A common type of bacteria found in our guts could contribute to bowel cancer, according to research funded published in Nature (2020; doi: 10.1038/s41586-020-2080-8). Scientists in The Netherlands, the U.K., and U.S. have shown that a toxin released by a strain of E. coli causes unique patterns or "fingerprints" of DNA damage to the cells lining the gut. The fingerprints were also seen in bowel cancer tumors, showing for the first time a direct link between the bacterial toxin and the genetic changes that drive cancer development.
The team suggested that detecting this specific DNA damage in the cells lining the gut could one day allow doctors to identify people at higher risk of the disease and become used alongside current bowel cancer screening tests. Other bacterial toxins from gut bacteria might have similar effects and the hunt for them is now on as researchers seek to determine whether this mechanism of DNA damage is widespread.
There are around 42,000 new bowel cancer cases in the UK every year, where it remains the second most common cause of cancer death. Understanding the early triggers that could lead to bowel cancer may help doctors prevent its development and detect it at its earliest stage, when treatment is most likely to be successful. This has led scientists to investigate the role that the microbiome-trillions of bacteria, viruses, fungi and other single-celled organisms-plays in the development of bowel cancer.
Hans Clevers, MD, PhD, and his team at the Hubrecht Institute in The Netherlands focused on one strain of E. coli producing a toxin called colibactin, and which is more often present in the stool samples of people with bowel cancer compared to healthy people. Because colibactin can cause DNA damage in cells grown in the lab, they thought the toxin might be doing the same to cells lining the gut.
The team used human intestinal organoids, miniature replicas of the gut grown in the lab, and exposed them to colibactin-producing E. coli. They analyzed the DNA sequence of the gut cells in the organoids after 5 months and found about double the DNA damage in them, compared to organoids exposed to "regular" E. coli that didn't produce the colibactin.
The researchers also found that the DNA damage caused by colibactin followed two very specific patterns-like fingerprints-which were unique to the toxin.
Study Details
To determine whether the DNA damage caused by the bacterium played a role in bowel cancer, the researchers then analyzed the DNA sequences of more than 5,500 tumor samples from the UK and Netherlands, with the help of Henry Wood, PhD, and Philip Quirke, MD, from the University of Leeds.
First, they checked for the two colibactin DNA damage fingerprints in over 3600 Dutch samples of various cancer types. The fingerprints were present in multiple tumors, and much more often in bowel cancers than other cancer types.
The researchers then refined their investigation on bowel cancer tumors specifically and analyzed over 2,000 bowel cancer samples from the UK, collected as part of the 100,000 Genomes Project run by Genomics England. Among these samples, the colibactin fingerprints were present in 4-5% of patients. This suggests that colibactin-producing E. coli may contribute to 1 in 20 bowel cancer cases in the U.K. It will be up to further studies to shed light on just how much of a role the toxin could play in these cases, and what other components of the microbiome may be involved in the early stages of bowel cancer.
"Things like tobacco or UV light are known to cause specific patterns of DNA damage," Clevers noted, "and these fingerprints can tell us a lot about past exposures that may have caused cancer to start. But this is the first time we've seen such a distinctive pattern of DNA damage in bowel cancer, which has been caused by a bacterium that lives in our gut."
Further down the line, the researchers say that looking for DNA damage fingerprints like the ones associated with colibactin in the cells of the gut lining could be used to identify those who are at a greater risk of developing the disease.
"Our goal is to understand the causes of bowel cancer, so discovering the role of colibactin represents an important step," Quirke stated. "We are now looking at other bacteria and their toxins associated with bowel cancer, and we hope to identify more DNA damage fingerprints to paint a better picture of risk factors.
"We will then need to work out how we can reduce the presence of high-risk bacteria in the gut. But this is all in the future, so for now people should continue to eat a healthy diet and participate in bowel cancer screening."