Genotoxic Genes in Certain Gut Bacteria Linked to Chronic Bowel Inflammation and Colon Cancer

Certain strains of gut bacteria - Escherichia coli bearing the polyketide synthase (pks) cluster of genotoxic genes – have been linked to chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis and to the development of colorectal cancer (CRC).

Polyketide synthases are a family of multidomain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites in bacteria, fungi, plants, and a few animal lineages. Polyketide synthase products include lipids with antibiotic, antifungal, antitumor, and predator-defense properties. They are an important source of naturally occurring small molecules used for chemotherapy. For example, many of the commonly used antibiotics, such as tetracyclin, and macrolides are produced by polyketide synthases. Other industrially important polyketides are rapamycin (immunosuppressant), erythromycin (antibiotic), lovastatin (anticholesterol drug), and epothilone B (anticancer drug).

Investigators at the University of Liverpool (United Kingdom) and colleagues in the USA and Canada used high-throughput sequencing to reveal that inflammation modified gut microbial composition in colitis-susceptible interleukin-10–deficient (Il10−/−) mice. Monocolonization with the commensal Escherichia coli strain NC101 promoted invasive carcinoma in azoxymethane (AOM)–treated Il10−/− mice. Furthermore, mucosa-associated pks+ E. coli were found in a significantly high percentage of human inflammatory bowel disease and CRC patients.

Other results published in the August 16, 2012, online edition of the journal Science revealed that deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10−/− mice, without altering intestinal inflammation.

Contributing author Dr. Jonathan Rhodes, professor of medicine at the University of Liverpool, said, "The fact that the pks-positive E. coli seemed to promote colon cancer in mice without causing increased inflammation led us to investigate its possible role in human colon cancer. The marked increase in the presence of these bacteria in the colon, not only in patients with inflammatory bowel disease, but also in patients with colon cancer who do not have inflammatory bowel disease, suggests that damage caused to DNA, as a result of the toxin that the pks genes produce, may promote the development of colon cancer."

Related Links:
University of Liverpool