Gut as a target for functional food

Trends in Food Science & Technology 22 (2011) 646e650

Gut as a target for functional food Makoto Shimizu* and Satoshi Hachimura Department of Applied Biological Chemistry, School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan (e-mail: [email protected]) FoSHU (food for specified health uses) are evidence-based functional foods regulated and approved by the Japanese government. Products to improve intestinal microflora were developed using probiotics/prebiotics and were approved as FoSHU to promote gut health. Food substances which suppress intestinal digestive enzymes were also used to develop FoSHU products to lower blood glucose or lipid levels. Recent studies have shown that dietary components, particularly probiotics/ prebiotics, may play important roles in regulating the gut immune system. Although scientific evidence is still lacking, they may suppress intestinal inflammation and allergic reactions and therefore may hold promise as ingredients in functional foods.

Food for specified health uses (FoSHU), a science-based health food in Japan Studies on physiological effects of food were carried out in Japan from 1984 to 1995 under the support of large-scale grant-aided national research projects. Based on the scientific data accumulated by the projects, Japan established a unique regulation system for functional foods in 1991 (Arai, 1996). In this system, a functional food with sufficient evidence to support a health claim can be approved by the government as “food for specified health uses (FoSHU)”, which can then be commercialized with a specific health claim (Arai, 1996, 2002). There are three essential requirements for FoSHU approval, those include (1) effectiveness based on science evidence with clinical studies, (2) the safety of the product with additional safety studies in human subjects, and (3) analytical determination of * Corresponding author. 0924-2244/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tifs.2011.06.002

the effective components (Shimizu, 2003). A human study should be well designed using an appropriate functional marker, appropriate sample size, and a sufficient number of subjects to prove statistically significant differences. Randomized, placebo-controlled, double blind studies are basically required, and are conducted using the food in question over a reasonably long-term period (1 month or longer). The documents should be prepared on the basis of substantiation not only by human intervention studies but also by in vitro metabolic, biochemical and animal studies (Shimizu, 2003; Yamada, Sato-Mito, Nagata, & Umegaki, 2008). Experimental results must have been published by a qualified journal with expert referees. Thus FoSHU is a functional food distinguishable from socalled health foods which have not undergone a scientific evaluation. Although regulation systems for functional foods are not yet internationally unified, the FoSHU system is recognized as the first one to review and approve label statements regarding effects of foods on the human body (Shimizu, 2003; Yamada et al., 2008). Currently available FoSHU products can be roughly classified into eight categories according to their specific health claims. Health claims are shown in Table 1, and these claims are permitted to be shown on the label of the products. Since the first FoSHU product was approved in 1993, the number of FoSHU products has been increasing, reaching more than 950 as of August 2010. A variety of functional ingredients have been used in these FoSHU products and mechanisms of health promotion are also diverse. Current FoSHU products can be divided into three groups according to their mechanisms of action (Fig. 1). However, the major target for the majority of current FoSHU products is the intestine. More than 70% of the products are gut-modulating food, which have been designed based on the mechanisms to modulate intestinal events (Fig. 1, Groups 1 and 2). Gut-modulating FoSHU products The first group of the current gut-modulating FoSHU is food to improve intestinal microflora (Fig. 1). FoSHU products, such as fermented milk beverages or yogurt containing probiotic bacteria (certain strains of Bifidobacterium and Lactobacillus that can survive in the intestinal tract) or prebiotics (oligosaccharides, indigestible dextrin, and other dietary substrates to enhance growth of beneficial bacteria in the intestinal tract), are widely used by the

M. Shimizu, S. Hachimura / Trends in Food Science & Technology 22 (2011) 646e650 Table 1. Categories of the current FoSHU. Foods to regulate gastrointestinal conditions Foods for those with slight hypertension Foods for those with slight hypercholesterolemia Foods for those who are concerned about their blood glucose levels Foods for those who are concerned about fat accumulation Foods to help mineral absorption Foods for those who are concerned about bone strength Foods less likely to cause tooth decay

people who are concerned about their gut health. These foods may increase intestinal bifidobacteria, thus aiding in the maintenance of good gastrointestinal condition (Ohashi & Ushida, 2009; Oku, 1996; Tokunaga, 1993). Changes in the number and ratio of intestinal bifidobacteria, and frequency and volume of evacuation after intake of the product, are used to validate the efficacy of this type of FoSHU products (Shimizu, 2003). Concentrations of short-chain fatty acids, such as propionic and butyric acid, prepared by intestinal microbiota are also important indicators, because they may contribute to the acidification of the intestinal environment and also activate intestinal epithelial cell functions (Guilloteau et al., 2010; Ohashi & Ushida, 2009). Intestinal nervous system and smooth muscle cells may also be stimulated by the short-chain fatty acids, resulting in the activation of bowel movement and thus prevent or alleviate constipation (Grider & Piland, 2007). The second group of gut-modulating FoSHU is food which regulates intestinal absorption of nutrients (Fig. 1). Reducing high blood glucose, cholesterol, and triglyceride levels after meal is a target of health authorities in advanced countries, as these factors may increase the risks of lifestyle-related diseases, including diabetes, atherosclerosis, obesity, and osteoporosis. The functional ingredients used for FoSHU which regulate intestinal nutrient absorption are shown in Table 2.

