Probiotics, Prebiotics, and Synbiotics: Bioactive Foods

Chapter 58

Resistant Starch as a Bioactive Compound in Colorectal Cancer Prevention Amir Amini*, Leyla Khalili†, Ata K. Keshtiban* and Aziz Homayouni* *Department of Food Science and Technology, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran, †Department of Nutrition, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran

1 INTRODUCTION Cancer involves the abnormal division and reproduction of cells that can spread throughout the body. Usually thought of as a single disease, cancer actually consists of more than 100 distinct types. The most prevalent types of cancers diagnosed are prostate, lung and bronchus, colorectal and urinary bladder cancers for men breast, lung and bronchus, colorectal and uterine cancers for women. The American Cancer Society (ACS) predicts that lifetime risk for developing cancer in the United States is slightly less than half of men and a little more than one-third of women. In the United States, cancer is responsible for almost one out of every four deaths annually (ACS: Cancer glossary, 2010. Accessed June, 10, 2010 from http://www.cancer.org/CancerGlossarylindex). Evidence suggests that one-third of more than 560,000 cancer deaths may be attributed to nutrition and lifestyle behaviors such as poor diet, physical inactivity, alcohol use, overweight and obesity. It is estimated that 50-70% of cancer deaths are potentially preventable by decreasing high risk behaviors; with approximately 30% of cancer deaths attributed to poor nutrition (Young, 2000). Most environmental risk factors are theoretically controllable to some extent by avoiding them and supplementing protective factors as much as possible. Major avoidable risk factors include: tobacco, betel quid and chewing tobacco, diet, infection, occupation, alcohol, sunlight, radiation, air pollution, medicine and medical procedures, industrial products, food additives, reproductive factors, sexual behavior, obesity, exercise (sedentary workers) and stress (Forman, 1992). Diet plays an important role in the etiology of cancer, but its relation to cancer is complicated. Excess intake of some food components such as fat and salt and insufficient intake of some other food components such as dietary fiber (DF), fresh vegetables and fruits raise the risks of esophagus, stomach, colon-rectum and breast cancer. It is important to avoid excess intake of fat, calories and salt. However, it is not easy to change dietary habits and food-processing methods. Thus, diet will also remain a major risk factor of cancer in the twentyfirst century (Tominaga, 1999). In epidemiological studies of colorectal cancer (CRC), diet is strongly associated with colorectal incidence rates. Crosssectional, case-control and prospective data demonstrate the increased risks for high meat and fat consumption, whereas a reduction in risk for individuals and populations consuming high amounts of DF and vegetables was seen. In a correlated study, Cassidy et al. determined the epidemiological inverse relationship between total starch intakes, resistant starch (RS) and large bowel cancer risks (Cassidy et al., 1994). It seems that RS may be a major protective factor against CRC.

1.1 Colorectal Cancer CRC is the third most common cancer in the United States and the second leading cause of cancer-related mortality in men and women (Tominaga, 1999). There are approximately 142,500 new cases of CRC per year, the incidence is higher in men than women (National Cancer Institute and US National Institutes of Health: colon and rectal cancer, 2010. Accessed July 1, 2010 from http://www.cancer.gov/cancertopics/types/colon-and-rectal). The highest rates have been seen in whites of northern European origin. Rates in Africa and Asia are lower, but they tend to raise migration and westernization. Factors that increase the risk of CRC include family history, long-term presence of inflammatory bowel disease, familial polyposis, adenomatous polyps and several dietary components. Polyps are considered precursors of colon cancers. Patterns of dietary practices may be more predictive of the risk of developing CRC (Anderson et al., 2004). Additionally food preparation methods may also influence the carcinogenic potential of meats and fatty foods (Dronamraju et al., 2009). There have Probiotics, Prebiotics, and Synbiotics. http://dx.doi.org/10.1016/B978-0-12-802189-7.00058-7 © 2016 Elsevier Inc. All rights reserved.

