Bacterial infection linked to bowel cancer


Researchers use army of organoids to detect distinct mutational signature.


Illustration of colibactin binding to specific DNA sequence. 

DEMCON | nymus3D, ©Hubrecht Institute

By Paul Biegler

A toxin produced by bacteria found in some probiotics – over-the-counter supplements used to treat conditions including irritable bowel and diarrhoea – has been linked to the development of bowel cancer.

Writing in the journal Nature, researchers led by Hans Clevers at the Hubrecht Institute in Utrecht, The Netherlands, report that a strain of the common gut bacteria E.Coli causes DNA mutations that establish it as a probable cause of the cancer.

The team created a small army of “organoids”, mini-intestines grown from cells that line the colon and rectum, and injected them with two strains of E.Coli.

One strain made colibactin, known as a “genotoxin” for its ability to damage cell DNA. The other was engineered so it couldn’t make colibactin.

The team then analysed the genomes of each mini-intestine, looking for a “signature” mutation in the DNA, a fingerprint similar to the changes that UV light produces in skin cells to cause cancer.

They found it in the form of a handful of alterations to adenine, one of the four bases or “letters” in the genetic code.

“I remember the excitement when the first signatures appeared on the computer screen,” says co-author Axel Rosendahl Huber.

“[T]he patterns were more striking than any signature we had analysed before.”

Having established the fingerprint of colibactin in their mini-intestines in the lab, the team began a hunt to see if the same mutations were present in real cancers.

They gathered samples from more than 5000 tumours in collections from the UK and The Netherlands and scoured the entire genome of each.

Despite the cancers coming from all parts of the body, including breast, lung and skin, the colibactin signature cropped up in one in particular.

“More than 5% of colorectal cancer had high levels of the footprint, while we only saw it in less than 0.1% of all other cancers, says co-author Jens Puschhof.

Colibactin-producing strains of E. Coli have already been linked to cancer. According to the authors, the gut bugs are found in 20% of healthy people, a figure that rises to 60% in people diagnosed with colorectal cancer.

The current study provides a direct cause to explain the statistical link.

“[T]his 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,” says Clevers.

The findings could prompt shifts in our approach to bowel cancer.

The authors suggest screening for colibactin-producing E. Coli might be used to gauge cancer risk. They also raise the prospect of trying to wipe out the bacteria with antibiotics to prevent cancer.

But colibactin is also produced by a strain of E. Coli called Nissle 1917, which has been used as a probiotic for over a century and has accrued evidence as a “good” gut bug.

Probiotics with the Nissle strain are, for example, included in consensus guidelines on the management of ulcerative colitis.

The new study raises questions about whether colibactin-producing strains of E. Coli deliver a net therapeutic benefit.

Clevers is calling for a wholesale review of our approach to the bacteria.

“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,” says Clevers.

“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”.

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Paul Biegler is a Eureka-Prize winning journalist, bioethicist and former physician writing on all things health and science.
  1. https://www.nature.com/articles/s41586-020-2080-8
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923317/#:~:text=Colibactin%2Dproducing%20bacteria%20induce%20chromosomal,include%20extra%2Dintestinal%20pathogenic%20E.
  3. https://www.genomicsengland.co.uk/about-genomics-england/
  4. https://www.nature.com/articles/s41586-019-1689-y
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  8. https://www.mutaflor.com.au/
  9. https://academic.oup.com/ecco-jcc/article/11/7/769/2962457
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