Health benefits of prebiotic fibers.

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Health Benefits of Prebiotic Fibers Diederick Meyer1 Sensus BV, Roosendaal, The Netherlands 1 Corresponding author: e-mail address: [email protected]

Contents 1. Prebiotic Fibers 1.1 Definitions and properties of dietary fiber 1.2 Definition of prebiotics 2. Physiological Effects of Different Prebiotic Fibers 2.1 Lactulose and lactitol 2.2 Galactooligosaccharides 2.3 Fructans 2.4 Glucose-based prebiotic fibers 2.5 Gums and other complex polysaccharides as prebiotic fibers 3. Nutrition and Health Claims Based on Prebiotic Fibers 3.1 Nutrition claims 3.2 Health claims for prebiotic dietary fibers 4. Future Developments 4.1 Final remarks References

47 47 53 54 54 55 58 64 68 70 70 71 74 77 77

Abstract This chapter describes the various compounds that can act as prebiotic fibers: their structure, occurrence, production, and physiological effects (health effects) will be presented. The basis for the description is the latest definitions for dietary fibers and for prebiotics. Using as much as possible data from human studies, both the fiber and the prebiotic properties will be described of a variety of compounds. Based on the presented data the latest developments in the area of prebiotics, fibers and gut and immune health will be discussed in more detail as they show best what the potential impact of prebiotics on health of the human host might be.

1. PREBIOTIC FIBERS 1.1. Definitions and properties of dietary fiber The definition of dietary fiber has been the subject of an almost endless debate, mainly because dietary fiber is not one single chemical entity like Advances in Food and Nutrition Research ISSN 1043-4526 http://dx.doi.org/10.1016/bs.afnr.2014.11.002

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2015 Elsevier Inc. All rights reserved.

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starch or cellulose. Some based the definition on physiological features, whereas other used its chemical composition. The original description by Hipsley (1953) described dietary fiber as nondigestible constituents of plant cells walls. Later, Trowell and others expanded the description to “consisting of plant polysaccharides and lignin which are resistant to hydrolysis by digestive enzymes of man.” More importantly, these authors also came up with the dietary fiber hypothesis related to health observations (Trowell, 1972, 1976). The definition of dietary fiber was based on (one of ) its physiological features, namely, its nondigestibility. Based on this feature, fiber determinations were developed mimicking the human digestion in a glass tube, to determine the fiber content of food, e.g., to assist food industry and enforcing authorities with nutritional labeling. In 1985, these efforts led to an approved AOAC method (AOAC 985.29) and in many countries it was used as a de facto definition of dietary fiber: material determined by this method is dietary fiber (AOAC 985.29, 2012). Soon it turned out that many nondigestible carbohydrates with physiological functions as dietary fiber were not assessed by this method or by other methods based on AOAC 985.29. This has led to the development of a battery of assays aimed at determining specific dietary fibers, such as AOAC 997.08 and 999.03 for fructans (AOAC 997.08, 2012; AOAC 999.03, 2012), or AOAC 2000.11 for polydextrose (AOAC 2000.11, 2012). A more detailed description of the development of dietary fiber definitions and assessments can be found in Prosky (2001) and Tungland and Meyer (2002). Figure 1 (left-hand picture) shows the situation before the latest developments that will be described below. The whole discussion on the definition has now led to two definitions for dietary fiber for labeling; they both are based on the nondigestibility. In the EU, dietary fiber (dietary fiber) means carbohydrate polymers (either naturally occurring or obtained by physical, enzymatic or chemical means, or synthetic polymers) that are not hydrolyzed by the digestive enzymes in the small intestine of humans. The carbohydrate polymers must have a degree of polymerization (DP) of three or more monomeric units (European Commission, 2008/100/EC) and for isolated fibers and synthetic polymers a beneficial physiological effect has to be proven based on generally accepted scientific evidence. The definition adopted by Codex Alimentarius Commission (2009; Alinorm 09/32/26) is based on the same type of carbohydrate polymers, but on those having a DP of 10 and above. However, a footnote which forms an integral part of this definition, states that the decision on whether or not to include carbohydrates from three to nine monomeric units should be left to national authorities (see also Harris & Pijls, 2009). Also this definition requires evidence for a beneficial physiological

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Health Benefits of Prebiotic Fibers

β-Galacto-oligosaccharides Raffinose/stachyose [AOAC 2001.02] Polydextrose [AOAC 2000.11]

Inulin/FOS [AOAC 999.03 / 997.08]

Resistant maltodextrins [AOAC 2001.03]

Total Dietary Fiber [AOAC 985.29 / 991.43] Pectin Arabinogalactan

Total Dietary Fiber [AOAC 2009.01 / 2011.25]

Resistant starch Cellulose [AOAC 2002.02] Arabinoxylan β-Glucan [AOAC 995.16]

AOAC 2009.01: Determination of Total Dietary Fiber (CODEX definition) AOAC 2011.25: Determination of Insoluble, Soluble and Total Dietary Fiber in Food

Figure 1 Analysis of dietary fiber before the development of AOAC 2009.01/2011.25 (left-hand side) and after (right-hand side). Reprinted with permission from Official Methods of Analysis of AOAC International. Copyright 2012 by AOAC International.

effect for carbohydrates obtained by physical, enzymatic or chemical means, and synthetic polymers. It should be stressed that from a physiological point of view, there is no reason to exclude oligomers with DP < 10 (Howlett et al., 2010). With this definition in mind, a universal method determining all dietary fibers in food was developed (McCleary, 2007; McCleary et al., 2010). These methods are now available as validated methods (AOAC 2009.01 and AOAC 2011.25) and they can be used to assess the total dietary fiber content of food irrespective of the type of fiber present (see Fig. 1) (AOAC 2009.01, 2012; AOAC 2011.25, 2012). Not surprisingly, also these methods have their disadvantages; apart from the laborious procedure it now emerges that some fibers still partially escape detection (e.g., Zielinski, DeVries, Craig, & Bridges, 2013). In connection with the issue about the DP required to classify as dietary fiber as in the Codex definition, it should be stressed that these or any other approved analytical method cannot discriminate dietary fibers with DP < 10 from those with DP 10 (Betteridge, Caers, Lupton, Slavin, & Devries, 2012). 1.1.1 Physiological properties of dietary fibers Dietary fiber is acknowledged worldwide for its positive effects on health and well-being. The benefits include positive effects on bowel habit, a

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Table 1 Physiological effects of various fiber types Effects

Soluble

Insoluble

Mixed type

Nondigestible oligosaccharides

Gastric emptying

Lower rate

None

?