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774 PART | V Probiotics and Chronic Diseases

been several types of supportive studies regarding the protective role of fruits and vegetables as a group, individual plant foods and high-fiber grains. The use of prebiotics and probiotics alters colonic microbiota, induces glutathione transferase, increases butyrate content of the stool, reduces toxic and genotoxic compounds and in animal models reduces the development of some precancerous lesions (Chau and Cunningham, 2006)

1.2 Preventive Methods The evidences that nutritional factors can promote or inhibit the development of CRC suggest that primary prevention may be essential for the control of this disease. Dietary constituents that have been implicated include fat and excess calories, reduced DF, alcohol, relatively inadequate intake of vitamins (retinoids, ascorbic acid, and alpha-tocopherol), minerals (calcium) and trace elements such as selenium (Cassidy et al., 1994). Cross-sectional, case-control and prospective data demonstrate a reduction in risk for individuals and populations consuming high amounts of DF and vegetables (Cummings et al., 1996a). The attributable population risk from low DF consumption is presently estimated to be 35%. The concept that a diet that is high in fiber, especially from fruits and vegetables, lowers the risk of CRC has been in existence for more than four decades, following the observation of the relative rarity of CRCs in African populations that consume a high-fiber diet (Burkitt, 1969). Fiber has been proposed to dilute or adsorb fecal carcinogens, modulate colonic transit time, alter bile acid metabolism, reduce colonic pH, or increase the production of short-chain fatty acids (Slavin, 2013). Subsequently, the relation between CRC and fiber has been evaluated in case-control and cohort studies. The majority of case-control studies have shown an association between higher intake of fiber and lower risk of colon cancer (Scott et al., 2008). More recently, the World Cancer Research Fund and the American Institute for Cancer Research estimated that 30-40% of cancer incidence could be prevented through good nutrition and exercise. Based on these and similar findings, there have been calls to change dietary habits and improve public awareness of nutrition role in cancer prevention. The fact that only 5-10% of all cancer cases are due to genetic defects, and the remaining 90-95% are due to lifestyle factors (including smoking, diet, alcohol, physical inactivity, obesity, and sun exposure), infections and environmental pollutants provides major opportunities for preventing cancer (Anand et al., 2008). Within the lifestyle factors, it is widely accepted that nutrition and related factors such as alcohol intake, obesity and physical activity play an important role in cancer occurrence. RS has been hypothesized to have specific anticancer properties, because this form of fiber is preferentially fermented into potentially beneficial short chain fatty acids (SCFAs) by selected probiotics in the colon. In preclinical models, animals were fed RS have a lower incidence of intestinal tumors (Le Leu et al., 2007). In humans, RS reduces cell proliferation in the upper part of the colonic crypts (Dronamraju et al., 2009), and some epidemiological studies have supported an inverse association between RS intake and colorectal neoplasia (Young and Le Leu, 2004). The ability of RS to prevent diseases such as cancer and inflammation in the colon has been investigated (Le Leu et al., 2007). Haenen et al. (2013) found that a diet rich in RS modulates microbiota composition, SCFA concentrations, and gene expression in pig intestine. A generous intake of DF reduces risk of developing the following diseases: coronary heart disease, stroke, hypertension, diabetes, obesity, and certain gastrointestinal (Conway, 2001; Le Leu et al., 2009). Furthermore, increased consumption of DF improves serum lipid concentrations, lowers blood pressure, improves blood glucose control in diabetes, promotes regularity, aids in weight loss, and appears to improve immune function (Mikulíková and Kraic, 2005). However, increased intake of DF directly influences the composition of the gut microbiota, promoting the growth of fermentative bacteria leading to increased production of SCFAs. The concomitant lower pH effectively alters the microbial composition, favoring the growth of butyrate producing bacteria (Walker et al., 2011). Increased production of butyrate directly benefits the colonic epithelium by providing the preferred energy source and also by inducing cell apoptosis, both protective factors against the development of colon cancer (Haenen et al., 2013).

1.3 Application of Prebiotics Prebiotics have received much attention as potential cancer prevention agents in the diet. A prebiotic, as defined by Gibson and Roberfroid, is “a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and activity of one or a limited number of bacteria in the colon that have the potential to improve host health” (Gibson and Roberfroid, 1995). A number of poorly digested carbohydrates are categorized as prebiotics, including certain fibers and RSs. Prebiotics have also been linked to the reduction of CRC. Friedenreich et al. concluded in a meta-analysis that the consumption of over 27 g of fiber per day resulted in 50% reduction in CRC compared to consumption of less than 11 g (Friedenreich et al., 1994). Inulin-type fructans that present in foods such as garlic, onion, artichoke and asparagus elevate the levels of bifidobacteria and increase SCFA concentrations in the intestinal lumen. Inulin and oligofructose reduce the severity of 1,2-dimethylhydrazine which induced colon cancer in rats (Clark et al., 2012). A further study demonstrated the

