Microbial Genotoxins in Colorectal Cancer Dynamics

Colorectal cancer arises from a complex interplay between host genetics, environmental exposures and the gut microbiota. A subset of commensal and opportunistic bacteria harbour biosynthetic pathways that yield genotoxins—secondary metabolites capable of directly damaging DNA in eukaryotic cells. Among these, colibactin, produced by Escherichia coli and related Enterobacteriaceae via the pks genomic island, has emerged as a paradigm. Its activity generates DNA interstrand cross-links, double-strand breaks and a characteristic mutational signature in both in vitro models and patient tumours. Other bacterial factors, including cyclomodulins and the Bacteroides fragilis toxin, perturb cell cycle control and precipitate genomic instability. These lesions can drive clonal expansion, early chromosomal aberrations and disruption of key regulatory pathways such as Wnt/β-catenin and p53. Beyond direct genotoxicity, microbial toxins modulate the tumour microenvironment through proinflammatory signalling, immune cell recruitment and alteration of stromal and fibroblast function. Collectively, these insights underscore the global significance of microbial genotoxins in colorectal carcinogenesis, with implications for early detection, preventive strategies and targeted modulation of the microbiome.

Research from Nature Portfolio

Recent studies have traced the footprint of pks+ E. coli in histologically normal colon crypts from patients with colorectal cancer, revealing elevated mutational signatures compatible with colibactin activity even before tumour formation. These patterns overlap with clonal driver mutations found in matched tumours, supporting a role for microbial genotoxins in early tumourigenesis. Complementary work utilising murine colon organoids demonstrates that short-term exposure to colibactin-producing bacteria induces Wnt-independence, chromosomal instability and aneuploidy, hallmarks of malignant transformation. The identification of distinct genomic aberrations implicates p53-related pathways and highlights an interplay between microbial insult and host DNA repair mechanisms that fuels neoplastic progression.

Microbial Genotoxins in Colorectal Cancer Dynamics publication trend

The graph below shows the total number of articles in microbial genotoxins in colorectal cancer dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Genotoxin: A compound that damages DNA, causing mutations, breaks or cross-links.

Colibactin: A hybrid polyketide-nonribosomal peptide genotoxin synthesized by the pks island in certain Enterobacteriaceae.

pks genomic island: A cluster of genes encoding enzymes for colibactin biosynthesis.

Mutational signature: A pattern of DNA alterations characteristic of a specific mutagenic process.

Organoid: A three-dimensional culture of primary cells that recapitulates organ architecture and function.

Wnt-independence: The ability of cells to proliferate without exogenous Wnt signalling, indicative of transformation.

References

1. Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer. Cancer Cell (2024).
2. Contribution of pks+E. coli mutations to colorectal carcinogenesis. Nature Communications (2023).
3. The Role of the Microbiome in the Etiopathogenesis of Colon Cancer. Annual Review of Physiology (2024).
4. High Prevalence of Mucosa-Associated E. coli Producing Cyclomodulin and Genotoxin in Colon Cancer. PLOS ONE (2013).
5. The Colibactin Genotoxin Generates DNA Interstrand Cross-Links in Infected Cells. mBio (2018).
6. Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells. Nature Communications (2021).