Researchers have identified mechanisms by which diet and antibiotic use together promote tumorigenesis by colon cancer cells at the anastomosis after colorectal surgery, reported in the March issue of Gastroenterology. 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 colorectal cancer surgery.
As many as 15% of colorectal tumors recur nearby after surgical resection. This could be due to a small number of tumor cells left behind after surgery, or shedding of cancer cells from the primary tumor into the lumen of the colon during tumor growth or surgical manipulation.
Although the surgical reconnection of the intestine after resection (anastomosis) is intended to be impermeable, studies in animals have shown that shed cancer cells can penetrate the anastomosis, resulting in local recurrence. However, little is known about the environment of the anastomosis or how shed cancer cells might penetrate it.
The anastomosis attracts collagenase-producing intestinal microbiota, such as Enterococcus faecalis, which can disrupt the intact anastomosis. Exposure to antibiotics, chemoradiation, or diet might affect localization of these bacteria to anastomotic tissues, causing tissue breakdown and leakage. Anastomotic leaks are associated with local recurrence of colorectal cancer—conditions at the site of a disrupted anastomosis might create opportunities for shed cancer cells to penetrate tissue and form tumors.
Diet affects the composition and function of the intestinal microbiome. The Western-style diet (high fat, low fiber, and decreased minerals and vitamins) has been associated with increased risk of colorectal cancer. Patients who consume high-fat, Western-type diets after colorectal cancer surgery have higher rates of recurrence, supporting the link between diet, the microbiome, and colorectal carcinogenesis.
Sara Gaines et al investigated whether diet-induced alterations in the intestinal microbiota promote penetration of the anastomosis by shed cancer cells, resulting in tumor formation in colons of mice
The authors fed mice either standard chow diet or Western-type diet (characterized by high fat, no fiber, and decreased minerals and vitamins) for 4 weeks. Some mice were given antibiotics or an inhibitor of collagenase production by bacteria, but not bacterial growth, in drinking water. Colorectal resections and anastomoses were then performed. The first day after surgery, mice were given enemas containing a collagenolytic rodent-derived strain of Enterococcus faecalis (strain E2), and on the second day they were given mouse colon carcinoma cells (CT26). Twenty-one days later, distal colons were removed, and colon contents (feces, distal colon, and tumor) were collected.
Gaines et al found colorectal tumors near colon anastomoses in 88% of mice fed the Western diet and given antibiotics, surgery, and E faecalis compared with only 30% of mice fed the standard diet followed by the same procedures.
Colon tumor formation correlated with the presence of collagenolytic E faecalis and Proteus mirabilis. Administration of antibiotics eliminated collagenolytic E faecalis and P mirabilis but did not reduce tumor formation. However, antibiotics promoted the emergence of Candida parapsilosis, a collagenase-producing microorganism.
Administration of a phosphate carrier compound (Pi-PEG), which suppresses bacterial collagenase production and preserves anastomotic integrity, reduced tumor formation and maintained diversity of the colon microbiome. The authors explain that although Pi-PEG does not affect proliferation of bacteria, the agent increases the local phosphate concentration to reduce microbial virulence, increase tight junctions, and promote intestinal healing after surgery.
Gaines et al then studied patients undergoing colorectal resection for the presence of collagenolytic organisms. The combination of mechanical bowel preparation and antibiotics reduced the total quantity of collagenase-producing microbes in patients. However, the quantity of collagenase-producing microbes in patients with obesity actually increased after mechanical bowel preparation, whereas mechanical bowel preparation decreased collagenolytic bacteria in patients with normal weight. These findings indicate a difference in response to bowel preparation between normal-weight and obese patients.
The authors conclude that cancer cells shed into the colon lumen can penetrate intact anastomotic tissues and form tumors. Colonization of anastomotic tissues by collagenolytic bacteria disrupts the healing intestine, resulting in increased permeability and transmigration of cancer cells. Collagenolytic bacteria are enriched in colons of mice fed a high-fat diet and obese patients, which might contribute to their increased rate of colorectal cancer recurrence after surgery.
Studies are needed to determine the mechanisms by which shed cancer cells lead to recurrence of colorectal tumors after surgery. Tracking of the colon microbiota, using microbiome and metabolome profiling, might be used to develop dietary recommendations and bowel preparations needed to reduce rates of local colon tumor recurrence.