No effect

Glucose absorption curve Flattening

Unknown ?

?

Fermentation in colon

Large extent Hardly

Variable Completely

Bowel habit

+

++

+

Blood cholesterol

Lowering

No effect

Variable Lowering

+

(+)+: (strong) positive effect; ?, no or conflicting data.

favorable effect on fermentation in the colon, a reduction of blood (LDL-) cholesterol levels and an improvement of blood glucose and insulin levels. Moreover there are associations from epidemiological evidence mainly between a lowered risk for colon cancer and for obesity with appropriate fiber consumption (e.g., EFSA, 2010b; Health Council of the Netherlands, 2006). An overview of the effects of different kind of fibers is presented in Table 1. Some dietary fibers, such as pectins or some gums, also have physiological effects due to their influence on the rheology of the intestinal content; a high viscosity is generally connected with a delayed gastric emptying and increased small intestinal transit time. A viscous environment in the small intestine may also inhibit absorption of nutrients with its physiological consequences. It should be noted that the evidence for much of the health benefits described below comes from epidemiological associations. In many cases it is not easy to carry out trials for such benefits with isolated dietary fibers, as these trials will take too long (e.g., for the lowered risk for colon cancer, or a lowered death rate from cardiovascular disease) and thus are very costly to carry out. For many of these diseases the lack of suitable and validated biomarkers also plays an important role; as an example, whereas the serum lipid level of cholesterol is an accepted biomarker for the risk for cardiovascular disease, such markers are not available for colon cancer, or obesity. 1.1.2 Effect on bowel movement The best known effect of dietary fiber is its influence on stool: it decreases the time for food passage through the entire gastrointestinal tract and increases fecal bulk. In fact, this feature is used by some authorities as a basis for their guidelines for fiber intake (Health Council of the Netherlands,

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2006; Institute of Medicine, 2005). Moreover, these effects can also be investigated easily in intervention studies with isolated fibers. As shown in Table 1 insoluble fibers have the strongest effect on bowel habit as they act as fecal bulking agents; e.g., what bran provides from 2.6 to 4.9 g/g (Cummings, Beatty, Kingman, Bingham, & Englyst, 1996; Maki et al., 2009), whereas soluble fibers such as pectin or inulin only provide about 1–2 g/g (e.g. Den Hond, Geypens, & Ghoos, 2000; Salminen et al., 1998). Their main effect is on stool consistency and frequency of defecation as they increase the softness of fecal matter. 1.1.3 Favorable colonic fermentation Dietary fibers reach the colon intact and there they can be fermented by specific colonic bacteria and converted into short-chain fatty acids (SCFA), lactic acid and gas. The extent of the fermentation depends very much on the type of fiber and the chemical composition. Insoluble fibers will be much less prone to bacterial fermentation than soluble fibers. Generally, this effect is considered beneficial for health (Brownawell et al., 2012; Howlett et al., 2010). The fermentation leads to a decrease in colonic pH creating circumstances that may be antagonistic to the growth of pathogens and putrefactive bacteria. Increased amounts of SCFA also seem to mediate a local growth of the intestinal epithelium, partly as a direct source of energy for colonocytes, partly via a stimulation of certain growth hormones. The resulting increased thickness of the intestinal wall reduces the risk of bacterial translocation. Another effect of fiber fermentation in the colon is the shift toward carbohydrate breakdown, which leads to products such as SCFA as opposed to protein fermentation which gives rise to potentially toxic metabolites such as ammonia, amines, phenols and sulfides. For instance, ammonia may be a potential liver toxin and it has been shown to promote colon cancer in rats (Hambly, Rumney, Fletcher, Rijken, & Rowland, 1997). The production of phenolic compounds such as skatole or indole, by intestinal bacteria has been associated with a variety of disease states in humans, including schizophrenia (Macfarlane & Macfarlane, 1995). Sulfur containing products such as hydrogen sulfide are shown to inhibit butyrate metabolism in colon cells (Roediger, Duncan, Kapaniris, & Millard, 1993). Other typical products of protein fermentation are branched chain fatty acids, e.g. iso-butyrate and iso-valerate are formed from the amino acids valine and leucine, respectively (Macfarlane & Macfarlane, 1995). These products are suggested to have a

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negative impact on health and may cause liver problems (Mortensen & Clausen, 1996). Considering the whole of available evidence from in vitro, animal and human studies, Windey, De Preter, and Verbeke (2012) conclude that protein fermentation no doubt yields intrinsically toxic luminal compounds that affect epithelial cell metabolism and barrier function. 1.1.4 Effect on serum lipids and blood glucose Part of the SCFA originating from fermentation by the microbiota (mainly acetate and propionate) will be absorbed into the bloodstream. There they can either be used as a fuel or give rise to specific systemic effects: propionate suppresses cholesterol synthesis in the liver which may the basis for the lowered blood lipid levels that are observed in some studies with human volunteers. Acetate may have a flattening effect on postprandial blood glucose. The effects of fermentable fibers on bile acid metabolism may also play a role to lower blood lipid levels. As this effect may lower the risk for cardiovascular disease, still a major cause of mortality and morbidity in the Western world, this feature is also used as a basis for the guidance for fiber intake (EFSA, 2010b; Institute of Medicine, 2005). 1.1.5 Overweight A high fiber diet is important for preventing overweight which seems to be mediated by the high satiating effect of high fiber food and food products. Recent evidence suggests that some fermentable fibers can contribute to an increased feeling of satiety and thus to less energy intake. The mechanism may reside in the fact that consumption of these ingredients leads to a change in the levels of gut hormones that regulate satiety in such a way that satiety is enhanced. For viscous fibers the effect on gut content rheology seems to be important (Wanders et al., 2011), as well as oral exposure time (Wanders et al., 2013). This latter feature seems to affect satiation positively, which also may lead a lower energy intake. 1.1.6 Colon cancer Epidemiological evidence suggests that the risk for colon cancer decreases with increasing fiber intake. The most recent data from the EPIC study (Murphy et al., 2012) show that total dietary fiber was inversely associated with colorectal cancer. However, intervention studies with fiber supplements