Group-2

Mineral supply Food ingredients used for current FOSHU products

Mineral absorption Nutrient absorption

Tooth,Bone

Blood sugar, Cholesterol, TG, Body fat Circulation system

Gut microflora

Blood pressure Metabolic system Constipation, Diarrhea Group-1

Intestinal epithelium

Group-3

Obesity, Bone strength

Fig. 1. Classification of the current FoSHU products depending on the targets and mechanisms of action.

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To regulate the blood glucose level following a meal, inhibition of intestinal digestive enzymes may be an effective approach. Substances such as indigestible dextrin, wheat albumin, and tea catechin were found to inhibit a-amylase, and are therefore used as functional ingredients for FoSHU products for those who are concerned about the blood glucose level (Wakabayashi, Kishimoto, & Matsuoka, 1995). A similar strategy has been used to develop FoSHU products with a cholesterol-lowering effect. Since soybean proteins and peptides have cholesterol-binding capacity, they are expected to capture cholesterol and inhibit cholesterol absorption at the intestinal epithelium (Nagaoka et al., 1999). Plant sterols were also found to be effective in inhibiting cholesterol incorporation into mixed micelles, which is an essential step of cholesterol absorption at the intestinal epithelium (Igel, Giesa, Lutjohann, & Von Bergmann, 2003). Polymerized tea catechins contained in oolong tea and peptides derived from globin digests were found to suppress lipase action in the intestinal tract (Hsu et al., 2006). Effectiveness of these compounds were validated by measuring the changes of blood glucose or lipid levels after oral intake of the respective products. Then the products have been approved as FoSHU items. Some of the foods which can enhance intestinal mineral absorption have been approved as FoSHU. Casein phosphopeptides (CPP) derived from milk caseins can bind with calcium, thereby maintaining calcium solubility in the lower small intestinal tract and increasing the efficiency of calcium absorption (Tsuchita, Suzuki, & Kuwata, 2001). CPP is therefore used for FoSHU products as a calcium absorption-enhancing ingredient, which may be helpful to promote bone health. Potential of food in modulating intestinal immune functions In addition to regulating bowel movements and nutrient absorption, modulation of the intestinal immune system can also be a target for functional foods. Inflammation, allergy, and infectious diseases may be suppressed by regulating the intestinal immune system, and food can play a part (Fig. 2). However, as of yet, no immune-modulating foods or ingredients have been approved with this FoSHU category. Anti-inflammation Intestinal epithelial cells are exposed to oxidative stress, which may contribute to inflammation of the gut mucosa (Pravda, 2005). Oxidative stress in intestinal epithelial cells has also been shown to promote the production of several cytokines, including IL-8, IL-6, IL-1b, and TNF-a, each of which can induce neutrophil recruitment, thereby augmenting tissue damage. The secretion of inflammatory cytokines like IL-8 may be an integral part of the immune response. Disturbed regulation of the balance of these cytokines plays a key role in the pathogenesis of inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis. We have demonstrated that a peptide,

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Table 2. Examples of functional ingredients used for FoSHU that regulate nutrient-absorption. Functions

Functional ingredient

Mechanisms of action

Enhance mineral absorption

Casein phosphopeptide (CPP) Fructooligosaccharide Heme Iron Indigestible dextrin

Increase Ca solubility in the lower small intestine Increase Ca solubility by lowering intestinal pH Supply iron of higher bioavailability Inhibit a-amylase activity, Retard intestinal transition rate of carbohydrate Inhibit a-amylase activity Inhibit a-glucosidase activity Inhibit a-amylase activity Inhibit a-glucosidase activity Capture and accelerate excretion of cholesterol and bile acids Retard intestinal transition rate of cholesterol Inhibit incorporation of cholesterol into mixed micelles in the intestinal tract Inhibit intestinal absorption of triglyceride Inhibit intestinal absorption of triglyceride Inhibit lipase action

Suppress blood glucose increase

Wheat albumin L-Arabinose

Suppress blood cholesterol increase

Guava tea-polyphenol Touch extract Soybean protein/peptide Low mol.wt. alginate Plant sterol, Stanol

Suppress blood triglyceride increase and body fat accumulation

Globin digests Coffee mannooligosaccharide Polymerized tea-polyphenol

carnosine, inhibited the enhanced proinflammatory IL-8 secretion that was induced by a hydrogen peroxide treatment of Caco-2 cells (Son, Satsu, Kiso, Totsuka, & Shimizu, 2008). Amino acids, such as histidine and taurine, also showed a similar inhibitory effect on the chemokine production in in vitro (Son, Satsu, & Shimizu, 2005; Zhao et al., 2008) and in vivo (Andou et al., 2009; Zhao et al., 2008) experiments. Anti-inflammatory effects of probiotic bacteria (Kanauchi, Mitsuyama, & Andoh, 2009) have also been reported. Anti-allergy Hypersensitivity to normally harmless antigens, such as those in food or pollen, can induce an allergic response. It has also become apparent that certain food components can inhibit allergic reactions. Lactic acid bacteria have been demonstrated to improve or reduce the risk of allergy, which may be mediated through modulation of the