Resistant Starch as a Bioactive Compound in Colorectal Cancer Prevention Chapter | 58 775

c apacity for the prebiotic RS type-3 Novelose 330, to reduce the incidence of colon carcinogenesis via induced apoptosis of damaged cells in rats (Bauer-Marinovic et al., 2006). This effect was attributed to the increased production of butyrate. In another study, the consumption of modified Arabinoxylan rice bran was able to enhance the activity of Natural Killer cells (NK cells) and the binding of NK cells to tumor cells. This demonstrated the ability of prebiotics to enhance the hosts’ immune response (Le Blay et al., 1999). RS has drawn considerable attention over the last two decades due to its demonstrated and putative positive impacts on health (Perera et al., 2010). RS is a component of dietary starch that is not absorbed in the small intestine of healthy individuals and thus like other DFs, reaches the colon undigested. RS is a potential source of fermentable substrate for anaerobic bacteria resulting in the production of gases (CO2, CH4 and H2) and SCFAs (Topping and Clifton, 2001). Butyric acid has generated the most interest as it may be protective against CRC. Butyrate is the primary energy source for colonic epithelium (Wang et al., 2012), and it also inhibits the growth of cancer cells in vitro and forces a more normal differentiated phenotype (Dongowski et al., 2002).

1.4 Treatment Methods There are two options for treatment or controlling of colorectal cancer, either medical or nutritional managements. Medical techniques that are common in cancer therapy are surgery, radiation-therapy, chemotherapy, biotherapy and hematopoietic cell transplantation. It has been suggested that eating behaviors play a very important role in health promotion and disease prevention. Chemoprevention involves specific compounds or drugs used to prevent, delay, or retard the development of cancer (Kashfi, 2009). One of the important dietary compounds that have a significant effect on cancer control and/or treatment are prebiotic compounds that, if they are in adequate amounts, will confer a health benefit on the host. Good nutrition is the groundwork that must be in place before and throughout cancer treatment and recovery. These principles are not optional if optimal outcomes are the objective. Through the scientific application of diet, nutritional supplements, and botanical agents, many of the side effects of conventional treatment can be prevented or ameliorated by protecting healthy cells from cytotoxic effects without interfering with the treatment. Most treatments have acute and long-term side effects that nutrition can address in many ways, including the enhancement and maintenance of the lymphocytic, renal, and hepatic elimination systems (Kendall et al., 2010). During the treatment continuum and follow-up, overall nutrition and nutritional agents are valuable tools for the cancer patient. Additionally, botanical agents concurrently with nutrition therapies are common and can be beneficial. The use of nutrition as a care protocol addresses four main points: (1) protection of healthy cells; (2) prevention and mitigation of specific toxicities related to the treatment of choice; (3) enhancement of therapeutic outcomes and (4) prevention of the onset of long-term side effects related to treatment toxicities (Lamsal and Faubion, 2009). The DF, including the RS, regulates the intestinal transit and is recognized as a modulator of carcinogenesis by the formation of fermentation products in the colon, including SCFAs and particularly the butyric acid, which are preferred substrate by the colonic epithelial cells (Henningsson et al., 2001).

2 RESISTANT STARCH The history of starch usage goes back thousands of years. Study of starch properties has increased in the last two decades. In addition to its proper jelling and adhesive characteristics, starch application in food industry has become extensive. It also provides the main source of energy in human diet. The main food groups containing starch are bread and pasta products (Homayouni et al., 2014). Hipsley was the first scientist who defined DF as non-digestible component of plants cell wall. There have been further improvements in the definition over the years. The American Association for Clinical Chemistry suggested the following statement: “DF is the leftover edible part of plants (polysaccharides, oligosaccharides and lignin) that are resistant to digestion and absorption in the small intestine. Complete or partial fermentation in the large intestine will be the following occurrence” (Buttriss and Stokes, 2008). These beneficial fibers have many health effects on gastrointestinal system that lead to an increase in human health. Activating the growth of advantageous microbiota (probiotics) in colon and increasing the fecal volume are the direct action of DFs. In fact, the result of probiotic fermentation in colon caused a decrease in bowel pH due to the production of SCFA. Prevention of constipation, diabetes, obesity and chronic disease are the most important indirect effects of DFs. These functional fibers are divided into four groups: (1) non-starch polysaccharides (NSPs), (2) lignin, (3) resistant oligosaccharides, and (4) insoluble RS (Westenbrink et al., 2013). There are some structurally analogies between RS and starch. RS is a small part of starch (mainly composed of linear part, amylose) that resist to hydrolysis and confront fermentation by probiotics (mainly Bifidobacterium species).


