Hidden treasure: do the clues to preventing and detecting colorectal cancer lie in the microbiome?

In two studies released in 2021 in Clinical Cancer Research and Genome Medicine, the team identified a unique bacterial signature associated with colorectal cancer, which was consistently found in stool samples from patients in four countries. This microbiome signature can be reliably detected in stool samples collected through an inexpensive card-based method (guaiac faecal occult blood test, or gFOBT) and analysed through ribosomal-RNA sequencing.   

Collectively, the findings not only hint at the existence of microbiome biomarkers for colorectal cancer but also may translate to a simple, effective and scalable screening test that could be used worldwide, including in under-resourced settings. Such testing could be used to decrease the incidence of the disease and help more people get diagnosed earlier, when treatment is more likely to be successful.   

The OPTIMISTICC team has made breakthroughs by integrating the complementary perspectives of the quantitative and clinical sides of the team, led by co-investigators Curtis Huttenhower, a bioinformatician based at the Harvard TH Chan School of Public Health, US, and Phil Quirke, a pathologist based at the University of Leeds School of Medicine, UK.

“I tend to take a basic approach, using computational techniques to answer questions about microbial ecology,” says Curtis. “Phil’s side of the team brings a translational perspective – I wouldn’t necessarily have considered the route to screening without their input.”   

Accordingly, the results reflect these dual perspectives: the team both identified bacteria associated with colorectal cancer and devised a simpler, less expensive approach to microbial testing that could enable broad initial screening of patients worldwide.  

“There are two arms to these findings – one technical and one biological,” explains Curtis. “From a technical perspective, in the stool of people with early-stage colorectal cancer, this very broad, gFOBT card-based approach can detect microbial signals that are similar to much more detailed, deep shotgun metagenomic studies of people with late-stage disease. I’m actually kind of amazed that these signals are comparable. They’re not as rich – you’re not measuring the whole microbial community, or individual strains, or all the chemical and functional activities that you could with a higher-quality sample. But it’s a good first-pass screen to test whether someone is at an elevated risk of colorectal cancer.”

From a biological perspective, the findings reveal a shift in the microbiome early in disease development. This shift is seen in samples collected from a range of countries: the UK and US (with high incidence of colorectal cancer), Argentina and Chile (with intermediate incidence), and Southern India and Vietnam (with low incidence but increasing cases).   

“What’s interesting is that ‘normal’ microbiomes vary dramatically between these countries,” says Phil. “But a consistent story is emerging, independent of the microbiome’s starting point, highlighting a group of bacteria associated with colorectal cancer. We don’t know yet if there’s a causative link between the bacteria and the disease. But the association is good enough when we’re looking to improve screening and trying to identify people at risk.”   

The team members operate in national healthcare contexts with different screening policies. The UK’s population-based National Health Service Bowel Cancer Screening Programme decides who should be referred for colonoscopy by looking for traces of blood in stool samples. Although stool tests are available in the US, screening in the private healthcare system relies heavily on colonoscopy.   

As Phil notes, “It’s less of a concern in the US, but colonoscopy is one of the biggest bottlenecks in the UK’s screening programme. Here, we’ve shown that microbiome analysis could provide a more effective screening approach if combined with looking for blood, which could help reduce the number of unnecessary colonoscopies while ensuring those who need one are referred.”   

The findings also hold promise for use in under-resourced healthcare settings worldwide, such as in developing countries where colorectal cancer incidence is increasing and the screening infrastructure is limited.    

“Freezing stool samples takes significant amounts of storage space; shipping on dry ice is expensive,” explains the studies’ first author, Caroline Young, a histopathologist based at the University of Leeds. “For these studies, we kept everything at room temperature – from sample collection in the pilot nations (Vietnam, Chile, Argentina and India) to shipment to and storage in the UK. The microbiome on the card remains stable enough for screening throughout. Our findings indicate microbiome analysis of gFOBT cards could offer a resource-light protocol, even in very hot countries with limited infrastructure.”

Looking forward, the team has clear plans to explore how their findings could translate to a wider screening programme that might make care accessible to all. The microbial biomarker pilot study will be expanded to examine whether detection of the signature is reproducible across additional populations. The UK screening programme recently moved from gFOBT to the faecal immunochemical test (FIT), a similar stool test with greater compliance and usage by the general population. Will the findings be consistent when this collection method is used? And could probing the microbiome signature reveal more information about the causes and early development of colorectal cancer?

“The question now is how we tie it all together,” Phil muses. “It’s a fascinating story that may lead us to the causes and prevention of colorectal cancer.”   

Written by Emily Farthing.

OPTIMISTICC is generously supported by Cancer Research UK and Nick and Annette Razey. 

This story first featured in our annual progress magazine - Discover: a year of scientific creativity.