Health Benefits of Symbiotic Functional Food Products

22 Health Benefits of Symbiotic Functional Food Products A. Anas Al-Nabulsi, S. Saddam Awaisheh, A. Salam Ibrahim, A. Saeed Hayek, and M. Jafar El-Qudah CONTENTS 22.1 Functional Foods........................................................................................................................... 395 22.2 Symbiotic of Probiotics and Nutraceuticals.................................................................................. 398 22.2.1 Probiotics.......................................................................................................................... 398 22.2.1.1 Probiotic Species and In Vitro Selection Criteria............................................. 399 22.2.1.2 Health-Promoting Effects of Probiotics........................................................... 399 22.2.2 Nutraceuticals................................................................................................................... 403 22.2.2.1 Isoflavones......................................................................................................... 403 22.2.3 Phytosterols...................................................................................................................... 404 22.2.3.1 Phytosterols and CHD...................................................................................... 405 22.2.4 Health Benefits of Symbiotic of Probiotics, Isoflavones, and Phytosterols..................... 405 References............................................................................................................................................... 406

22.1 Functional Foods In the last few decades, a radical change in the understanding of the role of food in human health promotion has been observed. This understanding has changed from the primary role of food as the source of energy and body-building components to the more subtle effect of bioactive food components on human health (Grajek et al. 2005). In addition, there has been an increasing public awareness about the role of foods in the well-being and life prolongation as well as in the prevention and treatment of cancer, cardiovascular diseases, and osteoporosis. Accordingly, a new category of health-promoting foods has emerged in the food market. This new food category has been known as functional foods (Hilliam 1998; Jones 2002). The concept of functional foods was launched for the first time by the Japanese Ministry of Health and Welfare in early 1980s under the “Foods for Specific Health Use” system (Huis in’t Veld and Havenaar 1997; Yamada et al. 2008). According to this system, more than 200 functional products have been marketed in Japan and around the world so far (Table 22.1). Even though several organizations have attempted to define the functional foods category, there is no globally accepted definition of it yet. The International Life Sciences Institute of North America has defined functional foods as “foods that, by virtue of physiologically active food components, provide health benefits beyond basic nutrition” (ILSI 1999). Whereas Health Canada (HC 1998a) defines functional foods as similar in appearance to a conventional food, consumed as part of the usual diet, with demonstrated physiological benefits, and/ or to reduce the risk of chronic disease beyond basic nutritional functions (HC 1998a). One of the most generally accepted definition is “any modified food or food ingredients that may provide health benefits beyond that conferred by the traditional nutrients the food contains” (Marriott 2000). Today, many scientific bodies proved that functional foods promote health benefits beyond the basic nutritional effects (Table 22.2) (Cencic and Chingwaru 2010;). Modulation of intestinal health and immune system, anticarcinogenic, antidiarrheal, hypocholesterolemic effects, and lactose intolerance 395

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Beneficial Microbes in Fermented and Functional Foods TABLE 22.1 Examples of Commercial Probiotic and Nutraceutical Functional Food Products

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Functional Ingredients Probiotic B. lactis Bb-12 L. acidophilus LA5 L. paracasei CRL 431 L. fermentum VRI003 L. reuteri RC-14 L. rhamnosus GR-1 L. paracasei F19 L. casei Shirota B. breve Yakult L. casei DN-114 001 B. animalis DN-173 010 Bifidus regularis L. johnsonii Lj-1 L. reuteri ATCC 55730 L. rhamnosus GG L. acidophilus NCFM B. lactis Bi-07 B. lactis HN019 L. rhamnosus HN001 L. rhamnosus LB21 Lactococcus lactis L1A B. longum BB536 L. acidophilus LB

Product Containing

Manufacturing Company

Sold as ingredient

Chr. Hansen (USA)

Yakult

Yakult (Japan)

DanActive fermented milk Activia yogurt

Danone (France) Danone (USA)

BioGaia probiotic chewable tablets or drops Culturelle Sold as ingredient

Nestlé (Switzerland) Biogaia (Sweden) Valio Dairy (Finland) DuPont Nutrition Biosciences (USA)

Sold as ingredient

Essum AB (Sweden)

