A study using human-derived intestinal organoids published in Nature has linked a strain of Escherichia coli regularly found in the human microbiome with an increased risk of colorectal cancer.1 The strain, pks+E.coli, produces a peptide called colibactin which has long been suspected to cause DNA damage. However, no persuasive links with colorectal cancer have previously been found.
“It was already known that genotoxic E.coli of this particular strain causes breaks in DNA,” said Hans Clevers, senior author of the work and group leader at the Hubrecht Institute for Developmental biology and stem cell research and at Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands. “There are 10 to 20 papers showing that pks+E.coli is genotoxic, but nobody had exactly established what it does to the DNA,” he added.
The researchers repeatedly injected human-derived colon organoids with pks+E.coli, or a control E.coli incapable of making colibactin over a period of 5 months, before whole-genome sequencing the DNA of the exposed organoids to look for mutations. In the pks+E.coli-exposed organoids, they found a specific mutational pattern that had not been described before — one which was lacking in the organoids exposed to pks+E.coli without the ability to make colibactin.
They then looked for this mutational pattern in databases of sequencing information from more than 5000 different cancer patients, spanning dozens of different cancer types.
“We found an unusual change in the DNA never seen before, allowing us to go back to real-life patients and asked, “Do we ever see this mutation signature in their cancers?’ We found this signature in about 10% of colon cancer patients and very rarely in other cancers — never in cancers where E.coli is not present,” said Dr Clevers.
The researchers picked up the mutation pattern in only 0.1% of tumor types other than colorectal cancers, also finding the signature in some cases of bladder and head and neck cancers, both sites where E.coli is known to sometimes be found.
“This is a timely and very exciting study, as the microbiome is a new frontier from both a prevention perspective and also from a clinical standpoint,” said Dr Mark Hanna, MD, colorectal cancer surgeon and assistant clinical professor in the division of surgical oncology at City of Hope in Upland, California. “I think this is persuasive; we know that E.coli is native to the colon, so this result makes sense in colorectal cancer. I would have found it harder to believe if the signature was found in other organs with no E.coli present, so this part of the work significantly strengthens the findings,” he added.
Helicobacter pylori has long been established to be the cause of many cases of stomach cancer, but there are also several other bacterial species where a causal link has been suggested, but has yet to be proven.
“There are at least 3 or 4 other suspected species which we will be investigating, including Fusobacterium. With several types of bacteria, there’s often an association reported, but never a clear relationship established. Now that this strategy has worked, it should be more straightforward to answer these questions with other bacteria,” said Dr Clevers.