Common toxin made in gut can cause bowel cancer

Discovery suggests screening for bug that creates toxin could prevent thousands of cases

Bowel cancer is the fourth most common cancer in Britain, with 42,000 new cases diagnosed each year. Photograph: Alamy

Scientists have raised fresh hopes for preventing bowel cancer after discovering that a common gut bacterium drives genetic mutations that can cause the disease.

Researchers found that a toxin secreted by a particular strain of the microbe E coli creates distinct mutations in DNA, which contribute to an estimated one in 20 bowel cancers in Britain.

The breakthrough suggests that thousands of cases of the disease might be prevented, or at least delayed, by screening for the strain and eradicating the bug in those who test positive. The treatment could involve a course of antibiotics followed by a faecal transplant to re-establish a healthy microbiome.

“We will be looking at its presence in individuals with and without cancer and whether it helps in bowel cancer screening,” said Philip Quirke, a professor of pathology at Leeds University and a senior researcher on the study. About 20% of the healthy population are thought to carry the bug.

Bowel cancer is the fourth most common cancer in Britain, with 42,000 new cases diagnosed each year. More than half could be prevented by a better diet, foregoing alcohol, quitting smoking and maintaining a healthy weight. While gut microbes have also been implicated in the disease, scientists have struggled to nail down how.

Hans Clevers and others at Hubrecht University in the Netherlands investigated the effects of a toxin called colibactin, which is produced by certain strains of E coli and another gut microbe called Klebsiella pneumoniae. Previous studies have shown that colibactin can damage the DNA in living cells.

The scientists grew tiny pieces of human intestine known as “miniguts” and injected them with colibactin-producing E coli on weekdays for five months. At the end of each week, the miniguts were treated with antibiotics to wipe out the infections. “If we don’t treat them, they fill up with bacteria and explode,” Clevers told the Guardian.

After five months, the researchers extracted DNA from the miniguts and compared the genetic material with that taken from a control group. These had been treated the same way, but with a strain of E Coli that had its colibactin-making machinery disabled.

“What we noticed was a unique mutational signature,” Clevers said. Colibactin gets in among the Gs, Ts, Cs and As on the DNA double helix and binds an A on one strand to an A on the other, the scientists found. The linkage means the DNA cannot be unzipped, effectively rendering it useless. The affected cell tries to mend the glitch but often botches the repair.

The researchers next searched for the mutational smoking gun in more than 5,000 DNA samples taken from patients with various cancers. It was present in more than 5% of colorectal cancers, but fewer than 0.1% of others. Among the others that bore the telltale genetic signature were cancers of the mouth and bladder, two areas that E coli can infect.

Strikingly, according to the study in Nature, many of the bowel cancers had multiple colibactin-related mutations, with some damaging a key anticancer gene called APC. By mutating the gene, colibactin weakened the body’s defences against the tumours.

It will take more work to understand the full implications of the discovery. Scientists must now find out how common colibactin-induced mutations are in the general population, how the number of mutations vary from person to person and whether those numbers correlate strongly with cancer risk.

“If this is strengthened by other studies, it might not be a bad plan to screen and treat people,” Clevers said. In the meantime, he urged people to be cautious about a related microbe called E coli nissle, which also secretes colibactin. The bug is sold as a probiotic and is going through clinical trials for conditions ranging from constipation to childhood diarrhoea and irritable bowel syndrome. “It might help in the short run, but it’s probably going to cause cancer in the long run,” Clevers said.

Mike Stratton, the director of the Wellcome Sanger Institute near Cambridge, found the same mutational signature in research published last year but had no idea what caused it. His work showed that the mutations built up by the age of 10, in line with the gut being colonised with bugs after birth. “If the exposure is taking place within the first decade of life, we may need to diagnose it within the first decade of life and treat it to avoid the mutations being generated,” he said.

“The key value of this work is that they’ve identified colibactin as the cause of this mutational signature and really for the first time demonstrated that a component of our microbiome can cause mutations in a human being. That is a really important observation,” Stratton added. Scientists will now hunt for other bacteria that may be mutating DNA with other toxic substances.

Written by Ian Sample, Science editor for The Guardian ~ February 27, 2020

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