Yogurt Consumption and Colorectal Cancer Risk Reduction

Introduction: Colorectal Cancer and Lifestyle Risk

Colorectal cancer is the third most common cancer in the world, with over a million people developing the disease each year (reviewed by Touvier et al., 2011; Aune et al., 2011; Pala et al., 2011; van Duijnhoven et al., 2009). The worldwide distribution of this disease is uneven, with developed economies such as North America and Western Europe generally having the highest prevalence rates. This fact lends significant support to the theory that the disease is primarily caused by lifestyle choices. Americans, for example, have one of the highest prevalence rates in the world, with a lifetime disease risk of 1 in 20 (National Cancer Institute [NCI], 2011). For the general population, the chance of dying from colorectal cancer is only 0.02%, but once diagnosed, the risk of death increases dramatically. The median age at first diagnosis is 70, and the chance of survival depends on several factors, including the stage of disease. In terms of age, survival reaches its lowest point (70%) between the ages of 75 and 84.

Genetics plays a small role in determining colorectal cancer risk, so a large number of studies have focused on risk contributions from environmental factors. In a large cohort study of middle-aged men, it was found that up to 71% of colorectal cancer risk can be attributed to lifestyle choices (Platz et al., 2000). This study examined the relative contributions of obesity, physical inactivity, alcohol consumption, previous smoking experience, red meat consumption, and folic acid dietary supplementation. Fruit and vegetable consumption (van Duijnhoven et al., 2009), vitamin D dietary supplementation, and dairy products (Aune et al., 2011) were also found to lower colorectal cancer risk. What we eat and drink therefore significantly determines our risk of developing cancer of the colon.

The Role of Gut Microflora

The gut is filled with an extraordinary number and variety of bacteria essential for digestive processes, nutritional needs, and colon health. It could therefore be argued that the gut microflora represents a first line of defense against consumption-induced trauma to the colon. Between 500 and 1,000 bacterial species normally colonize the human gut, and the population size can reach 100 million in a single host (reviewed by Sun, 2010).

The ability of this microenvironment to support colon health can be harmed by events such as a course of antibiotic treatment or ingestion of pathogenic bacteria, and the mechanisms involved in the latter are actively being investigated by researchers (reviewed by Sun, 2010). After colonizing the gut of mice with Salmonella, the stem cell compartment within the colon was found to be activated through the Wnt/β-catenin pathway, leading to epithelial dysplasia. Helicobacter pylori infections can lead to the formation of gastric ulcers and cancer, and studies using infected mice suggest that part of the signaling induced by the H. pylori infection is mediated by STAT-3 via the bacterially produced protein CagA. Activation of the JAK-STAT pathway by Salmonella may occur through a similar mechanism. These studies reveal that pathogenic bacteria directly modify mucosal cell function through the secretion of bacterial proteins. Other studies have found that colon epithelial cells respond to pathogenic infections by secreting antimicrobial peptides. The intestinal mucosa and immune system therefore interact directly at a molecular level with bacterial pathogens.

The role of the gut microbiome in protecting the colon from pathogenic infections was revealed when cancer patients undergoing colorectal resections were treated in a blind, randomized, placebo-controlled study with live probiotic organisms for several days before and after surgery (Gianotti et al., 2010). Laboratory tests indicated that probiotic treatment resulted in an immune profile consistent with the induction of tolerance, which included reduced lymphocyte proliferation rates after an in vitro lipopolysaccharide challenge and the relative absence of activated dendritic cell markers. In a mouse model for spontaneous inflammatory bowel disease (IBD), the administration of probiotics provided a significant anti-inflammatory effect, reduced colon injury, and offered protection against the emergence of pathogenic bacterial species (Xia et al., 2011). The gut microbiome therefore provides an important defense against inflammation and infections.

The immune response to infections is critical for protecting the colon from a variety of pathogens, and this response appears to depend on the evolutionary and lifetime infection history of an individual (reviewed by Bernstein, 2010). Some individuals, for example, are genetically predisposed to develop IBD, and the source of this predisposition has been traced to variations in DNA sequences encoding important immune regulators. Research has revealed that these sequence variations have probably evolved due to selection pressures imposed by specific parasites and pathogenic microbes encountered at some point in our evolutionary history. Persons with different ethnic backgrounds would therefore carry different sets of sequence variations due to the geographic differences that helped define ethnicity. In contrast, the "Hygiene Hypothesis" proposes that a lack of exposure to pathogens during childhood results in an immune system that failed to mature properly and is thus susceptible to dysregulation. This hypothesis is supported by the higher prevalence rates of IBD and colorectal cancer in developed countries, since the former represents an autoimmune disorder and the latter a failure in immune surveillance. A healthy gut microbiome could therefore provide a functional buffer between an inherited propensity for developing an immune-mediated disease of the colon, by promoting tolerance and protecting against infections.

Given the evidence supporting a causal link between inflammation and many different types of cancers, including IBD and colorectal cancer (Soderlund et al., 2010), the health of gut microflora would be predicted to influence colorectal cancer risk. Supplementing the diet with live-culture yogurt in IBD patients increased the number of regulatory T cells, reduced the prevalence of activated TNF-α+/IL-12+ monocytes and myeloid dendritic cells, decreased the number of IL-2+/CD69+ T cells, and lowered serum levels of IL-12 (Baroja, Kirjavainen, Hekmat, and Reid, 2007). In an experimental IBD mouse model, yogurt increased the number of IgA+ and apoptotic inflammatory cells and reduced CD8 T cell numbers in the large intestine (Gobbato, Rachid, and Perdigon, 2008). These studies suggest that the gut microbiome in the human intestine provides protection against inflammation, and therefore by extension against colorectal cancer.

References

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