Elucidating Age-Dependent Susceptibility to Colibactin Genotoxicity in Colorectal Cancer

Document Type

Article

Publication Date

2026

JAX Location

JGM

Abstract

While environmental factors such as diet and sedentary behavior are well-established colorectal cancer (CRC) risk factors, more research is needed to elucidate additional risk factors contributing to the drastic rise in early-onset colorectal cancer (EOCRC). Previous studies have shown that certain bacterial strains within the gut microbiota produce genotoxins and metabolites that may contribute to colorectal carcinogenesis. One such group includes phylogroup B2 Escherichia coli (E. coli). A substantial portion of B2 E. coli strains harbor the polyketide synthase (pks) pathogenicity island, which encodes the genotoxin colibactin. Colibactin is a polyketide-peptide hybrid that can induce DNA interstrand cross-links and subsequent double-strand breaks in colonic epithelial cells. Remarkably, colibactin-associated mutational signatures are detected more frequently in in EOCRC cases. In this study, we took an initial step toward evaluating age-dependent susceptibility to colibactin-induced DNA damage in the colonic epithelium, beginning with young mice as an initial approach to establish and characterize a colibactin-induced DNA damage model. To achieve this, young female C57BL/6J mice (3-5 months) were colonized with pks+ E. coli, an isogenic pks- control, or PBS vehicle control. DNA damage was quantified by immunofluorescence detection of γH2AX foci, alongside analysis of the expression of selected genes involved in p53 signaling, innate immunity, cell-cycle regulation, and the DNA damage response (DDR). Overall, colonization with pks⁺ E. coli did not induce a robust increase in DNA damage or DDR-associated gene expression compared with the pks⁻ and PBS control groups, indicating that colibactin susceptibility likely involves factors beyond colonization alone in the young epithelium.

Please contact the Joan Staats Library for information regarding this document.

COinS