Sold as ingredient Sold as ingredient

Morinaga Milk Industry (Japan) Lacteol Laboratory (France)

Isoflavones Novosoy (400/700) Soy milk Tofu Soy fusion Textured soy protein

Sold as ingredients Milk drink Fermented soy Flavored soy drink Powdered flour

ADM (USA) Whitewave (USA) Nasoya food, Inc. (USA) American soy (USA) Joy Soy (USA)

Sterols/Stanols Danacol Vegapure CardioAid Pro.active Lipophytol Vitasterol

Fermented milk products Sold as ingredient Fat spreads Fat spreads, fermented milk Fat spreads, milk products Soy drink, fat spreads

Danone (France) Cognis (Germany) ADM (USA) Unilever (UK) Lipofoods (Spain) Vitae-Caps S.A. (Spain)

alleviation are among the most proven benefits of functional foods (Chandra et al. 2008; FAO 2007; Gourbeyre et al. 2011; Jones 2000; Roberfroid 2000). Among the promising intestinal modulation targets for functional foods are the control of transit time, bowel habits, anticancer effect, balanced colonic microflora, and mucosal motility as well as those that modulate the proliferation of epithelial cells (Cencic and Chingwaru 2010; Steer et al. 2000). Other promising targets are also those associated with modifying gastrointestinal (GI) immune activity (Table 22.2). Various functional foods have been developed and marketed as a result of increasing health-promoting claims. Functional foods containing plant sterols and stanols; antioxidants; isoflavones; omega-3-fatty

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Health Benefits of Symbiotic Functional Food Products TABLE 22.2

Overview of Health Effects and Mechanisms of Action of Probiotics, Isoflavones, Phytosterols, and Their Symbiotic Health Effects


Hypocholesterolemic effect

Anticancer effect

Intestinal modulation and antidiarrheal effect

Immunity enhancement

Lactase compensation Osteoporosis attenuation

Probiotics

Isoflavones

Phytosterols

Direct cholesterol binding and assimilation

Upregulating the expression of cholesterol 7-α-hydroxylase enzyme and LDL receptor genes Enhancing bile acid synthesis and excretion

Displace cholesterol from bile salt micelles and compete for absorption in the brush border, thus suppress the absorption of dietary and biliary cholesterols in the intestine

Deconjugation of bile acids, which induces cholesterol drainage to synthesize new bile acids Inhibiting 3-hydroxy-3methyl-glutaryl (HMG)-CoA reductase enzyme Reduce tumor cell proliferation Increase tumor cells apoptosis

Inhibition of the production and activity of carcinogenic enzymes Inactivate mutagenic substances Amplify immune response to tumor tissue Binding mycotoxins and cyanobacterial toxins Production of antibacterial compounds Resistant colonization Trigger immune system Increase immunoglobulins levels, especially secretory IgA Activate macrophages Increase natural killer cell activity Increase the levels of cytokines Production of lactase enzyme

Modulation of endocrine system

Arresting cancer cell growth Inhibition of enzyme systems related to malignant activity Inducing apoptosis in tumor cells Death of cancer cells

The weak estrogenic activity of isoflavones

acids; medicinal herbs; anthocyanins and fat-reduced, sugar-reduced, or salt-reduced foods; probiotics; and prebiotics are major examples of functional foods products existing in the market (Awaisheh 2012; Awaisheh et al. 2013). Nowadays, there is an international interest in developing and processing new functional foods. The new strategy in the development of functional foods is to incorporate more than one bioactive component in a functional food in order to maximize health benefits.

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Beneficial Microbes in Fermented and Functional Foods

Functional foods containing more than one bioactive component is called a symbiotic product. Isoflavones, phytosterols (PSs), conjugated linoleic acid, and medicinal herbs are among the most commonly used functional ingredients besides prebiotics and probiotic bacteria (Abd El-Salam et al. 2011; Awaisheh 2011; Awaisheh et al. 2005).


