The intestinal microbiota disrupts colorectal cancer genetics
Familial adenomatous polyposis (FAP) is of genetic origin and progresses to colorectal cancer in most cases. According to an American and Dutch study, the disease could be explained by studying the intestinal bacterial biofilm.
In the early 1990s, the pathophysiology and hereditary nature of familial adenomatous polyposis (FAP) was clarified by the discovery of the mutation in the tumor suppressor gene APC (adenomatous polyposis coli). However, the presence of this mutation does not on its own explain the development and frequency of polyps, suggesting that other factors come into play. In this preliminary study, the researchers hypothesized that the intestinal microbiota plays a major role in the formation of polyps and hereditary colorectal cancer (CRC).
Analysis of the bacterial biofilm
Subjects with sporadic CRC often have intestinal dysbiosis. This microbiota imbalance however is still unknown in the hereditary form of the disease, as research has mainly focused on the associated genetic anomalies until now. Thanks to a study of the bacterial biofilm in resected colon tissue allowed the bacterial populations present, and implicated in tumor genesis, to be analyzed. They can differ within the same familial mutation. The researchers then conducted non-clinical tests to study in detail the mechanisms that could explain the pathogenesis of FAP.
The biofilms of subjects with FAP were mainly composed of Proteobacteria (60 to 70 %) and Bacteroides (10 to 30 %). Unlike the uninterrupted biofilm on the colon surface that is characteristic of patients with sporadic CRC, that seen in FAP subjects had an irregular patchy structure. In these heterogenous biofilms, the authors identified two predominant bacteria: Escherichia coli and Bacteroides fragilis. These bacteria are present in healthy individuals, but the results show that the genes encoding for oncotoxins, colibactin (clbB) and Bacteroides fragilis toxin (bft), are significantly more prevalent in the colonic mucosa of FAP patients.
Non-clinical analysis of the mechanisms of action of oncotoxins showed that co-colonization by enterotoxigenic (ETBF) E. coli pks+* and B. fragilis is essential to CRC pathogenesis. Compared to mono-colonized mice, co-colonized mice had a higher mortality rate and accelerated tumor development. The authors explain that degradation of colonic mucus by ETBF favors the adherence of E. coli pks+. Mutations of the APC gene are thought to modify interactions between host and bacterial cells and could be the cause of increased bacterial adhesion to the mucosa. This colon colonization is thought to promote the secretion of colibactins by E. coli pks+, thus degrading the DNA of colonic epithelial cells and accelerating ETBF-mediated tumor development. Both bacteria are also thought to drive production of IL-17, which maintains local inflammation. The authors finally specify that E. coli pks+ and ETBF commonly colonize the intestines of young children everywhere in the world. This chronic colonization of the colon is thought to damage the mucosa very early in life and to contribute to FAP pathogenesis—even perhaps sporadic CRC. In the future, analyses of the co-expression of clbB by E. coli pks+ and bft by ETBF could be useful to identify patients and improve the prevention of CRC.
* pks+ : polyketide synthase genomic island containing genes encoding for colibactin synthesis (clbB)
Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).