- A growing amount of epidemiologic and mechanistic evidence suggests that environmental factors (diet/lifestyle choices) and changes in the gut microbiome work together to influence the development of colorectal cancer (CRC)
- CRC risk factors that are have been linked to the gut microbiome include overweight and obesity, Western diets, intake of red and processed meat, alcohol consumption and smoking
- There is also evidence for links between the gut microbiome and factors that are thought to protect against CRC: physical activity; intake of fiber, marine omega-3 fatty acid, vitamin D and dairy; and metformin use
- Better understanding of these relationships may lead to development of gut microbiota–based strategies for CRC prevention
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Despite better adherence to screening, reductions in certain risk factors and advances in treatment, colorectal cancer (CRC) is still the third-most common cancer in the U.S. and the third leading cause of cancer-related deaths. This continued burden highlights the critical need to consider prevention strategies beyond screening.
One answer seems to be the gut microbiome, the trillions of microbes in the large intestine that encode 100-fold more unique genes than the human genome. A growing amount of epidemiologic and mechanistic evidence suggests that both diet, lifestyle choices and gut microbiome are linked to the development of CRC.
Mingyang Song, MD, ScD, assistant professor in the Department of Medicine at Massachusetts General Hospital, and Andrew T. Chan, MD, MPH, director of the Gastroenterology Training Program and a physician at the Mass General Cancer Center, believe better understanding of these relationships may lead to the development of gut microbiota–based strategies for CRC prevention. They review the evidence in Clinical Gastroenterology and Hepatology.
Overweight and Obesity
The gut microbiota appears to have a vital role in obesity-related metabolic alterations, including inflammation and insulin resistance. Moreover, both obesity and weight loss can induce substantial changes in the composition of the microbial community.
Now, a picture is emerging of how the gut microbiota might directly influence the relationship between obesity and CRC:
Increases in microbial-derived proinflammatory molecules disrupt the function of the gut barrier
Epigenetic changes (in colonic epithelial cells or in DNA methylation) change gene expression
Increased production of microbial metabolites and inflammatory mediators (e.g., secondary bile acid, prostaglandin E2) damage DNA and decrease antitumor immunity
Gut microbial structures and metabolite profiles differ dramatically between populations that consume different diets. For example, compared with people in the U.S., rural Africans whose diet is rich in fiber and low in fat have a lower abundance of potentially pathogenic proteobacteria. In turn, the prevalence of CRC is lower in Africa than in Western countries.
As another example, native Africans have a higher fecal level of short-chain fatty acids (SCFAs) than African Americans do. SCFAs have been shown to protect against CRC through beneficial effects on the immune and metabolic pathways.
Red and Processed Meat
Researchers also note the impact of red and processed meat on gut microbiota. For instance, heme iron in meat increases the abundance of mucin-degrading bacteria, leading to disruption of the colonic mucus barrier that separates gut bacteria from the host.
Additionally, the high content of saturated fat in red and processed meats is associated with increased secretion of bile acids. Most are reabsorbed in the small intestine, but those entering the colon are metabolized by anaerobic bacteria into secondary bile acids, which can induce DNA damage and apoptosis resistance.
Sulfur is present in amino acids from red meat and is routinely used as a preservative in processed meat. Sulfur-reducing bacteria in the colon lead to increased hydrogen sulfide, which can promote carcinogenesis through a variety of mechanisms.
Several lines of evidence indicate that the gut microbiota has a role in the tumorigenic effect of alcohol:
In humans, chronic alcohol consumption causes structural changes in the gut microbiota that have been linked to intestinal bacterial overgrowth and hyperpermeability of the gut barrier. This can result in the release of gram-negative microbial bacterial products into the systemic circulation, including endotoxins, which have been linked to systemic inflammation
Rats chronically exposed to alcohol display significant changes in numerous metabolic pathways including a significant decrease in SCFAs
Structural alterations of the gut microbiota in high consumers of alcohol appear to increase intracolorectal acetaldehyde to such high levels that it can initiate carcinogenesis
Smoking-associated changes relevant to CRC are thought to include ingestion of bacteria present in cigarettes, impaired clearance of pathogens, changes in the virulence of bacteria and fungi, immune disruption, and altered growth and structure of gut bacteria known to contribute to dysbiosis.
Smoking-related microbial changes may lead to altered composition of the mucus layer and increased inflammatory response. In addition, some in vitro and animal studies have found that cigarette smoke might decrease the production of SCFAs. Smoking cessation has been shown to restore, at least partly, the diversity of the gut microbiome.
Dr. Song and Dr. Chan also reviewed the evidence for links between the gut microbiome and factors that are known or suggested to protect against CRC: physical activity; intake of fiber, marine omega-3 fatty acid, vitamin D and dairy; and metformin use.
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