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do not show a relation between fiber intake and the occurrence of colorectal cancer (Health Council of the Netherlands, 2006), which may be due to the long time for colorectal cancer to develop.

1.2. Definition of prebiotics Originally prebiotics were defined by Gibson and Roberfroid (1995) as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improve host health.” More recently this definition was extended to include also host well-being next to health (Gibson, Probert, van Loo, Rastall, & Roberfroid, 2004; Roberfroid et al., 2010). As discussed by Roberfroid et al. (2010) three features are important for ingredients to be classified as prebiotics: • Survival through the gastrointestinal system (i.e. resistant to alimentary enzymes and to gastric acid, no absorption); • Fermentation in the large intestine by the intestinal microbiota; • Specific stimulation of presumably healthy species and/or of the activity of the microbiota (e.g., a shift from proteolytic to saccharolytic fermentation) and association with benefits for health and well-being of the host. From the description of dietary fibers above it is evident that the two first features are common to fibers and prebiotics; what makes prebiotics different from generic fibers is the specific stimulation of the microbiota. In the early days of prebiotic research focus was on the bifidogenic effect of inulin, oligofructose, and fructooligosaccharide (FOS) as this appeared to be the most prominent effect (and it was the effect originally noted in Japan during the first research work with FOS). This was sometimes found to be accompanied by an increase in fecal lactobacilli or a decrease in potential pathogens, such as clostridia species. More details on the effects of various prebiotic fibers on the composition of the fecal microbiota will be presented below. With these two definitions as a basis, a variety of prebiotic fibers will be presented: what is the evidence for dietary fiber effects and what for prebiotic effects. These will include effects on the colonic microbiota and associated physiological effects. Focus for the studies will be on human trials, but if these are not available the relevant data from experimental animal studies or from in vitro trials will be presented.

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2. PHYSIOLOGICAL EFFECTS OF DIFFERENT PREBIOTIC FIBERS 2.1. Lactulose and lactitol Strictly speaking these disaccharides are not dietary fibers, as will be clear from the definitions given above. Yet they are briefly discussed here as they exhibit physiological effects of dietary fibers and of prebiotics. Moreover, both ingredients are sometimes applied in foods for the latter purpose. 2.1.1 Lactulose With alkali isomerisation the glucose moiety of lactose is converted into a fructose residue, which results in a disaccharide of β-D-galactose β-1,4linked to fructose (Fig. 2A). Lactulose can also be synthesized enzymatically from fructose and galactose with a β-galactosidase (Ga¨nzle, Haase, & Jelen, 2008) and it occurs in low levels in sterilized milk. The disaccharide is not digested by humans and promotes growth of bifidobacteria in the colon (De Preter et al., 2006; Mangin et al., 2002; Tuohy et al., 2002). It is used on a large scale as a pharmaceutical to treat constipation (e.g., Kokke et al., 2008; Mangin et al., 2002) and in portosystemic encephalopathy (Orlandi, Brunelli, Benedetti, & Macarri, 1998). The latter application probably is based on the favorable effect of lactulose on colonic nitrogen metabolism which leads to a decreased level of ammonia, a potential liver toxin (De Preter et al., 2006). The other physiological effects of lactulose connected with the fermentation in the colon have been investigated less, but Van den Heuvel, Muijs, OH OH OH HO

HO HO HO

O

OH O H HO H O O

H OH

H

H

OH

H

H

HO OH

O OH

OH HO

H

Lactulose

OH

Lactitol

Figure 2 (A) (left) Chemical structure of lactulose and (B) (right) of lactitol.


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van Dokkum, and Schaafsma (1999) showed that this disaccharide stimulates calcium absorption in postmenopausal women. 2.1.2 Lactitol This sugar alcohol (4-O-(β-D-galactopyranosyl)-D-glucitol; Fig. 2B) is derived from lactose by reduction of the glucose part of the disaccharide. It is manufactured by catalytic hydrogenation of lactose. Originally developed as a low-caloric sweetener it has been shown that lactitol has prebiotic properties. Ballongue, Schumann, and Quignon (1997) showed an increase in bifidobacteria and lactobacilli in human volunteers (see also Kummel & Brokx, 2001). The fiber properties of lactitol include a laxative effect (Sacchetta, Bottini, Guarisco, Candiani, & Brambilla, 2000), and a decrease in cholesterol metabolism (Felix et al., 1990). As with lactulose, lactitol is also used in the treatment of hepatic encephalopathy and other liver diseases (Ballongue et al., 1997; Morgan, 1998; Shibasaki, Tsuboi, Hasegawa, Toshima, & Soga, 2001). Gee and Johnson (2005) reported interesting effects of lactitol consumption on gut hormones connected with satiety. In rats and probably also in humans, PYY and GLP-1 levels increased upon ingestion of lactitol. This may lead to less energy intake (see also Section 2.3.2).