22.2 Symbiotic of Probiotics and Nutraceuticals Nowadays, new trends in developing functional foods have emerged by incorporating more than one bioactive ingredient to promote more beneficial health effects (Abd-Salam et al. 2011; Vinderola et al. 2002; Zanini et al. 2007). Functional food products containing two or more bioactive ingredients are known as symbiotic foods (Awaisheh et al. 2013). Isoflavones, PSs, conjugated linoleic acid, and medicinal herbs are among the most commonly used bioactive ingredients besides probiotic bacteria and prebiotics (Abd El-Salam et al. 2011; Awaisheh 2011; Awaisheh et al. 2005; Cencic and Chingwaru 2010; Roberfroid 2007). Probiotic bacteria, to be considered as effective probiotic and to be able to exert their healthpromoting effects, must reach the intestine in high numbers in order to survive, adhere to the intestinal walls, and multiply (O’Sullivan 2001). Consequently, the viability of probiotic strains during product manufacturing and storage is very important, especially, in mixed strains and/or symbiotic products. A minimum count of 106 –107 CFU/g of probiotic has been suggested to consider the product as probiotic product with potential health properties (Stanton et al. 2001). Accordingly, the development of such multibeneficial symbiotic requires the establishment of suitable combinations of mixed probiotic strains and nutraceuticals mixture. This suitable combination requires the evaluation of the pattern and the extent of interactions among the probiotic strains and the probiotic strains with the nutraceuticals mixture. This possible interaction among probiotic strains may exert an inhibitory impact on the probiotic viability during product processing and storage (Awaisheh et al. 2012; Vinderola et al. 2002). Probiotic bacteria, such as lactic acid bacteria (LAB), are known to have a strong antibacterial activity against close LAB strains and other bacterial groups. Antibacterial activity of LAB is resulted from the production of various compounds (Awaisheh and Ibrahim 2009). So, it is a crucial challenge to maintain and enhance probiotic culture activity and survivability during processing and storage. Various studies demonstrated the fact that not all probiotic strains are suitable to be combined in one functional product, as these strains may have variable modes of inhibition effects against each other, either during product processing or storage (Awaisheh et al. 2012; Kailasapathy and Rybka 1997). These inhibition modes showed to include complete, moderate, or lack of inhibition. Accordingly, only strains with no inhibition effects were recommended for using in symbiotic product development (Awaisheh et al. 2012; Vinderola et al. 2002). The impacts of different nutraceuticals, particularly isoflavones and PSs, on the viability of probiotic bacteria have been assessed in very limited number of studies. However, the viability-enhancing effect of the mixture of isoflavones, PSs, and omega-3-fatty acids on Lactobacillus gasseri or Bifidobacterium infantis was revealed in fermented dairy product during processing and chilled storage (Awaisheh et al. 2005). Soy germ, rich in isoflavones, showed to have a positive effect on lactobacilli and bifidobacteria viability (De Boever et al. 2000). Also, mixture of two nutraceuticals, isoflavones and PSs, was found to significantly enhance the viability of eight single probiotic strains and did not affect the viability of the mixture of these probiotic strains (Awaisheh et al. 2012).

22.2.1 Probiotics Probiotic for life as a term is a relatively new and has been adopted by FAO/WHO in 2002 to describe a group of bacteria when administered in a sufficient quantity confer beneficial effects for humans and animals. Even though the term probiotic was used for the first time in 1965 by Lilley and Stillwell, to define compounds produced by microorganisms able to stimulate the growth of other microorganisms, probiotic concept is very old and is associated with the consumption of fermented foods by human beings for thousands of years (Gilliland 1990). Since ancient times, man has made and eaten


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probiotic foods, such as cheeses and milk made by LAB (Kopp-Hoolihan 2001). In the early ages, Hippocrates and other scientists had observed the curing effect of fermented milk at some digestive system disorders; also, Plinius, the Roman historian, stated that fermented milk products can be used for treating gastroenteritis (Suvarna and Boby 2005). Metchnikoff (1907) is accredited to be the father of the probiotic concept. In his famous book The Prolongation of Life, he stated that “The dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes.” This statement describes in a clear way what we call probiotics, the health-promoting bacteria, which are able to exert a positive role on intestinal flora. The definition of probiotics has been redefined several times since the first time it was proposed. For example, Fuller (1989), in order to elaborate the microbial nature of probiotics, had defined the word as “a live microbial feed supplement which beneficially affects the host animal by improving its intestinal balance.” Recently, a widely accepted definition of probiotics has been proposed as “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host” (Guarner and Schaafsma 1998). In general, probiotics are believed to promote many health benefits in both human and animals upon ingestion in sufficient amounts (Salminen 2001). Numerous types of probiotics food products have been introduced recently to the market (Table 22.1). But due to the historical association of LAB with fermented milk, most of probiotic food products are dairy products—fermented yogurts, kefir, and cheeses (Awaisheh 2011; Parvez et al. 2006). However, several nondairy probiotic products started to be introduced into the markets, such as chocolate (Prado et al. 2008), cereals (Blandino et al. 2003), beverages, fruits, and vegetable products (De Bellis et al. 2010).

