**2. Colon cancer**

Social and economic transformations related to urbanization and industrialization in Brazil resulted in changes in the morbimortality profile of the population. While, in the first half of the 20th century infectious disease event were the most frequent, from the 1960 metabolic diseases and noncommunicable grievances occupied the first place, contributing to the process of demographic transition, which favours the spread of cardiovascular and respirator disease, cancer and diabetes, as does the nutritional transition, with a marked reduction of malnutrition and large growth in the number of overweight people [14].

Known for many centuries, cancer was widely regarded as a disease of developed countries with large financial resources. However, for approximately four decades, this situation has undergone transformation, and most of the global burden of cancer can be observed in developing countries, especially those with low to medium resources [15].

Cancer has become a global public health problem of course, since the World Health Organization (WHO) estimates that in the year 2030 there will be 27 mil new cases of cancer, 17 million deaths and 75 million people living with the disease [15].

Cancer of the colon and rectum is the third commonest type of cancer among men and the commonest in women. It is estimated that in 2011, in Brazil, 14,180 new cases of colon cancer and rectum, occurred in men and women. These values correspond to a perceived risk 15 new cases per 100 thousand men and 16 per 100 thousand women [15].

This neoplasia is considered to have a good prognosis when diagnosed in the early stages. Colon cancer like others forms of cancer develops as a result of interaction between endogenous and environmental factors. Among the factors that may affect the risk of developing this disease are age, eating habits, physical activity, alcohol consumption, smoking, nutritional status, presence of polyps, cancer history of self and family, cases of ulcerative enterocolitis and chronic constipation [15,16].

218 Lactic Acid Bacteria – R & D for Food, Health and Livestock Purposes

probiotics on colon cancer development.

and colon cancer prevention.

**2. Colon cancer** 

immune system [1,3].

composition and the metabolic activities of the intestinal microbiota, the changing physicochemical conditions in the colon, the binding of dietary carcinogens, the production of short chain fatty acids (SCFA), the protection of the colonic mucosa and enhancement the

The anticarcinogenic effects of probiotic microorganisms *in vitro* and in animal studies are well documented [3]. In clinical trials, the probiotics are thought to play a protective role in the initial process of carcinogenesis. Nevertheless, it is important to determine whether the long-term administration of these microorganisms might result in changes in the incidence of CC in humans [13]. Additionally, there are several challenges for the development of probiotics, including the selection of the appropriate microorganisms, control of dietary intake, time and frequency of probiotic dosing and the use of accepted biomarkers for raised cancer risk that might be monitored during clinical trials [4,13]. Further experimental models are needed to understand the exact mechanisms involved in the influence of

Therefore, this chapter will discuss the effects of probiotics in colon cancer prevention and the possible mechanisms of action these microorganisms. Additionally, this chapter will also show the results of original work, carried out by our research group, about the effects of probiotic *Enterococcus faecium* CRL 183 (strain isolated from Tafí cheese, a homemade traditional highlands cheese the province of Tucumán, Argentina) on intestinal microbiota

Social and economic transformations related to urbanization and industrialization in Brazil resulted in changes in the morbimortality profile of the population. While, in the first half of the 20th century infectious disease event were the most frequent, from the 1960 metabolic diseases and noncommunicable grievances occupied the first place, contributing to the process of demographic transition, which favours the spread of cardiovascular and respirator disease, cancer and diabetes, as does the nutritional transition, with a marked

Known for many centuries, cancer was widely regarded as a disease of developed countries with large financial resources. However, for approximately four decades, this situation has undergone transformation, and most of the global burden of cancer can be observed in

Cancer has become a global public health problem of course, since the World Health Organization (WHO) estimates that in the year 2030 there will be 27 mil new cases of cancer,

Cancer of the colon and rectum is the third commonest type of cancer among men and the commonest in women. It is estimated that in 2011, in Brazil, 14,180 new cases of colon cancer and rectum, occurred in men and women. These values correspond to a perceived risk 15

reduction of malnutrition and large growth in the number of overweight people [14].

developing countries, especially those with low to medium resources [15].

17 million deaths and 75 million people living with the disease [15].

new cases per 100 thousand men and 16 per 100 thousand women [15].

Most cases of CC occur sporadically, being the most common type of adenocarcinoma, which develops from glandular cells that cover the wall of the intestine [17]. Adenocarcinomas grow from normal epithelium through an accumulation of mutations that result in malignant transformation [19].

Genomic instability is fundamental to this process and is related to the rearrangement of genes, or loss of DNA fragments, aneuploidy and loss of heterozygosis [19]. In addition, inactivation of tumor suppressor genes, such as APC, DCC, DPC4 and p53, along with the activation of oncogenes, of which the family of *ras* genes are the best well described, play important parts in the appearance of malignancy [17].