2.2. Galactooligosaccharides These ingredients come in two classes: β-galactooligosaccharides derived from lactose by enzymatic synthesis and α-galactooligosaccharides isolated from natural sources. 2.2.1 Galactooligosaccharides from lactose (GOS) These oligosaccharides are produced from lactose by the transglycosylating activity of β-galactosidase (Torres, Goncalves, do Pilar, Teixeira, & Rodriques, 2010). They consist of a limited number of β-1,6-linked galactosyl residues (DP 2–5) linked to a terminal glucose unit via an β-1,4-bond, but other bonds also occur such as β-1,3 and β-1,6 (Coulier et al., 2009; Ga¨nzle et al., 2008). These oligosaccharides are also known as transgalactooligosaccharides or β-galactooligosaccharides. The oligosaccharides are not digested in the human alimentary tract, and hence they classify as dietary fibers. However, this ingredient mixture as it is commercially available also contains nondigestible disaccharides, such as galactosyl-galactose; hence their actual fiber content is lower than their nondigestible carbohydrate content.

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The best documented fiber effects are for improved bowel habit (Surakka et al., 2009; Teuri & Korpela, 1998; Teuri, Korpela, Saxelin, Montonen, & Salminen, 1998). And this effect is also found in studies with infants (Ben et al., 2008). Data from human studies on serum lipid effect are not available. In animal model studies it has been shown that GOS may slow down the development of colon cancer (Wijnands, Appel, Hollanders, & Woutersen, 1999). Various human studies support the prebiotic effect of these ingredients, changes in colon microbial composition and activity following consumption of these compounds in dosages starting with about 5 g/d have been described (Alles, Hartemink, et al., 1999; Davis, Martinez, Walter, Goin, & Hutkins, 2011; Ito et al., 1990; Walton et al., 2012; Whisner et al., 2013). Also in infants bifidogenic effects of GOS have been reported, either of GOS alone (Ben et al., 2004, 2008) or in a 9/1 combination GOS/ inulin (e.g., Rinne et al., 2005; Scholtens et al., 2006). Other studies show that consumption of GOS leads to an increase in calcium absorption in adolescent girls (Whisner et al., 2013) and postmenopausal women (Van den Heuvel, Schoterman, & Muijs, 2000). Recently, Hughes et al. (2011) reported the results of a randomized, double-blind trial in a group of students who received 0, 2.5, or 5.0 g/day of GOS for 8 weeks around the time of fall final exams. Acute psychological stress was found to be directly related to symptoms of gastrointestinal dysfunction and cold or flu. GOS supplementation reduced these symptoms and the number of days with cold or flu. Ladirat (2014) show how GOS can contribute to the restoration of the composition and activity of the microbiota in healthy human volunteers after antibiotic treatment. With 7.5 g/d the production of butyrate is supported as well as the recovery of bifidobacteria, the numbers of which had gone down following the antibiotic treatment. Recent developments include the use of novel enzymes to produce novel types of GOS, the linkages of which may be different from the GOS described above. With the β-galactosidase from Bifidobacterium bifidum a novel GOS mixture was produced that also has bifidogenic properties in healthy humans (Depeint, Tzortzis, Vulevic, l’Anson, & Gibson, 2008), in elderly (Vulevic, Drakoularakou, Yaqoob, Tzortzis, & Gibson, 2008), and in IBS sufferers (Silk, Davis, Vulevic, Tzortzis, & Gibson, 2009). This ingredient also has shown to affect markers of immune function: in elderly people phagocytosis, NK cell activity, and anti-inflammatory cytokine IL-10 was increased, whereas the proinflammatory cytokine IL-1β decreased (Vulevic et al., 2008). In this trial no effects on serum lipids were

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found. This prebiotic also lowered the incidence and severity of travelers’ diarrhea in people traveling to high-risk countries (Drakoularakou, Tzortzis, Rastall, & Gibson, 2010). In conclusion, there is sufficient evidence to classify this type of GOS derived from lactose as prebiotic fibers. 2.2.2 Soybean galactooligosaccharides Another type of galactooligosaccharides is found in soybeans and other kinds of pulses, but raffinose can also be found in sugar beet (Van den Ende, 2013). For industrial production they are extracted from soybean whey, a byproduct from the production of soy protein, and concentrated to an oligosaccharide syrup. These α-galactooligosaccharides include raffinose (Fig. 3; DP 3), stachyose (Fig. 3; DP 4) and verbascose (DP 5) and consist of galactosyl residues linked α-1,6 to the glucose moiety of sucrose. Since α-galactosidase activity (required to hydrolyze these carbohydrates) is not present among human digestive enzymes, the oligosaccharides can reach the colon intact. But apart from being nondigestible, human studies for other dietary fiber effects are scarce. Nagura, Muraguchi, Uchino, Aritsuka, and Benno (1999) showed that with 5 g/d of raffinose defecation pattern improves in healthy human volunteers. Their other physiological effects appear to be similar to the other galactooligosaccharides; they are bifidogenic (Benno, Endo, Shiragami, Sayama, & Mitsuoka, 1987; Fernando et al., 2010; Fujisaki, Nagura, Kawamoto, & Sayama, 1994; Hayakawa et al., 1990; Nagura et al., 1999) and hence other effects can be expected from this change in colon microbiota. Also the data obtained in rats with raffinose administration support the OH OH

OH OH

O

O HO

HO

OH OH O

OH O HO HO

O

OH O

O

HO OH

OH

OH O

O OH

OH

HO HO

OH O

O

OH

OH O OH Raffinose

Figure 3 Galactooligosaccharides from soybean.

Stachyose

OH

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role of this trisaccharide as a prebiotic (Dinoto et al., 2006). It is also likely that soybean oligosaccharides can stimulate mineral absorption (Tenorio, Espinosa-Martos, Prestamo, & Ruperez, 2010). No other data from human studies for other physiological effects are available however, but the data obtained by Zheng et al. (2012) in weanling pigs show that soybean oligosaccharides have an effect on components of the immune system in these animals, that are similar to those described above for GOS from lactose.