22.2.1.1 Probiotic Species and In Vitro Selection Criteria The term probiotic bacteria comprises a group of bacteria called LAB, which in this context includes the species of Lactococcus, Lactobacillus, Streptococcus, Leuconostoc, Bifidobacterium, Pediococcus, and Enterococcus (O’Sullivan 2001; Vinderola et al. 2000). Among these, only strains of Lactobacillus, Bifidobacterium, and Enterococcus are commercially available as probiotics in foods, but other strains are also considered as probiotics, for example, Lactococcus, Pediococcus, Streptococcus, and Leuconostoc. All of these species and strains are part of the microbiota of the human GI tract (Holzapfel et al. 1998). Several species of these probiotics genera have been incorporated into a variety of food products, dietary supplements, and drugs. The most common strains incorporated in probiotic food products include Lactobacillus (L.) acidophilus, L. casei, L. plantarum, L. delbrueckii subsp. bulgaricus, L. rhamnosus, and L. reuteri; Bifidobacterium (B.) bifidum, B. infantis, B. adolescentis, and B. longum; Streptococcus thermophilus; and Enterococcus faecium (Awaisheh 2012; Cencic and Chingwaru 2010; Sanders et al. 2003). The selection of individual bacterial strains, for use as effective probiotics, is a complex process, especially as all of the features that an isolate should possess for maximum probiotic efficacy are not yet known (Salminen 2001). For bacterial strains to be used as an effective probiotic, they should possess several physiological and biochemical criteria, including human origin, gastric acidity, and bile acid resistance, ability to colonize within the GI tract, cholesterol assimilation, antimicrobial substances, lactase, and vitamin production (Awaisheh 2011; Dunne et al. 2001). Besides these criteria, effective probiotic strains may also need to possess the following characteristics: bile salt hydrolase activity, antioxidative characteristics, and the ability to withstand process and storage conditions, as these characteristics have been shown to be very important criteria in the selection process of probiotics that can be incorporated into foods (Dunne et al. 2001; O’Sullivan 2001).

22.2.1.2 Health-Promoting Effects of Probiotics 22.2.1.2.1 Modulation of Gut Health and Balance Human intestines are a normal habitat for a large number of bacterial species, harmful, neutral, and beneficial (probiotic) species (Holzapfel et al. 1998). The numbers and the ratios of beneficial to harmful species are the limiting factors in health or disease status of human (Holm 2001). Many factors


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that affect the composition of the large intestinal microbiota in humans include the age, susceptibility to infections, nutritional requirements, immunological status of the host and the pH, transit time, interactions between flora components, and availability of fermentable material (prebiotics) in the gut (Buddington and Weiher 1999; Holm 2001; Salminen 2001). Many studies concluded that gut health and consequently human health can be improved by the management of the gut microflora (Reid 2008). The quality of gut microflora can be managed by elevating the beneficial bacteria in the gut (Sanders 2000). This elevation can be achieved by either introducing exogenous probiotics (Salminen 2001) or using diets high with prebiotics to selectively promote the growth of endogenous probiotics (Roberfroid 2007; Slavin 2013). One of the most important actions to modulate gut microflora is the antibacterial activity of probiotics. Probiotic antibacterial effects against a broad spectrum of pathogenic bacteria are well known (Awaisheh and Ibrahim 2009; Coconier et al. 1997; Fuller and Gibson 1997). Antibacterial activity is one of the most important features in the selection of probiotics (Dunne et al. 2001). This antibacterial effect is accounted for by probiotic ability to produce many compounds and by-products with antibacterial activity, such as organic acids, bacteriocins, hydrogen peroxide, short-chain fatty acids, and acetyl aldehyde (Jacobsen et al. 1999). The ability of probiotics to exert resistant colonization against other bacteria in the intestines, and triggering the immune system in the gut, is another important mechanism possessed by probiotics to manage and modulate gut microflora (Gomes and Malcata 1999; Karaoglu et al. 2003). Many human studies confirmed the role of probiotic bacteria in modulating gut microbial composition and consequently human health (Madssen et al. 2001; Vanderhoof et al. 2000).

