Tracing the toxic fingerprint of a bacterium in our gut 

Sheltering in our gut is a collection of trillions of bacteria, fungi and viruses that call the human body home – making up a large proportion of our microbiome.

The vibrant community of bugs can help protect us from harm, programming our immune system as well as providing nutrients for our cells. But certain bacteria have been linked to a host of different diseases, from diabetes and mental health to cancer.

Clues from both the lab and clinic have suggested a link between the microbiome and bowel cancer. But there’s still a lot we don’t know.

According to Jens Puschhof, a PhD student at the Hubrecht Institute in the Netherlands, one of the big things that’s been missing is evidence of how the bacteria in our gut increase bowel cancer risk.

Until now.

The challenge at hand

Puschhof is part of a Cancer Research UK Grand Challenge team that’s uncovered a precise link between a common type of bacteria found in our guts and bowel cancer. Publishing their work in Nature, Jens says the study it’s a first, as “this link of bacteria damaging our genes to lead to cancer has not been made before”.

The human gut hosts hundreds of different types of bacteria. But the team focused their analysis on a single strain of E.coli that’s more common in people with bowel cancer’s poo than healthy people’s poo.

This particular strain of E.coli is said to be ‘genotoxic’, because it produces a toxin that damages human DNA, colibactin.

Their task was to investigate if the DNA damage caused by this strain of E.coli was in any way linked to the DNA faults found in bowel cancer.

A fingerprint caught red-handed

In order to tackle this challenge, the team created miniature replicas of the gut in the lab called organoids. These mini-guts help scientists to recreate the complexities of the human intestine in the lab, which they then exposed to colibactin-producing E.coli for 5 months.

The team spent the next weeks analysing the DNA sequences of the mini-guts. Eventually, they found that organoids exposed to the genotoxic E.coli had double the DNA damage of organoids exposed to E.coli that didn’t produce colibactin.

The study also revealed that the DNA damage caused by colibactin followed 2 very unique patterns, which acted like a fingerprint to identify the effects of the toxin.

To confirm whether this bacterium had a distinct role to play in the development of bowel cancer, the team began looking for these same fingerprints present in patients.

First, they checked the DNA of 3,600 cancer samples from a Dutch cohort. The fingerprints were present in multiple tumours, but much more common in bowel cancers than other cancer types.

The team then focused in on bowel cancer. With the help of Genome England’s 100,000 Genome Project – led by Professor Mark Caulfield – they gained access to 2,000 bowel cancer samples.  This allowed Dr Henry Wood and Professor Philip Quirke from the University of Leeds to confirm that the colibactin signature was present at the same frequency in UK cancers.

According to Puschhof, a study of bowel cancer of this scale is quite unique. “The Grand Challenge project has enabled us to look for the bacterial mutation fingerprint in 5,500 cancer genomes.”

The colibactin fingerprints were present in 1 in 20 patients, suggesting that this common strain of E. coli could play a role in 1 in 20 bowel cancer cases in the UK.

A very human element

A study of this kind is remarkable in more ways than one.

The team of researchers studying the microbiome work closely alongside patient advocates, who provide guidance on the very human element of their research.

“It’s a privilege to share my experiences as a patient. And hopefully it will keep in the back of the scientist’s minds that what they’re doing is impacting someone’s family, someone’s mother,” says Candace Henley, a patient advocate on the Grand Challenge team.

Henley has Lynch syndrome, an inherited genetic condition that’s linked to a high risk of bowel cancer. “I have 5 daughters and it makes it more important for me to find out more about bowel cancer because the future of my children and my grandchildren are in the hands of these great, intelligent, mindful gracious people.”

As she sees it, her role on the team is to push the researchers forward, to question them and to put patient impact in the front of their minds.  And John Barnes, another patient advocate on the team agrees.  He told us how their involvement in the project “has put a personal view-point to that research, and I think the reaction that we’ve had as patients from the researchers and the researchers have had from us puts it into more of a real life situation, and it’s heart-warming.”

But it is not just practical advice that the advisory panel gives. “We in the patient community want to tell you great job, keep going, we got you,” says Henley. “Even if we don’t understand the total magnitude of it, it’s the fact that they’ve made a significant finding or a significant difference. And that’s something that we celebrate.”

Implications for the future

Understanding the early triggers that lead to bowel cancer could help doctors to detect it earlier, at a stage when treatment is more likely to be successful.

And the research team believe that looking for colibactin fingerprints in the DNA of the cells of the gut lining could one day be used to identify those who are at a greater risk of developing the disease.

“Our goal is to find a way to identify and target these high-risk toxin carrying bacteria before they cause too much damage,” says Quirke, “it may help some people avoid bowel cancer entirely, which would be the ideal outcome. We may also be able to find other toxins to increase the number of people we can help in the future”

Lilly

Pleguezuelos-Manzano C., Puschhof J., Rosendahl-Huber A. et al. (2020) A mutational signature in human colorectal cancer induced by genotoxic pks+ E. coli. Nature. DOI: 10.1038/s41586-020-2080-8