2.3. Fructans These polymers are built up from fructosyl units and can be divided into two broad groups based on the linkage between the monomers, levans and inulins. 2.3.1 Levans Levans are β-2,6-linked fructans with variable degrees of β-2,1-linked side chains. They can be produced by a large variety of bacteria, but can also be found in some grasses (Vijn & Smeekens, 1999). Bacterial production involves levansucrases and uses sucrose as the substrate. Some bacteria can produce both inulin and levans (Anwar et al., 2010). In plants, other fructosyltransferases are involved in the biosynthesis of fructans (Ritsema & Smeekens, 2003). Levans are not produced commercially on a significant scale and only limited data on their physiological or health effects are available. In a few rat studies, levan was found to lower serum cholesterol levels, but surprisingly, no breakdown by colonic bacteria was observed (Belghith et al., 2012; Dahech et al., 2013; Yamamoto et al., 1999). Marx, Winkler, and Hartmeier (2000) showed that some Bifidobacterium spp. grew well on levan oligosaccharides. Levan-type exopolysaccharides from Lactobacillus sanfranciscensis showed bifidogenic properties in in vitro trials (Bello, Walter, Hertel, & Hammes, 2001). Human clinical trials to assess the physiological effects of this type of fructans are very limited thus far. Niv et al. (2012) could not find any effect of 8 weeks of levan consumption on bowel habit, serum lipid levels, gastrointestinal symptoms, and blood pressure. Kang et al. (2003) showed that in Korean women levan consumption for 12 weeks led to a significant reduction of body weight and body fat as well as a lower level of blood triglycerides. To conclude, levans could have prebiotic properties, but conclusive evidence from human trials is not available.

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2.3.2 Fructooligosaccharides from sucrose The other category of fructans is formed by inulin that are β-2,1-linked fructans sometimes with β-2,6-linked side chains. Often they contain a terminal glucose residue and Fig. 4 shows the chemical structure of linear inulins with or without glucose residue. These fructans are by far the best investigated prebiotic fibers to date. In fact, discovery of the bifidogenic properties of the FOS described below in the early 1980s can be considered as the start of all prebiotic research. These ingredients were first produced in Japan as Neosugar as a noncariogenic sugar replacer (Ikeda, Kurita, Hidaka, Michalek, & Hirasawa, 1999). They are produced from sucrose using the fructosyltransferase capacity of enzymes from molds or bacteria (Hidaka, Adachi, & Hirayama, 2001; Hirayama & Hidaka, 1993). The products are β-2,1-linked fructans with a chain length of maximally five monomeric units. These oligosaccharides have a terminal glucose residue and are nonreducing. Fiber properties of FOS include a positive effect on bowel habit in adults (Tominaga, Hirayama, Adachi, Tokunaga, & Iino, 1999) and in infants (Guesry, Bodanski, Tomsit, & Aeschlimann, 2000). The evidence for the potential to lower serum lipids is not unequivocal with some studies showing positive effects at 8 g/d intake (Hidaka, Tashiro, & Eida, 1991; GFn

Fm O OH

CH2OH

OH

O HO

OH

CH2 OH

HO HO HOH2C

O

O

HOH2C

O

OH

OH

CH2 OH HOH2C

CH2 OH

n O

O

HOH2C

m O

O OH

OH

CH2OH

CH2OH OH

O

OH

Figure 4 Basic chemical structure of inulins: left-hand figure: GFn with terminal glucose residue (degree of polymerization (DP) ¼ n + 2); right-hand figure: Fm without terminal glucose residue (DP ¼ m + 2).

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Yamashita, Kawai, & Itakura, 1984) while others found no effect at a higher intake of 20 g/d in type 2 diabetics (Luo et al., 1996, 2000). Yamashita et al. (1984) showed that in type 2 diabetics fasting blood glucose levels were reduced by consumption of 8 g/d of FOS. However, Luo et al. (1996) reported no changes in blood glucose concentrations in type 2 diabetics following 20 g/d of fructan consumption. Also taking the data obtained with inulin and oligofructose into account, it does not seem very likely that fructans have a significant lowering effect on fasting blood glucose levels (Bonsu, Johnson, & McLeod, 2011). In the early 1980s, it was noted that consumption of these short chain fructans led to an increase in bifidobacteria (Hidaka, Eida, Takizawa, Tokunaga, & Tashiro, 1986) and this can be viewed as the start of prebiotic research. Later studies confirmed this effect for daily intakes rates as low as 2.5 g/d (Bouhnik, Raskine, Simoneau, Paineau, & Bornet, 2006). In infants, a clear bifidogenic effect has not been reported (Guesry et al., 2000; Xia et al., 2012) at lower dosages, but Ripoll, Respondek, Wagner, Jeanne, and Gottrand (2011) found a bifidogenic effect in infants aged 4 months with a consumption of at least 2.5 g/d. Later research also showed that these fructans can improve magnesium absorption in postmenopausal women (Tahiri et al., 2001) and in adolescent girls (Van den Heuvel, Muijs, Brouns, & Hendriks, 2009). The data for improved calcium absorption are not totally convincing as only trends for an increase were found in postmenopausal women (Tahiri et al., 2003), and no effect in young girls (Van den Heuvel et al., 2009). There are also indications that FOS may favorably effect markers for colon cancer (Boutron-Ruault et al., 2005) and may relieve symptoms of Irritable Bowel Syndrome (IBS; Paineau et al., 2008). For FOS also effects on components of the human immune system have been reported. Guigoz, Rochat, Perruisseau-Carrier, Rochat, and Schiffrin (2002) showed a decrease in inflammation markers in elderly people and Shibata et al. (2009) showed that kestose (DP 3 FOS) exerted a beneficial effect in the clinical symptoms of children with atopic dermatitis. To conclude, there is ample evidence available both for the fiber effects of FOS and for the prebiotic effects. A recent development is the enzymatic production of a synthetic type of inulin with DP 3 to 17 (average DP of about 8) from sucrose using fructosyltransferase activity from Bacillus sp. 217C-1 (Wada, Sugatani, Terada, Ohguchi, & Miwa, 2005). This product has a positive effect on bowel habit (Tomono, Yamamoto, & Yamaguchi, 2010). Other data from


