Antioxidants Gone Bad: When the Microbiome Promotes Cancer

Antioxidants Gone Bad: When the Microbiome Promotes Cancer

In science, rarely are there ideas that are a hundred percent true all the time. Typically, there are some gray areas, and it’s these nuanced scenarios were mechanistic discoveries are often identified. For instance, pick up any health magazine or watch a few commercials, and you might be under the impression that antioxidants are always good. But what happens when they’re not? Well, that’s exactly what a team of investigators from the Hebrew University (HU) of Jerusalem’s Lautenberg Center for Immunology and Cancer Research set out to discover. What they found could make many people rethink their next cup of black tea or that piece of decadent dark chocolate.

Interestingly, the HU researchers found that certain cancer mutations are not necessarily bad actors, in and of themselves. In fact, in certain micro-environments like the gut, these mutations can actually help the body to fight cancer, not spread it. However, if the gut microbiome produces high levels of metabolites, like those found in certain bacteria and antioxidant-rich foods like black tea and hot cocoa, then it acts as a particularly hospitable environment to mutated genes and will accelerate the growth of bowel cancers.

Findings from their study were published recently in Nature through an article entitled “The gut microbiome switches mutant p53 from tumor-suppressive to oncogenic.”

The research team focused on the gut microbiome as they took a closer look at gastrointestinal cancers, and may have found the reason why only 2% of cancers take root in the small intestine. In contrast, a whopping 98% of cancers take place in the colon. One significant difference between these two organs is their levels of gut bacteria: small intestines contain few, whereas 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.

TP53 is a gene found in every cell. It produces a protein called p53, which acts as the cell’s barrier, suppressing genetic mutations in the cell. However, when p53 becomes damaged, it no longer protects the cell. Quite the opposite, it drives the cancer, helping tumors spread and grow.

To test their theory that gut flora was at play, the researchers introduced mutated p53 (“cancer-driving”) proteins into the gut. Amazingly, the small intestine reacted by converting the mutated p53 cancer driver back to normal p53, turning into “super-suppressors” that were better at suppressing cancer growth than healthy p53 proteins. However, when mutated p53 was introduced into the colon, they did no switcheroo but stayed true to their driving-cancer nature and promoted the cancerous 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.”

To further test their theory that gut flora was a major factor as to why mutated p53 were acting as tumor blockers in the small bowel but tumor accelerants in the colon, the scientists administered antibiotics to kill off the colon’s gut flora. Once they did, the mutated p53 was not able to go on its cancer spree.

What’s in this flora that makes colon cancer spread so quickly? A close analysis identified the culprit: gut flora that produces metabolites, aka “antioxidants,” which are found in high concentrations in foods such as black tea, hot chocolate, nuts, and berries. Amazingly, when the scientists fed mice an antioxidant-rich diet, their gut flora accelerated p53’s cancer-driver mode. This finding is of particular concern to those patients 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.

Source: https://www.genengnews.com/