22.2.1.2.2 Antidiarrheal Effect Probiotics can prevent or ameliorate diarrhea through different mechanisms such as the effects on the immune system (Gomes and Malcata 1999; Perdigon et al. 1999). They can also prevent infections because they compete with pathogenic viruses or bacteria for binding sites on epithelial cells and by resistant colonization (Ouwehand et al. 2002). The effect of probiotics on diarrhea was mainly studied on the three most common types of diarrhea: acute diarrhea, mainly due to rotavirus infection; traveler’s diarrhea; and antibiotic-associated diarrhea (Perdigon et al. 1999). Acute diarrhea is mainly caused by rotavirus. Rotavirus infection causes gastroenteritis, which is characterized by acute diarrhea and vomiting. Gastroenteritis is a leading cause of death and disease among infants, particularly in developing countries (Isolauri 2003). There is strong evidence that probiotics reduce the duration and severity of rotavirus diarrhea (Perdigon et al. 1999). L. rhamnosus GG has been shown to be effective in the treatment of infant rotavirus diarrhea; however, this is not a general property of all probiotics (Marteau et al. 2001). Consumption of Lactobacillus GG (1010 –1011 CFU/day) shortened the diarrheal phase from an average of 3.5 to 2.5 days in children hospitalized or treated at home for rotavirus infection (Isolauri 2003). Traveler’s diarrhea is defined as the passage of more than three unformed stools in a 24 h period in people who normally live in industrialized countries and who travel to tropical and semitropical areas (Dupont and Ericsson 1993). The potential mechanisms by which probiotics prevent infectious diarrhea include the exclusion of pathogens through competition for binding sites and available substrates, lowering of luminal pH and production of bacteriocins, and promotion of the production of mucus; this is described as commensal pathogen cross talk (Table 22.2) (Isolauri 2003). Lactobacillus GG had been found to significantly reduce the risk of diarrhea lasting more than 3 days (Szajewska and Mrukowicz 2001). In another study with 245 travelers, the risk of diarrhea on any given day was 3.9% in travelers who took Lactobacillus GG and 7.4% in control subjects who took a placebo (Hilton et al. 1997). Antibiotic-associated diarrhea is the most common side effect of antibiotic use. It is due to the growth of pathogenic Clostridium difficile. Probiotics might inhibit this growth by releasing inhibitory substances, as indeed has been shown in vitro for some strains (Drago et al. 1997). Several studies have shown that Lactobacillus GG can prevent antibiotic-associated diarrhea (Biller et al. 1995; Gorbach et al. 1987). In these studies, the therapeutic effect of Lactobacillus GG was investigated in patients with


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recurrent Cl. difficile infection, an infection that causes severe diarrhea and colitis. The conclusion from both studies was that Lactobacillus GG cured the recurrent infection.


