When The Microbiome Goes Wrong And Promotes Cancer

Researchers from the Hebrew University of Jerusalem’s Lautenberg Center for Immunology and Cancer Research set out to investigate what happens when antioxidants go wrong, and what they found may make some people rethink their dietary choices. 

The team discovered that certain cancer mutations are not always bad in and of themselves, and in certain micro-environments like the gut these mutations may even help the body to fight off cancer rather than spread it. But if the gut microbiome is producing high levels of metabolites such as those found in certain bacteria and antioxidant rich foods then it can act as a hospitable environment to certain mutated genes which could accelerate the growth of bowel cancers. 

This research focused on gut microbiome as the team examined gastrointestinal cancer, and they may have found the reason why only 2% of cancers take root in the small intestine as opposed to 98% of cancers taking place in the colon. One of the significant differences between these organs is their level of gut bacteria in which the small intestines contain few while the colons contain multitudes. 

“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 senior study investigator Yinon Ben-Neriah, PhD, professor at HU.

The TP53 gene is found in every cell, and it produces p53 protein which acts as the cell’s barrier to suppress genetic mutation within the cell; but when p53 becomes damaged it will no longer protect the cell, in fact it does the opposite to drive the cancer and help tumors grow and spread. 

To test their theory of the gut flora being at play mutated p53 proteins were introduced into the gut: The small intestines reacted by converting the mutated p53 back into normal p53 turning it into super suppressors that were better at suppressing cancer growth than healthy p53 proteins. When mutated p53 was introduced into the colon they stayed true to their cancer driving nature and promoted the cancerous growth and spread. 

“We studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion or ApcMin mutation,” the authors wrote. “Cancer in these models is known to be facilitated by loss of p53. We found that mutant versions of p53 had contrasting effects in different segments of the gut: in the distal gut, mutant p53 had the expected oncogenic effect; however, in the proximal gut and in tumor organoids, it had a pronounced tumor-suppressive effect. In the tumor-suppressive mode, mutant p53 eliminated dysplasia and tumorigenesis in Csnk1a1-deficient and ApcMin/+ mice and promoted normal growth and differentiation of tumor organoids derived from these mice. In these settings, mutant p53 was more effective than wild type p53 at inhibiting tumor formation. Mechanistically, the tumor-suppressive effects of mutant p53 were driven by disruption of the WNT pathway, through preventing the binding of TCF4 to chromatin.”

“We were riveted by what we saw,” Ben-Neriah added. “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.”

Antibiotics were administered to kill off the colon’s gut flora to further investigate their theory of the gut flora being a factor as to why mutated p53 were acting as tumor blockers in the small intestine but as accelerants in the colon; when this was done the mutated p53 was not able to promote the cancer spree. 

After analysis the team was able to identify the culprit behind what is in the flora that makes colon cancer spread so rapidly, and that was the gut flora producing metabolites such as antioxidants. When mice were fed an antioxidant rich diet the gut flora accelerated p53’s cancer driving mode, which may be of concern to those with a family history of colorectal cancer. 

“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,” concluded Ben-Neriah. Looking towards the future, those at high risk of colorectal cancer may want to screen their gut-flora more frequently and think twice about the foods they digest, antioxidant, and otherwise.

More research is needed to further investigate this new territory, one must also keep in mind to take this with a grain of salt as these results were achieved in animal testing, and what is yielded in such study does not always translate well, if at all, to humans.