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human studies are not yet available, but it seems highly likely that also this type of inulin will have the same properties as FOS or inulin and oligofructose from chicory roots. The data from experimental animal trials do support this assumption as this type of inulin affects the immune system positively (Ito et al., 2008) and lowers serum lipids in rats (Sugatani et al., 2008). The properties seem therefore completely in line with those of the FOS described above or inulin from chicory roots as described under Section 2.3.3. 2.3.3 Inulin and oligofructose from chicory roots Inulins are composed of a β-2,1-linked fructosyl backbone with a terminal glucose moiety (See Fig. 4). Some inulins contain β-2,6-linked side chains (Van Arkel et al., 2012; Vijn & Smeekens, 1999). They are present in a wide variety of plants and vegetables and form a part of the daily western diet (Van Loo, Coussement, De Leenheer, Hoebregs, & Smits, 1995). The background human consumption of inulins from wheat, onions (the main sources), leek and other vegetables ranges from 3 to 10 g/d (Van Loo et al., 1995). Industrially, inulins are extracted from chicory roots. The extract is purified and spray-dried (Boeckner, Schnepf, & Tungland, 2001). Oligofructose (also called FOS) are produced by enzymatic hydrolysis of inulin (Zittan, 1981). Since the β-2,1-bonds are not susceptible to hydrolysis in the human gastrointestinal tract, inulin and oligofructose reach the colon intact where there they are completely fermented, hence they qualify as dietary fibers. The physiological effects of inulin and oligofructose are identical, but the lowest effective dosages for physiological effects as found in human studies may differ. Inulin, oligofructose (and FOS) are perhaps the most intensively investigated prebiotic fibers, to date. As discussed in Section 2.3.2, extensive studies were performed on FOS in Japan starting in the 1980s. Later studies with oligofructose and inulin from chicory roots have shown the following physiological fiber effects of these ingredients. Improvement of bowel function is well documented for inulin and oligofructose in dosages ranging from 12 to 20 g/d (Dahl et al., 2014; Den Hond et al., 2000; Kleessen, Sykura, Zunft, & Blaut, 1997; Marteau et al., 2010). As described for FOS above, studies in humans for attenuation of serum lipid levels have yielded variable results (Brighenti, 2007). In two wellcontrolled studies in normal subjects (Pedersen, Sandstr€ om, & Amelsvoort, 1997; Van Dokkum, Wezendonk, Srikumar, & van den Heuvel, 1999) and in one comparable study in patients with type 2 diabetes

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(Alles, De Roos, et al. (1999)) no significant effects were found on either blood triglyceride, blood cholesterol or blood glucose regulation in normolipidemic healthy volunteers. On the other hand, Causey, Feirtag, Gallaher, Tungland, and Slavin (2000) observed a significant decrease of blood triglyceride levels after 3 weeks of ingesting 20 g/d inulin, and others (Balcazar-Munoz, Martinez-Abundis, & Gonzalez-Ortiz, 2003; de Luis et al., 2011) also detected lower cholesterol levels in dyslipidemic people with inulin consumption. An unequivocal conclusion is not easy, but in the majority of the human studies lipid lowering effects of inulin with daily intakes ranging from 10 to 20 g/d seem to be found, especially in dyslipidemic volunteers. The effect of inulin or oligofructose on blood glucose levels is also not unequivocal. Alles, De Roos, et al. (1999) reported no changes in blood glucose concentrations in type 2 diabetics following 20 g/d of oligofructose consumption. This seems also to be the case for inulin consumption at this daily intake in nondiabetic volunteers (Causey et al., 2000). Van Dokkum et al. (1999) showed that only with inulin (15 g/d) a decrease was observed in serum glucose, while 15 g/d of oligofructose had no effect. Daubioul, Horsmans, Lambert, Danse, and Delzenne (2005) showed that in volunteers with nonalcoholic liver disease, 16 g/d of oligofructose lowered serum glucose levels. In 12 weeks study with obese volunteers with type 2 diabetes Bonsu and Johnson (2012) did not find an effect of 10 g/d of inulin consumption on serum glucose levels (or on serum lipid levels). However, Gargari, Dehghan, Aliasgharzadeh, and Jafar-abadi (2013) did report an improvement in blood glucose levels in overweight and obese women with type 2 diabetes after 2 months of inulin consumption (10 g/d of long-chain inulin). Inulin or oligofructose are nonglycemic carbohydrates, their glycemic response is very low and is determined by their content of mono- and disaccharides (Meyer, 2007). Rafter et al. (2007) show that a synbiotic product consisting of inulin and Bifidobacterium lactis Bb12 and Lactobacillus rhamnosus GG favorably effects some biomarkers for colon cancer polypectomized and colon cancer patients. So far this is the only human trial with inulin and an effect on colon cancer. In animal model studies, inulin prevents early neoplastic lesions after chemically induced carcinogenesis (Reddy, Hamid, & Rao, 1997; Rowland, Rumney, Coutts, & Lievense, 1998). To conclude, there is good evidence from human studies for the important dietary fiber effect of improved bowel habit, for the effects on attenuation of serum lipid or blood glucose levels the evidence is not totally unambiguous.


