A mechanism by which a Western diet and antibiotic use may be able to promote tumorigenesis by colon cancer cells after curative resection was recently identified according to a study published in Gastroenterology.
Investigators sought to combine factors known to occur in the colon cancer surgery setting that might predispose patients to tumor formation, such as a Western diet (high fat, no fiber, and decreased minerals and vitamins), prophylactic antibiotic exposure, gut colonization by strains of collagenolytic bacteria, and exposure of anastomotic tissues to shed colon cancer cells.
Multiple aspects of the pathogenesis of colorectal cancer (CRC) are now known to be influenced by the gut microbiome. The investigators hypothesized that diet-induced changes in the gut microbiota promotes anastomotic penetration of shed cancer cells, enabling tumor formation. Mice were fed either a standard or Western-type diet for 4 weeks. A subset of the mice was administered antibiotics or a substance called Pi-PEG which inhibits collagenase production by bacteria while still allowing bacterial growth, in drinking water.
Colorectal resections and anastomoses were then performed. The following day, the mice were given enemas containing a strain of collagenolytic Enterococcus faecalis. The next day, they were given enemas containing mouse-derived colon carcinoma cells. Distal colons and contents (feces and tumor) were collected 3 weeks later. The intestinal microbiome was assessed by histology and 16S rRNA sequencing. The anatomical distribution of E. faecalis was mapped using in situ hybridization.
In mice given antibiotics, surgery, and E. faecalis, colorectal tumors were found more often in those that had been fed the Western diet than in those fed the standard diet (88% vs 30%; P <.05). The presence of E. faecalis and another collagenolytic bacterium, Proteus mirabilis, was correlated with colon tumor formation.
Therefore, researchers eliminated E. faecalis and P. mirabilis using a variety of antibiotics to validate their roles in tumor formation; however, surprisingly, this did not reduce tumor formation and, upon further investigation, was revealed to have promoted colonization by a collagenase-producing yeast, Candida parapsilosis.
As expected, mice that received Pi-PEG had reduced tumor formation relative to controls (66% vs 9%, P <.05) and had reduced amounts of tumor-associated bacteria, E. faecalis and P. mirabilis (1.1 × 10 vs 5.6 × 10 CFU/mg, P <.05); however, no significant difference was observed in the proportions of bacterial phyla.
Limitations include the current study design which was not able to prove causality of the association between tumor formation and collagenolytic organisms or between bacterial collagenase production and tumor formation.
The authors concluded, “Strategies to prevent emergence of these microbe communities or their enzymatic activities might be used to reduce the risk of tumor recurrence in patients undergoing CRC surgery.”
Gaines S, van Praagh JB, Williamson AJ, et al. Western diet promotes intestinal colonization by collagenolytic microbes and promotes tumor formation following colorectal surgery [published online October 23, 2019]. Gastroenterology. doi:10.1053/j.gastro.2019.10.020