacteria carrying intact cdtABC systems in human gut populations remains poorly characterized. Here, we integrated systematic screening of 60,008 complete bacterial genomes with analyses of 12,238 human gut metagenomes from 45 countries. We identified 871 intact cdtABC loci in 783 genomes, revealing a taxonomically restricted but genetically diverse carrier landscape. Carriers were detected worldwide, but the population signal was strongly dominated by an Escherichia marmotae lineage, a pattern that remained robust across minimum abundance thresholds. Most carrier-detected samples contained a single carrier, indicating pronounced lineage dominance. After carrier species were removed from the taxonomic profiles, the surrounding microbiome consistently distinguished samples with and without carriers across studies. This community signal was strongest for E. marmotae but remained detectable for other carriers and involved reproducible associations with Escherichia, Faecalibacterium and other gut taxa. By connecting intact loci with carrier lineages, global gut distribution and microbial community context, our study extends CDT research beyond isolated bacterial strains. These findings provide a basis for prioritising cdtABC carriers for functional validation and evaluating their potential relevance to colorectal cancer.