Gut-dwelling bacterium singled out as the possible cause of colorectal cancer

A microbe that is common in the human intestine is suspected of playing a major role in the development of colorectal cancer, the second deadliest and third most common kind in the world, with two million diagnosed cases and one million deaths a year.

A team of scientists from Yale University recently discovered in a group of volunteers that some strains of the bacterium Morganella morganii produce molecules called indolimines that are toxic for human DNA. In the laboratory, the researchers proved that these substances cause tumors in mice. The finding was published in the journal Science on October 28.

A human being has more bacterial cells (38 trillion) than human cells (30 trillion). However, defecation can reverse the proportion in favor of human cells. Through this act, in which a third of the microbes in the colon is expelled, the person ceases to be numerically bacterial and becomes fully human. Most of these microorganisms are harmless, or even beneficial, but some can cause illness, explains Noah Palm, lead author of the study, and it is possible that the indolimines have an effect on colorectal cancer. However, much more work will be needed to prove that they are indeed the cause.

The lifetime risk of colorectal cancer is 1 in 23 in men and 1 in 25 in women, according to data from European tumor registries. The usual risk factors are age, smoking, alcohol consumption, obesity and a diet low in fruit and high in processed meats. Having an inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease, increases the risk as well.

Palm’s team developed a new technique that allows for the simultaneous study of a hundred types of microbes and their products. The researchers detected the (previously unknown) indolimines in strains of Morganella morganii in people with inflammatory diseases. However, even though there is a larger amount of this bacterium in patients with inflammatory bowel disease or colorectal cancer, it is also present in seemingly healthy people. Even the epithelial cells of the intestines of healthy individuals show some mutations that can be caused by toxins from these communities of microorganisms, such as indolimines, explains Palm.

Morganella morganii, which measures one thousandth of a millimeter, is commonly found in water, soil and the intestines of mammals. It is usually a benign microbe, but it is also associated with urinary tract infections.

Spanish biotechnologist Cayetano Pleguezuelos and his colleagues at the Hubrecht Institute in the Netherlands were the first to show the direct connection between the bacteria that live in the human digestive system and the genetic alterations that cause the development of cancer. The researchers saw that a specific strain of Escherichia coli produces a toxic molecule called colibactin which damages the DNA of human cells. This was confirmed in miniature versions of intestinal tissue generated in the laboratory. Their discovery was published in the journal Nature on February 27, 2020, while the human race had its attention on another microorganism: a coronavirus that was spreading around the world from China.

Pleguezuelos applauds the new work, but suggests prudence. “Our intestinal microbiota is very complex, with many different species of bacteria, and among them there are mutualistic relationships, symbiosis, negative competition… and there are many other parameters. Bacteria can produce these toxic compounds in humans but, for some reason, they may not be able to reach the epithelial cells of the intestine and damage the DNA. These factors are not seen in experiments with mice,” he warns.

The Spanish researcher believes that the new Yale University technique “opens the door to evaluating a large number of bacteria and their ability to damage DNA.” A person that weighs 70 kilos has about 46 kilos of human cells, according to a study carried out by a team from the Weizmann Institute of Science in Rehovot, Israel. The heaviest ones are muscle and fat cells. The 38 trillion bacteria only weigh about 200 grams, but they make up an extremely complex universe. “Their ability to carry out different enzymatic reactions is immense. And we don’t know most things,” says Pleguezuelos.

The Spanish biotechnologist explains that every agent that damages human DNA causes a specific pattern of mutations called a mutational signature. Pleguezuelos and his colleagues identified the mutational signature of the harmful strains of the Escherichia coli and found this characteristic trace in more than 5% of the colorectal cancer patients that were analyzed, compared to 0.1% detected in other types of tumors. Of course, that figure must be taken with a grain of salt – pending further studies in other populations – but it gives an idea of the magnitude of the problem: 5% of the two million annual cases means 100,000 colorectal cancer patients with the mutational signature of these harmful strains of Escherichia coli.

Doctor Palm points out that most cases of colorectal cancer occur in people who have no family history. Therefore, environmental factors, including the microbiome, play a key role in most colorectal cancer cases. However, he explains, it is still impossible to calculate the relative importance of the microbiome against other environmental factors.

Although currently there are no specific treatments to prevent DNA damage induced by the microbiome, treatments could be developed to neutralize, or even eliminate, these toxin-producing microbes.