Strain of E coli Linked to About 5% of
Colorectal Cancer

Liam Davenport

March 03, 2020

New research suggests that one strain of the common bacterium Escherichia coli may be involved in the development of colorectal cancer (CRC).

The finding may lead to new diagnosis approaches in the future, but for right now, the researchers warn that taking probiotics — some of which contain toxin-secreting strains of E coli — may not be such a good idea.

The study was published online in the journal Nature February 27, and was led by a team at the Hubrecht Institute (KNAW) and the Princess Máxima Center for Pediatric Oncology in Utrecht, the Netherlands.

The researchers focused on a particular strain of E coli that produces the toxin colibactin, because this strain is found more frequently in stool samples from people with CRC than in stool samples from healthy individuals.

Colibactin is already known to cause DNA damage in cells in vitro, and the team suspected that the toxin might be doing the same to cells lining the gut.

To test this theory, they developed small replicas of intestinal tissue known as human intestinal organoids, and they exposed this cultured tissue to the toxin-secreted strain of E coli. They found that these bacteria induced a unique pattern of mutations in the DNA of human cells, while other strains of E coli did not.

The team then analyzed tissue from more than 5500 tumor samples taken from patients with CRC in the Netherlands and the UK. They found the same unique pattern of mutations in about 5% of the tumors.

"Our study describes a distinct mutational signature in CRC and implies that the underlying mutational process directly results from past exposure to bacteria," the researchers comment. 

"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," lead author Hans Clevers, MD, PhD, of the Hubrecht Institute, said in a press statement.

He also suggested caution in the use of probiotic products, as some contain the same toxin-secreting strain of E coli that was the focus of their study.

"There are probiotics currently on the market that contain genotoxic strains of E coli. Some of these probiotics are also used in clinical trials as we speak," he said.

"These E coli strains should be critically re-evaluated in the lab. Though they may provide relief for some bodily discomfort in the short term, these probiotics could lead to cancer decades after the treatment," he warned.

Bacteria Probably Only Part of the Story

The contribution of E coli-produced colibactin is likely to be only one part of the picture, commented Ian Johnson, PhD, nutrition researcher and emeritus fellow at the Quadram Institute Bioscience, Norwich, United Kingdom. He was not involved in the research, and was one of several experts commenting on the new finding on the Science Media Centre.

"This is a complex disease that is likely to have many contributory causes," he said.

"The risk of colorectal cancer varies by about fivefold between countries, and the risk is consistently higher in populations consuming typically western diets and having a high prevalence of obesity," Johnson noted.

"It would be valuable in the future to discover whether gut bacteria implicated in the development of colorectal cancer are also more common in populations at higher risk, and if so, how they can be reduced."

This study is "a great step toward understanding the connection between the presence of bacteria producing DNA-damaging toxins and specific types of errors in the genome," commented Nicola Valeri, MD, PhD, team leader in Gastrointestinal Cancer Biology and Genomics at The Institute of Cancer Research, London, UK.

"Interestingly, these findings echo and complement observations from recent studies in the field and provide important insights into the role bacteria may have in promoting cancer progression," he said.

"Taken together, these observations could help us design better studies that aim at early detection and prevention of bowel and other cancers," he added.

Specific Pattern of Mutations

The researchers note that 18 genotoxic strains of E coli have been identified that harbor a 50 kb hybrid polyketide-nonribosomal peptide synthase operon (pks) responsible for colibactin production.

Colibactin and similar genotoxins damage human DNA in a specific mutation pattern or signature, which has also been observed with carcinogens such as tobacco smoke and ultraviolet light.

"These signatures can have great value in determining causes of cancer and may even direct treatment strategies", said study coauthor Ruben van Boxtel, PhD, also from the Hubrecht Institute, in a press statement.

The team exposed human intestinal organoids derived from primary crypt stem cells to a pks-positive E coli strain as well as to a strain incapable of producing active colibactin, injecting them into the lumen.

After five cycles over 5 months of bacterial injection followed by organoid culture for 2 to 3 weeks, the organoids were assessed for DNA damage, which revealed a pks-specific single base substitution (SBS) and small indel (ID) signature.

"I remember the excitement when the first signatures appeared on the computer screen," said investigator Axel Rosendahl Huber, a PhD student at Princess Máxima Center.

"We had hoped for some indication of a signature that we could follow up on in other experiments, but the patterns were more striking than any signature we had analyzed before," he added.

To determine whether these mutational signatures occur in human tumors, the researchers examined whole genome sequencing data from a Dutch set of 3668 solid cancer metastases.

The SBS signature was seen in 7.5% of colorectal cancer tumors, the ID signature was seen in 8.8%, and both signatures together were seen in 6.25% of colorectal tumors.

The signatures have also been seen in other cancer types, but less frequently — in 1.6% of head and neck tumors, and between 2% and 4% of urinary tract tumors.

The team also looked at 2208 colorectal cancer genomes from the Genomics England 100,000 Genomes Project, finding that the signatures were present in 4% to 5% of patients.

This work was supported by Cancer Research UK Grand Challenge grant OPTIMISTICC; the gravitation program CancerGenomiCs.nl and NOCI from the Netherlands Organisation for Scientific Research; the Oncode Institute (partly financed by the Dutch Cancer Society); the European Research Council under an ERC Advanced Grant; and a VIDI grant of the Netherlands Organisation for Scientific Research. The study authors have disclosed no relevant financial relationships.

Nature. Published online February 27, 2020. Abstract

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