Fig. 2. The intestinal immune system regulating allergy and infectious diseases. Arrowheads indicate possible action points of food factors.

intestinal immune response (Torii et al., 2011). Modulation of T cell responses may be important in this process, since allergy has been shown to be related with excess Th2 response. We and others have shown that certain lactic acid bacteria contained in fermented milk products are capable of inhibiting development of Th2 response through enhancement of IL-12 secretion by antigen presenting cell populations (Murosaki et al., 1998; Shida et al., 2002). Other proposed mechanisms based on results from in vitro and animal studies may include induction of regulatory T cells (Enomoto et al., 2009), and apoptosis of activated cells (Kanzato et al., 2008). Nondigestible oligosaccharides have been shown to be effective in allergy models. We have shown that raffinose (a nondigestible oligosaccharide contained in sugar beets and other edible plants), could inhibit IgE responses in a mouse model of food allergy (Nagura et al., 2002). In this system dietary raffinose modulated the response of Peyer’s patch cells. Such effects may be through modulation of intestinal flora since such oligosaccharides have been shown to alter intestinal microbiota. Other food components such as polyphenols have been shown to inhibit allergic reaction in human tests (Maeda-Yamamoto, Ema, & Shibuichi, 2007). Epigallocatechin gallate can inhibit histamine release and expression of the high-affinity IgE receptor through binding to the 67kD laminin receptor (Fujimura, Yamada, & Tachibana, 2005). It is not totally clear yet if such polyphenols directly act on cells of the intestinal immune system. Anti-infection Another target for immunomodulation by foods is the intestinal IgA response. The intestinal immune system responds to pathogens and commensal bacteria by producing IgA antibodies. It has been demonstrated that lactic acid bacteria (Takahashi, Nakagawa, Nara, Yajima, & Kuwata,

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1998) and dietary oligosaccharides augment IgA responses (Nakamura et al., 2004). Such probiotic bacteria or prebiotic food components lower the risk of infection, and the elevation of IgA response may play a role in augmentation of host defense (Shida & Nanno, 2008). Recently the importance of cell types other than T or B cells, such as dendritic cells, have been shown in the intestinal IgA response (Tezuka & Ohteki, 2010). The cellular target of lactic acid bacteria and oligosaccharides in enhancement of IgA response may well be such cells other than T and B cells. Concerning non-T non-B cells, intestinal epithelial cells also mediate IgA response. A unique example of a food component modulating IgA production through intestinal epithelial cells is nucleotides (Nagafuchi et al., 2002). Feeding nucleotides enhances intestinal IgA response. Production of TGF-b, an IgA switch factor, by intestinal epithelial cells is enhanced in nucleotide-fed mice (Nagafuchi et al., 2002). In addition, expansion of gd-intestinal intraepithelial lymphocytes mediated by IL-7 production by epithelial cells may also be involved in the IgA enhancing effect (Nagafuchi et al., 2000). Conclusion Accumulating scientific data suggest that a variety of health-promoting effects may result through modulating intestinal functions with dietary substances. Thus the intestine is promising as a target organ to design foods with novel health-promoting functions. Although recent studies have suggested that dietary substances, such as probiotics and prebiotics, can modulate the intestinal immune system, in vivo studies, including a human intervention trial, should be made to prove immune-modulating effects of food. References Andou, A., Hisamatsu, T., Okamoto, S., Chinen, H., Kamada, N., Kobayashi, T., et al. (2009). Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology, 136, 564e574. Arai, S. (1996). Studies on functional foods in Japan e State of the art. Bioscience, Biotechnology, and Biochemistry, 60, 9e15. Arai, S. (2002). Global view on functional foods: Asian perspectives. British Journal of Nutrition, 88, S139eS143. Enomoto, M., Noguchi, S., Hattori, M., Sugiyama, H., Suzuki, Y., Hanaoka, A., et al. (2009). Oral administration of Lactobacillus plantarum NRIC0380 suppresses IgE production and induces CD4þCD25þFoxp3þ cells in vivo. Bioscience, Biotechnology, and Biochemistry, 73(2), 457e460. Fujimura, Y., Yamada, K., & Tachibana, H. (2005). A lipid raftassociated 67kDa laminin receptor mediates suppressive effect of epigallocatechin-3-O-gallate on FcepsilonRI expression. Biochemical and Biophysical Research Communications, 336(2), 674e681. Grider, J. R., & Piland, B. E. (2007). The peristaltic reflex induced by short-chain fatty acids is mediated by sequential release of 5-HT and neuronal CGRP but not BDNF. American Journal of Physiology - Gastrointestinal and Liver Physiology, 292, G429eG437. Guilloteau, P., Martin, L., Eeckhaut, V., Ducatelle, R., Zabielski, R., & Van Immerseel, F. (2010). From the gut to the peripheral tissues:

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