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Genetic signature links bacterial toxin to colon cancer

Colibactin causes key cancer mutations

by Laura Howes
February 28, 2020

A fluorescent micrograph of a gut organoid
Credit: Cayetano Pleguezuelos-Manzano, Jens Puschhof, Axel Rosendahl Huber, ©Hubrecht Institute
This gut organoid (labelled with a green fluorescent protein) is about 10 micrometers in diameter and is filled with colibactin-producing E. coli (blue).

For over a decade, scientists have found correlations between the bacteria in our guts and our health. Researchers in the Netherlands have now shown that one of those bugs produces a metabolite that causes specific mutations in colon cancer (Nature 2020, DOI: 10.1038/s41586-020-2080-8).

The toxin, or toxins, dubbed colibactin have proven tricky for chemists to isolate and study. But specific mutations found in the new research supports the work of chemists that suggested how colibactin interacts with DNA. Researchers say the work also backs up the idea that eliminating or neutralizing colibactin-producing bacteria in the intestinal tract could prevent colorectal cancer in a significant number of people.

“It’s exciting to see how far the colibactin field has come,” says Emily Balskus, a Harvard University microbial chemist who showed last year how colibactin specifically binds to adenine residues in DNA.

To investigate whether colibactin’s potential to bind onto gut cell DNA might lead to colorectal cancer, Hans Clevers and his team at the Hubrecht Institute teamed up with Ruben van Boxtel’s group at Princess Máxima Center. Together the researchers created miniature replicas of the human gut grown in the lab called organoids. The benefit of these organoids, van Boxtel explains, is that they use human cells and are more genetically stable than a conventional cell culture. This allows the researchers to identify mutations caused by colibactin more easily.

Structure of colibactin.

They exposed the organoids to colibactin-producing Escherichia coli. Five months later, the scientists analyzed the DNA of the gut cells and found about double the DNA damage compared with organoids that had not been exposed to colibactin. The DNA damage followed a very specific pattern unique to colibactin: one adenine–thymine (A–T) pair was either deleted or substituted, but only if it was three bases down from a T–A pair. So the group searched databases of colon cancer genomes looking for this pattern. They found it: around 5% of tumors in the databases had the same mutational signature. In fact, many of them had multiple colibactin-related mutations, with some damaging a key anticancer gene called APC.

That signal from the genomic data supports the finding that colibactin binds to adenine residues and cross-links DNA, says Jason Crawford, a Yale University chemist. Crawford was part of the team that deduced the structure of the major colibactin metabolite from a version of the molecule bound to DNA. “This is a nice example of cancer biological studies supporting the relevance of select chemical mechanisms proposed in the colibactin field,” he says.

For Balskus, the big question is what to do with this information. Perhaps screening for the strain and eradicating the bug in those who test positive could help treat or prevent colon cancer. Around 20% of people have colibactin producing bacteria in their guts but they don’t all get ill. She adds, though, that more work needs to be done to find the mechanism connecting colibactin binding to cancer risk. In turn, that biological data could help chemists confirm the form of colibactin that gets from the bacteria into gut cells, and how exactly the colibactin binds to DNA.


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