¶ … Medicine Yogurt Consumption Lowers Colorectal Cancer 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 though, with developed economies like North American and Western Europe generally having the highest prevalence rates. This fact lends significant support to the theory that this disease is primarily caused by lifestyle choices. For example, Americans 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 determines our risk of developing cancer of the colon.

The Role of Gut Microflora

The gut is filled with an amazing number and variety of bacteria essential for digestive processes, nutritional needs, and colon health and therefore it could be argued that the gut microflora represents a first line of defense against consumption-induced trauma to the colon. Between 500 and 1000 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 such events 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/?-catenin pathway, leading to epithelial dysplasia. Helibacter pylori infections can lead to the formation of gastric ulcers and cancer, and studies using infected mice suggest part of the signaling induced by the H. pylori infection is mediated by STAT-3 via the bacterial-produced protein CagA. Activation of the JAK-STAT pathway by Salmonella may occur through a similar mechanism. These studies reveal pathogenic bacteria directly modify mucosal cell function through the secretion of bacterial proteins. Other studies have found 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 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 provided protection against the emergence of pathogenic bacteria 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 seems to depend on the evolutionary and lifetime infection history for 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 sequence encoding important immune regulators. Research has revealed that these sequence variations have probably evolved due to selection pressures imposed by a specific parasite and pathogenic microbe burden encountered at some point in our evolutionary history. Persons with different ethnic backgrounds would therefore...

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-?+/IL-12+ monocytes and myeloid DC 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 the gut microbiome in the human intestine provides protection against inflammation, and therefore by extension against colorectal cancer.

Probiotics and Colorectal Cancer Risk

Although dairy products in general have been shown to reduce the risk of colorectal cancer (Aune et al., 2011) the protective effect of live-culture probiotics in the form of yogurt has not been determined. To address this issue Pala et al. (2011) conducted a prospective study using a large Italian cohort that was originally recruited as part of a pan-European study (EPIC) investigating the link between nutrition and cancer.

Methods

A total of 45,241 subjects were recruited for the current study and the male to female ratio was approximately 1:2. Exclusion criteria at the beginning the study period was cancer (except for non-melanoma skin cancer), incomplete patient information, and an extreme ratio in either direction for total energy consumption and basal metabolic rate.

Information on the diets of the study subjects was collected through validated questionnaires that probed their lifestyles. Additional information was also collected that was used to control for possible confounding variables, which are as follows:

Yogurt Lowers Colorectal Cancer Risk 12

Smoking status

Education

Gender

Profession

Physical activity

Body mass index (BMI)

Alcohol

Red meat

Animal fat

Calcium

Fiber

Simple sugar

The frequency of occurrence for lifestyle habits were also graded into three or more categories. For example, physical activity was categorized as recreational, sporting, or job related. The primary outcome measure was a diagnosis of colorectal cancer, which in turn was divided into cancer of the proximal or distal colon, overlapping lesion, not otherwise specified colon cancer, or rectal cancer.

Outcome

During the 12-year follow-up period 116 men and 173 women (289 total; 0.64%) were diagnosed with colorectal cancer (Table 1). Of these, 215 had cancer in the colon and 74 in the rectum. The mean follow-up period was 9 years and the mean age at enrollment was 51. The mean age at the end of the follow-up period was 60 with an age range of 30-86.

Yogurt consumption was stratified into three tertiles for men and women (Table 2; none, 10 g per day, or almost 100 g per day), so that a dose response effect might be obtained and to determine whether gender modifies the association between yogurt consumption and cancer risk. In general, people who ate very little yogurt tended to consume more red meat, fiber, alcohol, and had less education (Table 3).

Calculations of an association between yogurt consumption and cancer risk utilized three separate models: Model 1 corrected for energy intake levels only, Model 2 corrected for energy levels, red meat, calcium, fiber, animal fat, and simple sugars, and Model 3 corrected for all variables in model 2 plus alcohol, smoking, education, BMI, and degree of daily physical activity. Overall, yogurt consumption lowered cancer risk (hazard ratio (HR) for model 1 = 0.62, model 2 = 0.64, and model 3 = 0.65). These results therefore indicated yogurt provides a significant reduction in cancer risk. In addition, the three tertiles of yogurt consumption revealed a significant linear dosage response (p = 0.001/0.002). Interestingly, the fat content of the yogurt did not alter the protective effect.

When the results were stratified using the three models, men…