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Colorectal cancer (CRC) is a major global health burden as its ranks third in terms of incidence and second in mortality worldwide. It has increased steadily in recent years, including in younger age groups. As with many chronic diseases, it is the interaction between genetic and environmental factors (also referred to as “exposome”) that determines the risk for CRC development and outcome. Environmental risk factors include western dietary habits, smoking, obesity, diabetes, and heavy alcohol consumption, with the gut microbiome playing an important role of mediating between environmental factors, in particular our diet and the development (“carcinogenesis”), formation and progression of CRC.

“Scientific evidence has demonstrated associations between CRC prevalence, and the composition and function of the gut microbiota…”

The gut microbiome plays an important role in energy homeostasis, keeping the intestinal epithelium intact, protecting against pathogenic organisms, and maintaining a healthy immune system. Emerging evidence has demonstrated associations between CRC prevalence, and the composition and function of the gut microbiota, suggesting a role of the gut microbiome in colorectal carcinogenesis. Much of the focus on microbiome research in CRC has been on microbes as pathogenic drivers of CRC, in the hope that these efforts can be leveraged for preventive, diagnostic, and therapeutic purposes. Human data and data from mechanistic studies in cell culture and animal models support a role of specific microbes as potentiators of tumor development — including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, colibactin-producing Escherichia coli and Peptostreptococcus anaerobius. Chronic low grade immune system activation of the colon also plays an important role the development of dysplasia and CRC. For example, in patients with inflammatory bowel disease, chronic, severe inflammation of the colon increases the likelihood of developing CRC. More subtle inflammation, such as the changes occurring in individuals with metabolic endotoxemia in otherwise healthy colonic tissues plays an important role in the conversion of a healthy colon to one with dysplastic, precancerous lesions. Disruption of the intestinal barrier by inflammatory mediators facilitates bacterial translocation from the intestinal lumen into the gut-associated immune system and into the systemic circulation and, ultimately, exposure of immunogenic microbial compounds to both epithelial cells and antigen-presenting cells. Activation of immune signaling pathways by bacterial stimuli results in a loss of homeostasis that drives an inflammatory environment conducive to the development of colon cancer. The presence of colorectal adenoma, the early stage of CRC, has also been found to be associated with changes in the gut microbiome, raising the possibility of future use of such microbiome changes as biomarkers enabling screening tests and early diagnosis.

The changes in the gut microbial ecosystem have been attributed to key dietary factors in the Standard American Diet (SAD), such as low intake of fruits and vegetables, high consumption of animal-based products, and ultra-processed foods. There are multiple mechanisms and pathways through which the gut microbiota can affect CRC formation and progression, including inflammation, tumor-inducing metabolites, genotoxins, and oxidative stress.

“Emerging evidence confirms that colorectal cancer and gut microbiome composition and diversity alterations are directly correlated, suggesting a role of the intestinal microbiota in colorectal carcinogenesis”.

Based on a number of large epidemiological studies, largely plant-based and vegetarian-style diets such as the traditional Mediterranean diet, with consumption of an abundance and variety of fruits, vegetables, nuts and whole grains, low in red meat, and especially processed meat have been associated with a low risk for developing CRC, and have been recommended as an important component of CRC prevention measures. Even though it remains to be determined, which individual component of the Standard American Diet (SAD) is the main factor underlying the increased prevalence of colon cancer, the high consumption of red meat and dairy products has been implicated as potential risk factor in a number of studies. However, a recent meta-analysis published in the prestigious journal Nature Medicine of epidemiological studies on the association of unprocessed red meat consumption and several health outcomes, including CRC, failed to show a significant correlation. Regardless of the causative role of red meat in colon carcinogenesis, the more colorful the meals, the better, as the plant compounds responsible for the various colors of vegetables and fruit which often belong to the polyphenol group have been shown to have beneficial effects on the gut microbiome, and may reduce the risk for the development of colon cancer. Altogether, diets made up to 75% of fruits and vegetables and low in animal products are the most recommended for protection from CRC.

“…one would expect that dietary assessment and nutrition counseling would be an integral part of CRC prevention programs.”

In view of the close relationship between diet, the gut microbiome and CRC risk, one would expect that dietary assessment and nutrition counseling would be an integral part of CRC prevention programs. This relationship may be one of the drivers of increasing CRC risk in younger age groups, which has resulted in lowering of the recommended age for colon cancer screening, but not in increased efforts in dietary counseling. Such efforts are nearly absent in gastroenterology practices with large numbers of colon cancer screening, and the topic of diet has largely been absent in the recent discussions about the most cost-effective approaches to colon cancer screening.

By Emeran Mayer, MD and Jill Horn