Clinicians and researchers have long wondered why cancer in the small intestine is rare while it's so common in the colon; two percent of gastrointestinal cancer happens in the small intestine while 98 percent is colorectal. Scientists wanted to know more about whether bacteria in the gut were playing a role in this phenomenon. Their work has revealed that some gut bacteria can actually create an environment that is hospitable to cancer-promoting genetic mutations. The findings have been reported in Nature.
"Scientists are beginning to pay more and more attention to the role gut microbiomes play in our health: both their positive effects and, in this case, their sometimes pernicious role in aiding and abetting disease," explained Professor Yinon Ben-Neriah at the Hebrew University of Jerusalem's Lautenberg Center for Immunology and Cancer Research.
Cells carry a gene called Trp53, which produces the p53 protein (shown in the video above). This protein can help suppress tumor growth by controlling the cell cycle, and preventing cells from dividing too fast - the hallmark of a tumor. It can also detect mutations in the genome and direct their repair or cause unfixable cells to self-destruct. But when p53 picks up mutations and can't do its job correctly, it can actually promote cancer growth.
In this study, Trp53 mutations (to produce mutant p53 proteins) were introduced into a mouse model of intestinal cancer. The researchers found that in the small intestine, the mutant p53 was actually suppressing cancer more than normal p53 proteins. In the colon, however, the mutant p53 behaved as expected, and began to drive the spread of cancer. The small intestine carries the vast majority of gut microbes, which seemed to be having an incredible effect on this system.
"We were riveted by what we saw," said Ben-Neriah. "The gut bacteria had a Jekyll and Hyde effect on the mutated p53 proteins. In the small bowel, they totally switched course and attacked the cancerous cells, whereas in the colon they promoted the cancerous growth."
In order to show that the gut bacteria were responsible for this functional conversion, the researchers killed off the microbiota in the colons of their model with antibiotics. This time, the mutant p53 did not promote cancer growth there.
The work suggests that mutations that seem to promote cancer are not the only culprits. There are microenvironments in the gut that can encourage the spread of cancer through their effect on the mutations. If high levels of certain metabolites like those produced by certain foods rich in antioxidants or bacteria that produce a lot of them are present, the mutations are given a hospitable environment. When the researchers fed their mouse model a diet high in antioxidants, they found that p53 was more likely to encourage cancer growth.
This research may be especially useful for people that have a family history of colorectal cancer; they may want to consider the findings when making dietary choices. Black tea and cocoa, for example, are very high in antioxidants.
"Scientifically speaking, this is new territory. We were astonished to see the extent to which microbiomes affect cancer mutations--in some cases, entirely changing their nature," said Ben-Neriah.