As mentioned, SCFAs (mainly acetate, propionate and butyrate) caused a reduction of pathogenic bacteria and tumor cells (Sáyago-Ayerdi et al., 2011). Because butyrate is preferential fuel for probiotics, prevention of CRC is more influenced by RS consumption (Conlon et al., 2012). In fact, it is a potent proapoptotic agent that might aid removal of cells with damaged DNA. Colonic production of butyrate by fermentation is associated with reduced tumor mass in an animal model, provided that fermentation is active in the distal colon (Young et al., 1996). The fermentation of RS may be particularly important as a protective factor in CRC because both in vivo and in vitro studies have shown that fermentation of starch increases the amount of butyrate other fatty acids. Butyrate was first suggested as a protective factor in CRC because it is a major product of fermentation in the colon and it is known to suppress cell proliferation (Cummings et al., 1996a). It also inhibits histone deacetylation, leading to arrested growth in the Growth 1 phase and alteration of chromatin accessibility to DNA repair enzymes (Muir et al., 1995). Butyrate induces differentiation in colon carcinoma cell lines and in rodents luminal butyrate levels are inversely associated with colonic cell proliferation, and positively associated with histone acetylation (Jacobasch et al., 2013). High-starch diets fed to mice reduced proliferative activity in the colon (Caderni et al., 2001). Although starch intake is frequently disregarded in dietary surveys, it is possible that RS acted as a major protective factor against CRC. Furthermore, population studies suggest that CRC risk can be lowered by increased RS consumption possibly through increased butyrate production (Cassidy et al., 1994). Fermentation may be important in the prevention of CRC via other effects including altering gut microbiota toward a more beneficial composition microbiota. RS might regulate mutational load in the colon and eliminate DNA-damaged cells that might otherwise progress to malignancy, thereby exerting a protective effect at the early stages in the onset of cancer (Young and Le Leu, 2004). It is reported that consumption of adequate amounts of RS may improve glucose and lipid metabolism in rats, and positive mineral utilization was also reported (Lopez et al., 2001). The effective dosage of RS able to exert these beneficial effects is considered 6-12 g/d; whereas the recommendation for daily intake of other DFs has been 38 g/d (Ötles and Ozgoz, 2014). Bioactive compounds are substances which stimulate the probiotic growth. It has been shown that these components can be used as a “fat controller.” The subtractive effect of RS on rodent fatness was measured by Zheng et al. These effects showed the excellence of RS compared to traditional DFs (Homayouni et al., 2014). It has been reported that RS had a significant reduction effect on fatness; as a result, RS titled as a bioactive component (Tacer Caba et al., 2012).

2.1 RS Types In most of the papers, four RS types were mentioned, though type five (resistant maltodextrins) was considered recently (Cummings and Stephen, 2007; Frohberg and Quanz, 2008; Jiang et al., 2010). Physically inaccessible starch that is protected by botanical cell wall is named RS1. The starch with granular crystalline structure has been known as RS2. RS3 and is found in retrograded starchy foods, while RS4 has been modified by chemical reactions such as cross bonding and esterification. All RS types have many technological merits which makes them superior DF toothers. White color, bland flavor, small particle size, lower water-holding capacity, and higher water-binding capacity than traditional fibers, made it applicable in a wide variety of functional foods (Fuentes-Zaragoza et al., 2010). Food applications of RS were reviewed by some researchers (Asp, 1997; Fuentes-Zaragoza et al., 2011; Homayouni et al., 2014; Sajilata et al., 2006; Sharma and Yadav, 2008).