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The bifidogenic effect of inulin and oligofructose—when taken in relatively small amounts of around 5–15 g/day—is well established in different age groups (Meyer & Stasse-Wolthuis, 2009). This effect appears to be independent of chain length of inulin-type fructans (see also Meyer, 2012) and a clear dose–response relationship has not been found. The order of magnitude of the bifidogenic response likely is more dependent on the initial number of bifidobacteria before the supplementation is started. Recent research data give no reason to change these conclusions on the bifidogenic effects of fructans (e.g., Roberfroid et al., 2010). Two recent studies in human volunteers have confirmed the bifidogenic effects of inulin from both Jerusalem artichoke (Helianthus tuberosus; Ramnani et al., 2010) and globe artichoke (Cynara scolymus; Costabile et al., 2010). These types of inulin have the same molecular structure as inulin from chicory roots. Dewulf et al. (2013) and Lomax et al. (2012) provided further evidence for this effect with 8 g/d of a 1/1 mixture of long-chain inulin and oligofructose. Lugonja et al. (2009) confirmed the bifidogenic effects of chicory-derived inulin in formula-fed infants, whereas the studies by Veereman-Wauters et al. (2011) and Closa-Monasterolo et al. (2013) provide the evidence that a 1/1 mixture of long-chain inulin and oligofructose provokes a bifidogenic effect very similar to that of breast feeding. In connection with this we should also mention the large body of evidence for the bifidogenic effects of a GOS/inulin mixture (9/1) in infants of different age (see Section 2.2.1 on GOS). Recent data show that also other species such as Faecalibacterium prausnitzii (Dewulf et al., 2013; Ramirez-Farias et al., 2009), or a more specific bifidogenic effect, i.e., the stimulation of Bifidobacterium adolescentis (Ramirez-Farias et al., 2009) by the consumption of inulin or oligofructose. Inulin and oligofructose are thus not merely bifidogenic. Also, there are many indications to support the hypothesis that inulintype fructans may reduce the production of potentially toxic metabolites by suppressing specific enzyme activities in the colon. In addition, consumption of these ingredients may increase the concentration of compounds that could be beneficial for the host. Oligofructose (Van den Heuvel, Muys, van Dokkum, & Schaafsma, 1999) and inulin (Abrams et al., 2005; Coudray et al., 1997) stimulate calcium absorption in young adults. Based on this effect also an improved bone mineral density was found after one year consumption of 8 g/d of inulin in adolescent boys and girls (Abrams et al., 2005). Similarly, inulin stimulates

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calcium and magnesium absorption in postmenopausal women (Holloway et al., 2007; Kim et al., 2004) which may also contribute to a better mineral balance in this group at risk for bone loss. Other beneficial effects arise from the influence on the human immune system. Data for humans are scarce, but Cummings, Christie, and Cole (2001) showed that travelers to high-risk countries had a trend for lowered occurrence of diarrhea with oligofructose consumption of 10 g/d. Later analyses of the data showed that the severity of diarrhea was significantly lower (Macfarlane, Macfarlane, & Cummings, 2006). Lewis, Burmeister, and Brazier (2005) looked whether oligofructose (12 g/d) could prevent antibiotic-associated diarrhea. Although they found an increase in bifidobacteria in the feces of the patients, they did not find any protective effect of oligofructose consumption in these elderly people. Other investigators showed that oligofructose consumption at 2 g/d led to fewer episodes with diarrhea or fever in children aged 7–19 months (Waligora-Dupriet et al., 2007) with a concomitant trend for an increased content of fecal bifidobacteria and a significant decrease in potential pathogens, such as clostridia. The work by the group of Delzenne has shown that inulin and oligofructose also affect our energy balance. First in animal studies, but later also in human studies it was found that especially consumption of oligofructose led to a lower energy intake, possible based on increased feelings of satiety (Cani, Joly, Horsmans, & Delzenne, 2006; Verhoef, Meyer, & Westerterp, 2011). The latter phenomenon might be the consequence of an effect on gut hormone levels that affect satiety. The effect on energy intake may also lead to weight loss, by the loss of body fat mass (Parnell & Reimer, 2009). To conclude, there is ample evidence available from human studies showing that inulin and oligofructose from chicory are prebiotic dietary fibers.

2.4. Glucose-based prebiotic fibers There is a large range of glucose-based oligomers and polymers commercially available that resist human digestion, and thus that can be classified as dietary fibers. Below some of these will be presented, namely, those that have well-established fiber and prebiotic features. The overview is not meant to be complete, and more data can be found in the reviews by Slavin, Savarino, Paredes-Diaz, and Fotopoulos (2009), Fuentes-Zaragoza et al. (2011), and S´liz˙ewska, Kapusńiak, Barczy nska, and Jochym (2012).


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2.4.1 Iso-malto-oligosaccharides This mixture of α-(1,6)-linked glucosides is manufactured from starch by enzymatic treatment with a mixture of α-amylase, α-glucosidase, and pullulanase. The mixture thus obtained has a DP up to 5. A large portion of this ingredient reaches the colon; the remainder is degraded by intestinal enzymes, leading to a rise in blood glucose levels (Kohmoto et al., 1992; Oku & Nakamura, 2003). Others showed that the intake of iso-maltooligosaccharides with 10 g/d by human volunteers resulted in a selective increase of bifidobacteria (Kohmoto et al., 1991). It is also reported that these oligosaccharides stimulate bowel movement in elderly male volunteers (Chen, Lu, Lin & Ko, 2001) and that consumption is associated with a bifidogenic effect and a decrease of total cholesterol levels with an intake of 10 g/d in elderly people (Yen, Tseng, Kuo, Lee, & Chen, 2011). However, other research failed to find a bifidogenic effect of these oligomers at a consumption of 10 g/d as shown by the data of Bouhnik et al. (2004). In conclusion, the data for the bifidogenic effects of isomaltooligosaccharides are less consistent than for inulin of oligofructose. The limited data for physiological effects show effects similar to those of inulin: improved defecation pattern and lowering of total cholesterol levels (in elderly). 2.4.2 Polydextrose Polydextrose (PDX) was developed as a low-caloric bulking agent to be used as a fat, sugar, or starch replacer. It is prepared by thermal polymerization of glucose, with sorbitol and an organic acid, such as citric acid, as a catalyst. Various types of glycosidic bonds arise during this process, and the complexity of the structure prevents hydrolysis by mammalian enzymes (Craig, Holden, Auerbach, & Frier, 1998). This means that the material passes intact into the colon where it behaves like a dietary fiber. The physiological effects of this material consumed with 20 g/d include stool bulking and softer stools and bifidogenic changes in the fecal microbiota ( Jie et al., 2000). At a lower dosage of 8 g/d no effect on fecal bifidobacteria or lactobacilli was found (Hengst, Ptok, Roessler, Fechner, & Jahreis, 2008), but at this dosage improvement of stool habit was noted. PDX is nonglycemic and may therefore help in blood glucose homeostasis (Craig et al., 1998). More recent data on the prebiotic and fiber effects can be found in Section 2.4.3. Recent publications support the notion that PDX may be able to reduce food intake, probably by increasing feelings of satiety (Astbury, Taylor, & Macdonald, 2013; King, Craig, Pepper, & Blundell, 2005). Recently, it was

