Gut Microbiome Variations May Be Predictive of Precancerous Colonic Lesions, CRC

People with precancerous colonic lesions show significant differences in their gut microbiome compared to the general population up to 5 years before the lesions develop, according to a large, 22-year analysis from the Dutch Microbiome Project cohort study.

The findings suggest a possible role for gut microbiota in the development of colorectal lesions and cancer, said study lead Ranko Gacesa, PhD, from the Department of Gastroenterology, University of Groningen, the Netherlands, who presented the results here at the United European Gastroenterology (UEG) Week 2023.

"It [also] suggests that gut bacteria might enhance currently used noninvasive fecal tests for the detection of colorectal polyps, and even that microbiome-modulating therapies might play a role in prevention of colorectal cancer," said Gacesa, who won the award for best abstract in the meeting session.

The gut microbiome is known to be linked to colorectal cancer (CRC); in particular, the bacteria Bacteroides fragilis and Alistipes finegoldii  have been found to cause CRC in mouse models, explained Gacesa.

In the current study, Gacesa and colleagues looked at the potential for the gut microbiome in humans to play a role in the detection of precancerous colonic lesions. The noninvasive fecal immunochemical test (FIT), recently shown to be a preference among patients, produces a high number of false-positive results, leading to many unnecessary colonoscopies.

"It has been calculated that the use of a fecal microbiota analysis combined with FIT in the early-stage prediction of CRC could result in a high true-positive rate and a low false-positive rate," said Gacesa. "In this way, we might reduce the false-positive rate by around 50%."

"Ideally, we don't want to detect cancer when it is already established and is hard to treat. We want to detect it as early in its development as possible," he said.

Longitudinal Analysis Using Large Dutch Databases

To determine the direction of the relationship between CRC and the gut microbiome, the Dutch researchers conducted a longitudinal analysis from 2000 to 2022, looking at whether CRC alters the gut microbiome, as well as whether changes in the microbiome contribute to the development of precancerous lesions and CRC.

They drew on data from the Dutch colorectal cancer screening program, comprising FIT results in people aged 55 years and older, and colonoscopy if referred. They recorded cases of colonic biopsies from the extensive Dutch national database of medical biopsies (PALGA). These were then linked with Dutch microbiome project data sourced from fecal samples of 8208 individuals taken between 2012 and 2015.

"This allowed us to associate gut microbiome compositions and functions to detailed histological information about precancerous lesions and CRC, including when lesions were detected relative to fecal sampling [and a reading of the gut microbiome]," Gacesa explained.

The analysis determined the composition, function, and genomic profiles of gut microbiota in participants who developed precancerous colorectal lesions before fecal sampling from 2000 to 2015, and in those participants who developed lesions after fecal sampling, between 2015 and 2022. Clinical phenotypes, comprising the type and size of lesions, were noted. The control group included 2123 individuals from the general population with normal colonoscopy findings.

More Precancerous Lesions Found After Fecal Sampling

There were more cases of precancerous lesions found after fecal sampling, reported Gacesa.

Before fecal sampling, 219 participants had colonic lesions, including low-grade dysplasia, high-grade dysplasia, and serrated polyps, and 26 cases of CRC. A total of 315 participants developed assorted colonic lesions after fecal sampling, with a total of 29 cases of CRC.

When the researchers looked at microbiome diversity in people who had experienced precancerous colonic lesions 1 to 5 years before fecal sampling, they found that diversity was lower compared to controls. Microbiome diversity was also decreased in participants who developed colonic lesions after sampling.

The microbiome composition and function were different between patients with preexisting and future lesions, and varied based on the types of lesion.

"We saw a drop in some commensal bacteria, including Faecalibacterium, in both those with recent pathologies and those who developed them in the future. We also saw a massive spike in Alistipes finegoldii in those who had CRC, strongly suggesting it is closely linked to CRC in people," reported Gacesa.

Among bacterial species linked with the future development of precancerous lesions were those from the family of Lachnospiraceae, and the genera Roseburia and Eubacterium. Microbiome composition had a moderate predictive power for future lesions and CRC.

"Precancerous lesions are linked to the gut microbiome," Gacesa said. "Adenomas — both preexisting ones (before fecal sampling), and ones that came after fecal sampling — are significantly linked to the microbiome composition."

More Time Needed

Loris Lopetuso, MD, gastroenterologist, from Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy, who co-moderated the session, remarked that the data were intriguing and important.

"We really need to find new predictors of tumorigenesis," he said. "We already have some good predictors, mainly FIT, but these are not enough. These gut microbiota look promising."

He added that the study by Gacesa's team was one of the largest he had seen. "But I would note that, methodologically, we need to remember that the time between a fecal sample and the development of polyps can be very large," Lopetuso emphasized. "This study looked at around 5 years only. Also, the microbiota can change from one day to the other in response to stress, diet, and many other things."

However, "this could be the beginning of a longitudinal study between cases and controls because many years are needed," he added.