22.2.1.2.3 Improving Coronary Heart System Health High serum cholesterol concentrations are associated with the development of coronary heart disease (CHD), which is the leading cause of death all over the world (WHO 2007a). Since the early observations by Mann and Speorry (1974) and the later reports of cholesterol uptake by intestinal LAB and bifidobacteria from media (Gilliland et al. 1985; Pereira and Gibson 2002), more attention has been given to the potential hypocholesterolemic effect of probiotics in humans. Probiotics have been shown to lower serum cholesterol via different mechanisms, including direct cholesterol binding and assimilation in the intestine (Gilliland et al. 1985; Noh et al. 1997); deconjugation of bile acids, which induces cholesterol drainage to synthesize new bile acids (Liong and Shah 2006); and inhibiting 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase enzyme (Table 22.2) (Fukushima and Nakano 1996). Many animal studies have shown the hypocholesterolemic ability of probiotics. In a study by Akalin et al. (1996), it was shown that yogurt and acidophilus yogurt had significantly decreased the blood lipids in rats, including serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations. In another study by Usman and Hosono (2000), the effect of L. gasseri on serum lipids and fecal steroids in hypercholesterolemic rats was studied, and it was found that serum TC and LDL-C were significantly reduced. In a recent study by Awaisheh et al. (2013), the supplementation of hypercholesterolemic rats with mixed probiotics treatment consisted of eight probiotic strains: two strains of each of L. acidophilus, L. casei, L. gasseri, and L. reuteri had significantly reduced serum TC and LDL-C concentrations. Numerous human studies had reported the hypocholesterolemic efficacy of several probiotic strains. Schaafsma et al. (1998) reported that the milk fermented with strains of L. acidophilus and yogurt containing 2.5% FOS had decreased TC and LDL-C concentrations in human subjects. In a study by Xiao et al. (2003), the effects of milk fermented by B. longum on blood lipids in healthy adult male was reported to produce a significant decrease in serum TC. However, Bertolami et al. (1999) found that a fermented milk product with E. faecium and S. thermophilus (Gaio) produced little but a significant decrease in the TC and LDL-C in hypercholesterolemic volunteers.

22.2.1.2.4 Anticarcinogenic Effect Cancer is the world’s second biggest killer after cardiovascular diseases, but one of the most preventable noncommunicable chronic diseases (Rafter et al. 2007). Mortality from colorectal cancer (CRC) is second only to that of lung cancer in men and breast cancer in women. Diet makes an important contribution to the risk of CRC (up to 75% of cases being thought to be associated with diet), implying that the risk of CRC is potentially reducible (Ma et al. 2010). Evidences from a wide range of studies support the opinion that the colonic microflora has a crucial role in the etiology of CRC. This has led to more interest in dietary factors such as probiotics and prebiotics in order to prevent and treat CRC (Sanders 2000; WHO 2007b). Different mechanisms have been found to be involved in the anticarcinogenic activity of probiotic bacteria, including: 1) reduction of tumor cell proliferation and increased apoptosis; 2) inhibition of the production and activity of many carcinogenic enzymes that convert procarcinogens into carcinogens, such as nitroreductase, β-glucosidase, β-glucuronidase, and urease, produced by putrefactive bacteria such as Clostridium, Coliforms, or Bacteroides species; 3) inactivation of mutagenic substances; 4) amplifying the immune response to tumor tissue including modulation of cytokine production and T-cell function; and 5) binding of certain mycotoxins and cyanobacterial toxins. (Table 22.2) (Commane et al. 2005; Rafter 2003; Reddy 1999; Roy et al. 2009; Wollowski et al. 2001). The ability of probiotic bacteria to bind mutagenic compounds directly contributes to reduce cancer risk in human. In many studies, it was shown that certain probiotics can bind aflatoxins, N-nitroso compounds, and heterocyclic aromatic amines. This can lead to reducing the levels of carcinogenic compounds and reducing DNA damage (Geier et al. 2006; Peltonen et al. 2001). In animal and human studies, using the same enzymes as end points, it has been demonstrated that there is a general reduction in microbial


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enzyme activities and a concomitant decrease in fecal mutagenicity (Hosoda et al. 1996; Marteau et al. 2001). This beneficial effect could be accounted for by a favorable change in the composition of the intestinal flora following the introduction of the probiotic bacteria (Steer et al. 2000; Wollowski et al. 2001). Several probiotics strains have been shown to exert anticarcinogenic activity. For example, L. rhamnosus and Bifidobacterium lactis have been shown to induce apoptosis in cancer cell line Caco-2 (Al-Tonsy et al. 2010). In another study, L. plantarum was shown to have a role in controlling inflammation in the gut and may also be important for the activation of systemic immunity through the induction of TLR-2, confirming TLR-2 as an innate immune sensor, and accordingly attenuates colon cancer (Paolillo et al. 2009). Also, L. reuteri was found to secrete factors that potentiated apoptosis in myeloid leukemia– derived cells induced by tumor necrosis factor (Chandra et al. 2008). Daily intake of a viable L. casei was found to postpone the recurrence of bladder tumors in a randomized, controlled, and multicenter study in 48 Japanese patients. After 1 year, tumors recurred in 19 of 23 (83%) patients in the control group compared with 12 of 21 (57%) patients in the L. casei group (P < 0.01), in which 4 patients were lost to follow-up (Aso et al. 1995). One hypothesis for the prevention or delay of tumor development by lactobacilli is that they might bind to mutagenic compounds in the intestine, thereby decreasing the absorption of these mutagens.

