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Colorectal cancer

Bacterial biofilms and toxins prompt a perfect storm for colon cancer

Two new studies have added to the evidence that gut microbiota alter colon tumorigenesis. One showed that patients with familial adenomatous polyposis (FAP) harbour tumorigenic colonic biofilms and another detailed how a bacterial toxin affects a tumorigenic inflammatory cascade.

Digestion of the mucus layer by enterotoxigenic Bacteroides fragilis enables pks+ Escherichia coli to adhere to epithelial cells. Bacterial toxins stimulate release of IL-17, leading to immune cell infiltration and inflammation. DNA damage to epithelial cells from bacterial toxins could lead to mutations and, ultimately, polyp formation. Credit: Laura Marshall/Macmillan Publishers Limited

Previously, Cynthia Sears and colleagues found that enterotoxigenic Bacteroides fragilis (ETBF) could induce colon tumours in susceptible mice. “We sought to understand how bacteria, both ETBF and others, might contribute to the development and growth of colon cancer,” explains Sears. In later work, biofilms — aggregates of bacteria in a mucus matrix — were shown to be associated with sporadic human colon cancer. Now, in the first study, the colonic mucosae of patients with FAP (hereditary colon cancer caused by APC mutations) were investigated.

The researchers first examined surgically resected tissue from six patients with FAP, which revealed the presence of patchy biofilms in the mucus layer of the majority of patients. By using fluorescent in situ hybridization probes on these tissues, plus culturing studies with banked mucosal tissue samples from patients with FAP (n = 25), the biofilms were found to be dominated by two subtypes of bacteria with carcinogenic potential: ETBF and Escherichia coli positive for the polyketide synthase (pks) island responsible for the synthesis of genotoxic colibactin.

Experiments with ETBF and pks+ E. coli were performed in two mouse models of colon tumorigenesis. In one model, mice monocolonized with either species displayed few to no tumours, but pronounced tumour induction and enhanced mortality occurred in tumour-prone mice co-colonized with ETBF and pks+ E. coli, suggesting a requirement for both species in tumorigenesis.

“the biofilms were found to be dominated by two subtypes of bacteria with carcinogenic potential”

Interestingly, quantification of mucosal adherent bacteria revealed a marked increase in adherent pks+ E. coli in co-colonized conditions with ETBF compared to pks+ E. coli monocolonization. In vitro experiments with mucin-producing monolayers revealed that mucus degradation by ETBF probably enhanced pks+ E. coli colonization. A shift in the niche of this species could facilitate the delivery of genotoxic colibactin to colonic epithelial cells (CECs), increasing the risk of mutations in genes such as APC. As previous work had implicated IL-17 as a key factor in ETBF-induced tumorigenesis in mice, the researchers also co-colonized mice that were deficient in IL-17, which ablated tumour formation.

In a second study, Sears and colleagues further explored ETBF and the role of IL-17 in colon tumorigenesis. Using ETBF with deletion of the B. fragilis toxin (BFT), the ApcMin mouse model of colon tumorigenesis plus ApcMin mice with knockout of genes encoding IL-17 or the IL-17 receptor (IL-17R), the investigators first showed that BFT and CEC-expressed IL-17R are required for colon tumorigenesis. Examining regional colonic expression of IL-17 target genes, the investigators found that ETBF colonization via BFT secretion initiates IL-17-dependent NF-κB activation in distal CECs that leads to production of a proximal to distal gradient of C-X-C chemokines. These chemokines mediated the recruitment of CXCR2-expressing protumoural myeloid cells in the distal lamina propria that correlate with the distal localization of ETBF-induced colon tumours.

“Our papers advance our understanding of what might be the early bacterial and mechanistic events contributing to colon tumour development,” concludes Sears. “We are now studying paediatric patients with FAP to determine if ETBF and pks+ E. coli are present in the colon mucosa before the onset of tumour formation,” she adds. “This would open up the possibility that removing these bacteria from the gut or blocking the action of toxins would diminish tumour formation and perhaps extend the time that a patient with FAP could avoid colectomy.”

References

  1. 1

    Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Chung, L. et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe http://dx.doi.org/10.1016/j.chom.2018.01.007 (2018)

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Dickson, I. Bacterial biofilms and toxins prompt a perfect storm for colon cancer. Nat Rev Gastroenterol Hepatol 15, 129 (2018). https://doi.org/10.1038/nrgastro.2018.16

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