E. coli toxin could be linked to rising rates of bowel cancer in younger adults

Childhood exposure to a toxin produced by E. coli could be contributing to the rise of bowel cancer in under-50s, according to research we funded through Cancer Grand Challenges.

E. coli is a vital part of a healthy gut microbiome, but some strains can produce a toxin called colibactin, which is capable of altering DNA. (Other E. coli strains are better known for causing food poisoning and diarrhoea, but they aren’t thought to produce colibactin).

The latest study from team Mutographs has shown that DNA changes caused by colibactin are much more common in younger adults with bowel cancer than they are in those who develop the disease later in life.

Colibactin-linked DNA changes also appear to happen early, before cancer develops. More work needs to be done to establish a direct causal link, but the findings suggest that more people could be developing early-onset bowel cancer because more people are being exposed to colibactin as children.

The team is now planning further studies to test that hypothesis. If it proves to be true, scientists should be able to develop new ways of predicting and preventing early-onset bowel cancer by tracking colibactin and targeting the strains of E. coli that produce it.

A potential culprit behind the rise in early-onset bowel cancer

While bowel (or colorectal) cancer in younger adults is still comparatively rare, researchers from other Cancer Grand Challenges teams have already shown that it is a “growing global phenomenon” that could be linked to changes in the risk factors people encounter during childhood.

This study, published today in Nature, uncovers evidence pointing to a specific cause for the rise.

Led by researchers at the University of California San Diego (UC San Diego), the Mutographs team analysed 981 bowel cancer genomes from patients across 11 countries not including the UK. They found that colibactin-linked mutation patterns were 3.3 times more common in adults diagnosed with bowel cancer before they turned 40 than they were in those diagnosed in their 70s or later. The patterns were also particularly prevalent in countries with higher rates of early-onset cancer.

UC San Diego Professor Ludmil Alexandrov, senior author of the study, said: “These mutation patterns are a kind of historical record in the genome, and they point to early-life exposure to colibactin as a driving force behind early-onset disease.”

Previous studies have shown that colibactin-related mutations happen in the first 10 years of life. The Mutographs team found that colibactin-linked mutation patterns are also linked to “driver” mutations that appear at the earliest stages of tumour development.

“If someone acquires one of these driver mutations by the time they’re 10 years old, they could be decades ahead of schedule for developing colorectal cancer, getting it at age 40 instead of 60,” said Alexandrov.

The next steps for our early-onset cancer research

Although this study draws an important link between the childhood microbiome and the risk of early-onset cancer, we can’t yet say exactly what that link means. Longer term controlled studies tracking the effects of colibactin exposure on children as they grow up will be needed to fully establish whether the toxin causes cancer or is just associated with it.

Other research will also be needed to work out what factors disrupt children’s microbiomes and lead to the presence of E. coli strains that produce colibactin.

Dr David Scott, the director of Cancer Grand Challenges, said: “It’s unclear how the exposure originates, but we suspect that a combination of factors – including diet – may intersect during a crucial phase in the development of the gut microbiome.”

He also stressed that, whatever researchers find out about the causes and effects of colibactin exposure, it’s unlikely there is just one driver behind the rise of early-onset bowel cancer.

“This study adds an important piece to the puzzle of early-onset cancers, but it isn’t conclusive, and more research will be needed,” Scott said. “Other Cancer Grand Challenges teams, like OPTIMISTICC and PROSPECT, are looking deeper into the microbiome and other environmental factors to uncover what’s behind the global rise.”

Members of team Mutographs are also planning ways to follow up this study and answer the outstanding questions about the microbiome, colibactin and early-onset bowel cancer. At the same time, they’re looking into developing a colibactin poo test that could one day be used to identify people at higher risk of early-onset bowel cancer.

“This reshapes how we think about cancer,” said Alexandrov. “It might not be just about what happens in adulthood – cancer could potentially be influenced by events in early life, perhaps even the first few years. Sustained investment in this type of research will be critical in the global effort to prevent and treat cancer before it’s too late.”

Cancer Grand Challenges was co-founded by Cancer Research UK and the National Cancer Institute in the US. Team Mutographs brought together researchers from UC San Diego, UC San Francisco, the Wellcome Sanger Institute and King’s College London and the International Agency for Research on Cancer in France.