22.2.1.2.5 Immune Stimulation Effect of Probiotics The function of the immune system is to protect human body against pathogens, food antigens, and colonizing microflora through eliciting a complex cascade of responses, including the launching of protective reactions and suppressing activity (Gourbeyre et al. 2011). Improperly directed or balanced immunological activity can lead to serious health problems, especially in the elderly, those on immune-suppressing drugs, and those suffering from immune-related diseases (Deplancke and Gaskins 2001). Probiotic bacteria are believed to mediate the immune response. Several probiotics genera, in addition to Lactobacillus and Bifidobacterium, have been evaluated as immune stimulators or biological response modifiers with varying degrees of success (Gomes and Malcata 1999). Many studies, using in vitro assessments of the immune response in both animal models and human studies, have provided a baseline understanding of the degree and type of probiotic-induced immune response (Salminen 2001). The ability of probiotics to positively influence immune activity without eliciting a harmful inflammatory response is one of the important selection criteria (Donnet-Hughes et al. 1999; Isolauri et al. 1995). Different probiotic forms, viable probiotic cells, dead cells, or fermented products, have been shown to mediate immune activity. Several mechanisms have been proposed to explain the probiotic ability to enhance both specific and nonspecific immune responses, including increasing levels of immunoglobulins, especially secretory IgA; activating macrophages; increasing natural killer cell activity; and increasing the levels of cytokines (Table 22.2) (Gourbeyre et al. 2011). Orally administered bifidobacteria was found to play a role in increasing, to some extent, the production of IgA antibodies. However, it should be noted that closely related strains of Bifidobacterium spp. and L. acidophilus differ between each other in immune stimulatory properties, so that some strains may not have all the properties necessary for this type of activity (Kado-Oka et al. 1991). Matsuzaki et al. (1998) found that mice fed with L. casei strain Shirota had higher production of spleen cells with Th1 cell–associated cytokines, such as interferon-g and interleukin-2, than those in the control group.

22.2.1.2.6 Compensation for Lactase Deficiency Lactose is the predominant carbohydrate in milk that is hydrolyzed by the enzyme lactase (β-galactosidase) to form glucose and galactose. Some individuals may lack lactase enzyme due to a genetic defect, leading to symptoms including cramps, flatulence, and diarrhea (De Vrese et al. 2001). These symptoms are called lactose intolerance (lactose malabsorption), and lactose intolerance discourages individuals from the consumption of milk (Ibrahim and O’Sulivan 1999). Subjects with low intestinal lactase activity absorb lactose from yogurt or milk containing L. acidophilus better than from milk; this is because most of lactose is converted into lactic acid by yogurt starter culture and L. acidophilus (Fuller 1989; Gomes and Malcata 1999). Several probiotic strains have been shown to produce lactase enzyme and


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consequently compensate lactase deficiency (Table 22.2) (De Vrese et al. 2001; Jiang et al. 1996). The ingestion of milk containing B. longum had improved lactose digestion and caused a moderate reduction in the total excretion of breath hydrogen (Jiang et al. 1996). Moreover, a classical mutagenesis protocol (chemical mutagens) was found to moderately increase the lactase production of B. breve, B. longum, L. delbreukii subsp. bulgaricus, and S. thermophilus, and demonstrate their potential for use in lactose malabsorption cases (Ibrahim and O’Sulivan 1999).


