Several physiological barriers prevent the translocation of pathogenic microbes to tissues. Generally, the first of these firewalls encountered by invading pathogens are the epithelial tissues lining the skin, oral cavity and respiratory, gastrointestinal and urinary tracts. Under homeostatic conditions, epithelia function as selectively permeable barriers impenetrable to most microbes. However, if epithelial function is impaired, opportunistic pathogens can become invasive and access underlying cells and tissues.
In the last decade, a strain of Escherichia coli (E. coli) which colonises approximately 20% of healthy individuals, has been linked to several epithelial disorders, including Crohn’s disease, IBD, and to colorectal, urogenital and oral cancers. The strain, which harbours the polyketide synthase genomic island (pks+ E. coli), encodes the genotoxic peptide, colibactin, which binds and damages host cell DNA. Colibactin produces a characteristic mutational signature which has now been reported by several groups independently in colorectal, urinary tract and oral cancer patients. Unlike many other pathogenic bacteria, pks+ E. coli lack proteolytic enzymes and cannot breach an intact epithelial barrier.
The current study employed several mouse models of oral barrier dysfunction and cancer, which provided a unique opportunity to study pks+ E. coli in an in vivo setting. We hypothesised barrier impaired mice would be highly susceptible to pks+ E. coli infection and therefore vulnerable to the genotoxic properties of colibactin. To mimic colonisation of the oral cavity in humans, we established an inoculation method which yields a sustained, low-level infection. Indeed, our results suggest that pks+ E. coli can colonise barrier impaired tissues where they evade host detection and elimination systems to persist intracellularly for prolonged periods. This work paves the way for pks+ E. coli-guided clinical practices, informing oral cancer prevention strategies and improving patient stratification. Our findings may also be applicable to other epithelia exposed to pks+ E. coli.