2.2 RS Health Advantageous Several diseases, especially digestive ones are caused by inadequate or inappropriate diets. It is reasonable to accept an increase in consuming of RS which is among the important indigestible carbohydrates and has approximately half calorific value (8 kJ/g) compared with digestible starch (Topping and Clifton, 2001). Most health effects of RS can be ascribed to its fermentation by the colonic microbiota (Robertson et al., 2000). Therefore, producing SCFA by probiotics makes an environment less liable to the development of cancerous tumors (Yao et al., 2009). Other effects of RS consumption are preventing constipation, increasing excretion frequency and fecal bulk, decreasing production of mutagenic compounds, and lowering the colonic pH and ammonia levels (Fuentes-Zaragoza et al., 2011; Toden et al., 2005). RS can prevent diabetes by lowering postprandial insulin response, increasing insulin sensitivity, lowering postprandial glucose response, and delaying onset of insulin resistance (Nestel et al., 1996). It can reduce total liver cholesterol by causing higher excretion rates of cholesterol and bile acids (Hashimoto et al., 2006; Toden et al., 2005; Topping et al., 2008). Increased absorption of calcium and magnesium by producing SCFA in large bowel is another effect of RS (Scholz-Ahrens et al., 2007; Younes et al., 2001). Reducing energy intake due to its low caloric value that resulting in less appetite, can prevent obesity (Bodinham et al., 2010; Brown, 2004). RS prevent diarrhea by shortening of the duration of rotavirus diarrhea by probiotics (Raghupathy et al., 2006; Ramakrishna et al., 2000). Prevention of CRC is another important benefit of RS. Producing


FIGURE 58.1 Health advantages of resistant starch.

SCFA by fermentation of RS caused by anaerobic bacteria; acetic, propionic, and butyric acid can lower the lumen pH; creating an environment less prone to the formation of cancerous tumors (Homayouni et al., 2014). The most cited health benefits of RS are shown in Figure 58.1.

3 EPIDEMIOLOGICAL STUDIES Consumption of fiber and RSs is well-thought-out as the protective step in prevention of colon cancer. A number of previous cross-sectional studies have made international comparisons between dietary intake and CRC incidence (Birt and Phillips, 2014; Cassidy et al., 1994; Chau and Cunningham, 2006). The strong inverse associations found by Cassidy et al. together with other data, suggest an important, though not exclusive, role for starch in protection against CRC. The hypothesis is that fermentation in the colon is the mechanism for achieving CRC protection, via the specific contribution of butyrate to reduce the proliferation and induction of differentiation (Cummings et al., 1996b). This demonstrates a preference for butyrate production by the bacterial flora when starch is the main substrate for fermentation. The documented laxative effects of starch in addition to those of NSPs and the protective relation between increased stool weight and CRC, all suggest a mechanism for the epidemiological associations (Cummings and Macfarlane, 1997a,b). In contrast to the limited number of human interventions evaluating dietary RS, several studies have been done on laboratory animals about the impacts of RS on the prevention of colon cancer. Le Leu et al. conducted extensive studies on rats treated with the colon carcinogen Azoxymethane and/or fed diets high in protein to damage the colonic epithelium. Feeding high fiber or RSs increased fecal bulk, fecal pH, butyrate concentration and epithelial apoptosis, and it decreased cell proliferation markers and colon carcinogenesis (Le Leu et al., 2002, 2007). A meta-analysis of six case-control studies found that a high intake of fiber was associated with an approximate 40-50% reduction in risk of colon cancer (Kumar et al., 2012). Nofrarías Martínez-Puig, Pujols, Majó and Pérez found that pigs fed a diet-containing RS had higher concentration of butyrate in the colon, and the fermentation of raw potato starch (RS2) decreased peripheral T-cell populations and immune reactivity and apoptosis in the colon (Martínez-Puig et al., 2007).

4 CONCLUSION Previous studies showed that the prevention of CRC was significantly influenced by the presence of butyric acid in the large intestine. Butyrate was first suggested as a protective factor in CRC because it is a major product of fermentation in the colon, and it is known as a suppressor of cell proliferation. It also inhibits histone deacetylation and alteration of chromatin accessibility to DNA repair enzymes. Butyrate induces differentiation in colon carcinoma cell lines. Epidemiological data suggest that RS is protective against CRC, possibly via butyrate. Both in vivo and in vitro studies have shown that


fermentation of starch increases the amount of butyric acid formed compared to other fatty acids. High-starch diets fed to mice reduced proliferative activity in the colon. In fact, consumption of RS caused a high fecal bulk which is a key effect to the excretion of tumor or pathogen cells. With regard to the important role of RS in diet and its capability to be a source of prebiotic component, the food industry is showing more interest on this natural bioactive ingredient.

ACKNOWLEDGMENT The authors sincerely thank to Dr. Alikhah from Shervin Publishing Group. We also declare herein that we have no conflict of interests.

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