22.2.2 Nutraceuticals The efficacy of dietary components to play beneficial roles beyond basic nutrition has led to the development of the functional food concept and nutraceuticals (Laparra and Sanz 2010). The term nutraceutical was first proposed in 1989 by Stephen DeFelice, which was coined from nutrition and pharmaceutical (Brower 1998). A nutraceutical is defined as “a product isolated or purified from foods that is generally sold in medicinal forms or associated with food, that provides medical or health benefits, including the prevention and/or treatment against chronic diseases” (HC 1998b). Thus, nutraceuticals differ from dietary supplements in the following aspects: (1) nutraceuticals do not only supplement dietary effect but also aid in the prevention and/or treatment of disease and/or disorder, and (2) nutraceuticals are used as conventional foods or as sole items of a meal or diet (Trottier et al. 2010). So far, the term nutraceutical, as commonly used in marketing, has no regulatory definition. Several naturally derived nutraceuticals have been studied in human health. Polyunsaturated fatty acids (which include the omega-3 and omega-6 fatty acids), and phytochemicals, such as isoflavones, PSs, green tea, soy, and lycopene, are examples of important nutraceuticals that play role as healthy bioactive compounds (Awaisheh et al. 2005, 2013; Cencic and Chingwaru 2010). Many of these bioactive compounds have been found to have high therapeutic effects as anticarcinogenic, antiestrogenic, anti-inflammatory, immunomodulatory, and antioxidants (Cencic and Chingwaru 2010; Laparra and Sanz 2010).

22.2.2.1 Isoflavones Isoflavones are the major phytoestrogens naturally found in plants and exist in at least 15 different chemical forms, particularly, genistein, daidzein, and glycitin (Erdman 2000). Soy is the richest source of isoflavones, as high levels of these compounds are present in soybeans (5–30 mg/100 g) (Messina 1999). Several soy functional products have been developed as rich sources of isoflavones (Table 22.1). Isoflavones have a structure similar to estrogen and have the capacity to exert both estrogenic and antiestrogenic effects. They may block the effects of estrogen in some tissues, for example, the breast and uterus, but act like estrogen in providing possible protection against bone loss and heart disease (Setchell 1998). Isoflavones are normally found in nature in conjugated forms, which are not bioavailable for humans, since only the deconjugated forms can be absorbed. The biotransformation of the ingested isoflavones to deconjugated forms takes place by the action of intestinal microflora (Setchell and Cassidy 1999). Several effects on human health have been reported including lowering the risk of heart diseases, osteoporosis, breast cancer, and menopausal symptoms (Cassidy et al. 1995; Erdman 2000).

22.2.2.1.1 Isoflavones and Cancer Epidemiological studies have shown that populations with high intakes of soy foods, such as those of China, Japan, and other Asian countries, usually have a reduced incidence of cancers of the breast, prostate, colon, and uterus (Mason 2001). In addition, experimental evidence from in vitro and animal studies, on the effects of isoflavones on cancerous cells, has led to the suggestion that isoflavones could reduce the risk of cancer in humans (Messina and Loprinzi 2001). Dietary studies have shown that isoflavones inhibit most types of hormone-dependent and hormone-independent cancer cell lines in vitro, including colon cancer (Kennedy 1995). Animal studies, using classic models of chemically induced breast cancer, showed that a diet containing soy protein significantly reduced tumor formation and that this effect was lost when isoflavones were removed from the soy protein (Kim et al. 1998).

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Mechanism of action: It has been demonstrated that the anticancer effects of isoflavones may be due to several mechanisms, including arresting cancer cell growth, inhibition of enzyme systems related to malignant activity, inducing apoptosis in cancer cells, and death of cancer cells, without altering cell cycle distribution (Table 22.2) (Kennedy 1995; Kim et al. 1998; Setchell 1998).


22.2.2.1.2 Isoflavones and Coronary Heart Disease There are increasing evidences that the consumption of soy protein in place of animal protein beneficially alters blood cholesterol levels and may provide other coronary heart benefits (Anderson 2001; Awaisheh et al. 2013; Huang et al. 2005; Mason 2001). Epidemiologists have long noted that Asian populations, who consume soy foods as a dietary staple, have a lower incidence of CHD than those who consume low soy diets (Erdman 2000). Several human meta-analysis studies concluded that isoflavones significantly lowered TC, LDL-C, and triglycerides without affecting HDL-C (Taku et al. 2007; Zhan and Ho 2005). These effects were greater in subjects with higher baseline cholesterol values (