Colorectal cancer, including colon and rectal cancers, is the uncontrolled growth of cells in the large intestine. As one of the most prevalent cancers, colorectal cancer is the second largest contributor to cancer-related deaths in the world. Causes include genetic predisposition, dietary factors, and non-cancerous diseases, and increasing evidence links a natural product of gut bacteria to the disease. (Cannan & Pederson, 2016). This product is called colibactin and is produced by “commensal Enterobacteriaceae that harbor the pks (or clb) gene cluster” (Carlson et al., 2025). Commensal bacteria are bacteria that benefit from their host without significantly harming it. The specific bacteria referred to here—examples of which include strains of E. coli—possess the pks gene cluster, which codes for a biosynthetic pathway that allows for the creation of colibactin, involved in DNA damage. This harm to DNA is a key factor in the progression of colorectal cancer. 

Until recently, scientists lacked specific information on how exactly colibactin damages DNA. In a recent study, Carson and fellow researchers sought to address this issue. Understanding the particular manner in which colibactin harms DNA holds tremendous value as a foundation for the development of cancer-treating pharmaceuticals. 

Colibactin’s unstable nature makes studying the toxin challenging, and scientists resorted to working with “fragments or more stable but imperfect analogs” of the molecule (Cutts, 2025). In an “unconventional” approach, scientists used living E. coli BW25113 to produce the colibactin that they experimented with (Balskus, as cited in ScienceNews, 2025). Ultimately, this research shed light on colibactin’s specific role in damaging DNA. Notably, the scientists uncovered that colibactin “alkylates within the minor groove of AT-rich DNA” (Carlson et al., 2025). Alkylation is characterized by the addition of an alkyl group to another molecule. In this case, alkylation alters the structure of DNA and can interfere with base-pairing. In the case of colibactin, the specific alkylation leads to the formation of interstrand cross-links, covalent bonds between DNA bases that create lesions that block transcription and replication. 

Interstrand crosslinks are “highly toxic” DNA lesions, and they can lead to double-strand breaks when the cell attempts DNA replication (Vare et al., 2012). Furthermore, if the cell’s damage response mechanisms—triggered by double-strand breaks—are unsuccessful, a mutation can result. These resulting mutations are characterized by a specific colibactin mutational signature. This signature primarily involves substitution of thymine by cytosine and nucleotide insertions or deletions in AT-rich regions (Carlson et al., 2025). As these mutations accumulate, they may damage critical tumor-suppressor genes that typically kill cancer cells. Specifically, this study named mutations in “driver genes such as APC” (Carlson et al., 2025). APC, Adenomatous Polyposis Coli, is a tumor suppressor gene that is associated with colorectal cancer when mutated. 

This study by Carlson and colleagues has significant implications for medicine. By illuminating the specific way in which colibactin causes DNA damage, this study lays the groundwork for potential future methods of inhibiting colibactin.

 

 

References 
Carlson, E. S., Haslecker, R., Chiara Lecchi, Aguilar, M. A., Vyshnavi Vennelakanti, Honaker, L., Stornetta, A., Millán, E. S., Johnson, B. A., Kulik, H. J., Balbo, S., Villalta, P. W., D’Souza, V., & Balskus, E. P. (2025). The specificity and structure of DNA crosslinking by the gut bacterial genotoxin colibactin. BioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.05.26.655968 
Cutts, E. (2025, December 4). How a bacterial toxin linked to colon cancer messes with DNA. Science News. https://www.sciencenews.org/article/toxin-colon-cancer-dna-mutation

Duan, B., Zhao, Y., Bai, J., Wang, J., Duan, X., Luo, X., Zhang, R., Pu, Y., Kou, M., Lei, J., & Yang, S. (2022). Colorectal cancer: An overview (J. A. Morgado-Diaz, Ed.). PubMed; Exon Publications. https://www.ncbi.nlm.nih.gov/books/NBK586003/ 
Vare, D., Groth, P., Carlsson, R., Johansson, F., Erixon, K., & Jenssen, D. (2012). DNA interstrand crosslinks induce a potent replication block followed by formation and repair of double strand breaks in intact mammalian cells. DNA Repair, 11(12), 976–985. https://doi.org/10.1016/j.dnarep.2012.09.010