Generally, the colon tumor is detected for the first time as a polyp (mass of cells growing out of the wall of the colon), although nowadays it is possible to detect small lesions affecting the crypts, called aberrant crypts foci (ACF) [18]. ACF are not only morphologically but also genetically distinct lesions and are precursors of adenoma and cancer. Tumors can appear anywhere in the colon, although most sporadic rectal colon cancers are located on the left side of the distal colon (including the rectum and sigmoid colon) [19].

Epidemiological studies have pointed to the high consumption of red meat, fat and low fiber intake, typical of the Western diet as risk factors in the etiology of this type of cancer [20].

One of the possible effects of a Western diet on colon cancer is related to increased excretion of bile acids [21]. In addition, the increased ammonia production in rats consuming a diet rich in protein has also been linked to an increased risk of cancer [22]. However, high consumption of fruits, cereals, fish and calcium may reduce the risk of developing colon cancer [23].

The effect of diet on carcinogenesis can be modulated by changes in metabolic activity and composition of the intestinal microbiota [23]. Several studies have trial to establish relationships between bacteria and colon cancer. We know that various bacterial metabolites are carcinogenic, examples being, the nitrosamines, phenol, indole, ammonia and amines [13].

There is multiple evidence that bacteria play a key role in the emergence of chronic inflammatory bowel diseases. Experimental studies demonstrate the impossibility of developing this inflammation in the absence of bacteria and researches have tried for many years trying to identify a possible causative agent of inflammatory bowel diseases. Studies suggest that chronic inflammatory intestinal activity seems, paradoxically to be triggered by bacteria belonging to the normal commensal which take on microbiota in situations as yet unknown, a pathological role that can activate the local immune apparatus [24].

There are many types of intestinal bacteria that produce a variety of metabolites that modulate the normal development and functioning of the host. On the other hand, the metabolic activity of intestinal microbiota can generate compounds that are harmful such as reactive oxygen intermediates. These molecules, which include superoxide, hydrogen peroxide, hypochlorous acid, singlet oxygen and hydroxyl radical, can cause oxidative damage to cellular DNA and increase the risk of colon cancer [25]. Studies have shown that *Enterococcus faecalis* can produce superoxide and hydrogen peroxide, causing damage to DNA in skin cells, in both *in vitro* and *in vivo* tests [26].

Probiotics and Intestinal Microbiota: Implications in Colon Cancer Prevention 221

With advances in molecular biology, it is known that the intestinal microbiome, contains 100 times more genes than the whole human genome [34]. Thus, a close relationship is evolving between the human gut microbiota. The human intestine exhibits to a symbiotic relationship that plays a key role in human homeostasis, including metabolism, growth and immunity

One of the primary functions of the intestinal microbiota is the harnessing of energy from elements of the diet that could be lost through excretion [36]. The polysaccharides are not absorbed in the colon, but metabolized by resident microorganisms to short chain fatty acids (SCFA), such as propionate and butyrate, which are absorbed by passive diffusion [37]. SCFA production is dependent on the available fermentation of substrate, such as, starch or other polysaccharides, results butyrate, acetate and propionate [37]. SCFA concentrations are higher on the right side of the colon than on the left and this is probably due to the greater availability of carbohydrates [29]. The SCFA have an important role in the maintenance of the epithelial layer. Studies show that epithelial cells acquire about 70% of their butyrate oxidation [29]. The butyrate also acts as a trophic factor for cells in intact tissues [38]. In addition, it has been proposed that butyrate lowers the risk of colon cancer by its ability to inhibit the genotoxic activity of nitrosamines and hydrogen peroxide, as well as to induce various levels of apoptosis, differentiation and the cell cycle stop colon cancer

Other researchers also cite the effect of butyrate on mediators of inflammation, it has been proved that this SCFA is able to inhibit the expression of some cytokines (TNF, IL-6, IL-1) and to inhibit the activation of nuclear factor B (NF- B) [40]. Other functions of the gastrointestinal microbiota include digestion of poorly digested nutrients, modification of bile acids, and nutritional supplementation by auxotrophic of mutants additional compounds that cannot be acquired by food consumption, such as folic acid and biotin [41]. The non-pathogenic commensal microbiota has a profound impact on the normal physiology of the GI tract. It ensures the efficiency of bowel motility, intestinal growth and immunity, as well as digestion, nutrient absorption and fortification of the mucus barrier

Researchers have made advances in the characterization of GI microbiota defining the responses that may contribute to the development of inflammatory bowel diseases, such as, colon cancer [43]. Given the importance of a better understanding of intestinal microbiota, the TGI has been often studied. In recent decades, various intestinal simulators have been and are being developed, to facilitate the study of the intestinal microbial ecosystem and its

The FAO/WHO refers to probiotics as live microorganisms that administered in adequate doses, benefit the health of the host [11]. The beneficial effects of ingesting probiotics

**3.2. Methods for** *in vitro* **evaluation of effects of probiotics on intestinal** 

[35].

in animal models [39].

[42].

interactions [44, 45].

**microbiota** 

Given the role of intestinal microbiota in colon carcinogenesis, it is suggested that factors that modulate beneficially the composition and/or activity of the microbiota could inhibit the development of CC.
