Microbiota, colibactin and colon cancer: a snaphot

February 16, 2017

Microbiota and host have co-evolved into a complex super-organism in which numerous and intricate relationships benefit the host in many key aspects of life, such as nutrition and metabolism. For instance, the microbiota is required for the pre-processing of nutriments prior to uptake by the host or synthesis of vitamins necessary for the host. However, this symbiotic relationship may be disturbed and promote disease when the host regulatory circuits that control homeostasis are perturbed or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), occur. Current growing evidences indicate a key role for the bacterial microbiota in carcinogenesis. Indeed, many cancers occur in tissues with a high exposure to microbiota, especially colorectal cancer (CRC), considered a major cause of death in the western world. Intestinal microorganisms are thought to cause the onset and progression of CRC using different mechanisms, such as the induction of chronic inflammatory state, the biosynthesis of genotoxins interfering with the cell cycle regulation or directly damaging DNA, or the production of toxic metabolites.

However, few putative procarcinogenic bacteria have been identified. The Enterococcus faecalis strains produce superoxide, which can induce DNA damage and chromosomal instability in colonic epithelial cells. Enterotoxigenic Bacteroides fragilis produces the fragilysin toxin, which is genotoxic and causes cell proliferation by cleavage of the tumour suppression factor E-cadherin. Colonic malignancies allow Streptococcus gallolyticus subsp gallolyticus to colonise established colorectal tumours, leading to tumour development by induction of the proinflammatory cyclo-oxygenase 2 pathway. However, the current strongest candidate for being a contributor to colon carcinogenesis are Escherichia coli strains of the phylogenetic group B2 harbouring the polyketide synthetase (pks) island. The pks island, encoding for polyketide-synthase enzymes, drives the synthesis of the non-ribosomal peptide genotoxin colibactin. Colibactin has been suggested to have an impact on cancer development. In fact, colibactin induces double-stranded DNA breaks in infected eukaryotic cells and chromosomal instability both in vitro and in vivo. In vitro, this DNA damage induces a cell cycle arrest leading to megalocytosis, a phenotype characterised by an enlargment of the cell body and nucleus. Very recently, it has been demonstrated that colibactin-producing bacteria indirectly enhance tumour growth by inducing the emergence of senescent cells secreting growth factors. Moreover, Escherichia coli strains harbouring the pks island are more prevalent in biopsies of patients with human colorectal tumours compared to those obtained from controls. Importantly, recent works from Arthur and coworkers demonstrated that the presence of pks+ E. coli is able to promote invasive carcinoma in colitis-susceptible interleukin 10-/- mice. Indeed, deletion of the pks island from the E. coli NC101 reduced DNA damage, tumour numbers and bacterial invasion; nevertheless, inflammation has been reported to be an important player in such a process. Thus the colibactin toxin appears to be a major driver of tumorigenesis in a context of chronic inflammatory bowel diseases. Altogether, these findings highlight the important role played by the microbiota in CRC, especially the prominent one of colibactin-producing E. coli strains.

Although E. coli from the B2 group represent the predominant carrier of the pks island, many proteobacteria species carry the colibactin island, including strains that live in symbiosis with sponges and honeybees, suggesting that colibactin could mediate evolutionarily conserved microbe-host interactions. The pks island is detected in many species from the Enterobacteriaceae family, like Klebsiella pneumoniae, Enterobacter aerogenes and Citrobacter koseri that are well known members of the microbiota.

Concerning K. pneumoniae, colibactin has been shown to be associated to highly virulent isolates. Moreover, pyogenic liver abscess, an emerging disease caused by K. pneumoniae, is suggested to correlate with an increasing risk of colorectal cancer. Indeed, there is a high prevalence of colibactin-positive K. pneumoniae strains among the K. pneumoniae isolates responsible of pyogenic liver abscesses. These strains have been shown to cause DNA damage in vitro and in vivo. These observations, suggest that, like for E. coli, there is a link between genotoxic K. pneumoniae and CRC.

To date, colibactin has not been fully isolated and purified, thus the complete structure of colibactin has yet to be defined and the various steps required for its synthesis are poorly characterised. Evidences show that colibactin requires direct contact between bacteria and cells to induce megalocytosis. However how the toxin is secreted from bacteria and transferred to the cell is largely unknown.

It is crucial to understand the mechanisms and the components involved in the secretion of colibactin. These findings might unravel new pathways for toxin secretion that could be the basis for new screens aiming at identifying new therapeutical molecules acting as inhibitors of this specific secretion pathway. Such molecules could be useful to prevent tumorigenesis in patients having chronic inflammatory bowel diseases who are colonised with colibactin-producing E. coli.


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