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shown that PDX also may increase fat oxidation in overweight people, next to an effect to increase satiety (Konings, Schoffelen, Stegen, & Blaak, 2013). 2.4.3 Soluble Gluco Fiber Soluble Gluco Fiber (SGF), also known as Soluble Corn Fiber (SCF) in the United States, is manufactured from corn starch. Timm, Thomas, Boileau, Williamson-Hughes, and Slavin (2013) compared polydextrose and SGF for effects on gastrointestinal function (20 g/d in healthy adults). They found a significant increase in stool wet weight and an increase in stool frequency as measured over 5 days. Vester Boler et al. (2011) also reported an increase in stool wet weight and an increase in stool frequency as measured over 5 days in healthy men when consuming 21 g/d of these fibers (SGF and PDX). A fecal bulking effect of 1.4 g/g for PDX and 0.9 g/g with SCF was found and these numbers are in line with those of other fermentable fibers (Causey et al., 2000; Den Hond et al., 2000; Salminen et al., 1998). Analysis of fecal samples showed clear signs of increased and improved fermentation: lowering of the fecal pH, lower levels of fecal ammonia, of phenolic compounds and branched chain fatty acids. As described above, these fermentation products are potentially harmful. Stewart, Nikhanj, Timm, Thomas, and Slavin (2010) investigated these effects at a lower consumption rate of 12 g/d. With this consumption rate no effects on stool weight or frequency, pH, total SCFA, or on serum levels of triglycerides, cholesterol, glucose, insulin, ghrelin, or C-reactive protein were found. Kendall et al. (2008) show that both the glycemic and the insulinemic response of SGF are lower than the standard response from glucose consumption. SGF does not have a lowering effect on the GR of glucose, which makes it similar in behavior to many other nonviscous dietary fibers. Monsivais, Barter, Christiansen, Perrigue, and Drewnowski (2010) studied the acute effects on energy intake and satiety of four types of cornderived fibers in a preload study of about 12 g fiber and SGF was one of the fibers investigated. They found that satiety ratings with all fibers were higher compared to a low-energy control, but were not different from each other. SGF did not suppress energy intake relative to an isoenergetic control. Vester Boler et al. (2011) are the first showing a bifidogenic effect for SGF in humans, but clearly the effect occurs at much higher concentrations (21 g/d) than for inulin or oligofructose, which both are bifidogenic with 5 g/d (Meyer & Stasse-Wolthuis, 2009). Hooda et al. (2012) also describe the effects SGF (and polydextrose) consumption (21 g/d) on the


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composition of the human gut microbiota. The consumption of SCF led to an increase of fecal Clostridiaceae, Veilonellaceae and a lower level of Eubacteriaceae. The abundance of Faecalibacterium (F. prausnitzii is well known for its anti-inflammatory properties and an important producer of butyrate) was greater with SCF. Surprisingly, a lower level of Bifidobacterium spp. was found with an increase in Lactobacillus spp. with SCF consumption. The data for bifidogenic effects of SGF seem therefore not consistent, but positive effects on the fecal microbiota have been shown. Weaver, Martin, Story, Hutchinson, and Sanders (2010) investigated the influence of SGF and PDX on bone calcium content and strength in a rat model and at 10% in the feed. PDX increased bone Ca content, whereas SGF showed the greatest benefits for bone properties, i.e., higher whole body mineral content and density and greatest BMD and breaking strength of the distal femur. The effects of SGF (and some other soluble dietary fibers) on gut inflammation in a mouse model for inflammatory bowel disease were published recently by Bassaganya-Riera et al. (2011). SGF, inulin and resistant starch ameliorated disease activity in this model, but PDX and acacia gum showed much less clinical activity. The positive effects of SGF and inulin might be due to effects on components of the immune system, such as on cytokine production. The increased IL-10 production (IL-10 is supposed to have anti-inflammatory properties) is an example of this. In conclusion, SGF seems to behave much like the other prebiotic fibers described, but the evidence is less in number of studies and consistency of data than for others. 2.4.4 Other resistant starches As a final example of a commercially available resistant starch that exhibits prebiotic dietary fiber features, Nutriose is mentioned. It is manufactured from starch by a highly controlled dextrinization process, that results in a product with 1,2 and 1,3 glycosidic linkages and a DP of about 10–30. The product has some fecal bulking effect and reduces intestinal transit time (Vermorel et al., 2004). A clear bifidogenic effect has not been found, but it leads to an increase of the number of saccharolytic bacteria in the fecal microbiota (Lefranc-Millot et al., 2012); hence a favorable change in metabolic activity is induced (Table 2). Moreover, this type of resistant starch has a beneficial impact on feelings of satiety and reduces body weight in overweight men (Guerin-Deremaux et al., 2011) and it may improve markers for metabolic syndrome (Li et al., 2010).

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Table 2 Overview of products arising from fermentation in the colon Products from fermentation Products from fermentation of carbohydrates (saccharolysis) of proteins (proteolysis) Bacterial biomass, gas (CO2, H2, CH4)

SCFA (acetate, propionate, butyrate) Lactate

BCFA (iso-butyrate, iso-valerate) Sulfides (H2S, CH3S) Ammonia, amines Phenols (indole, p-cresol, skatole)

SCFA, short-chain fatty acids; BCFA, branched chain fatty acids.

2.5. Gums and other complex polysaccharides as prebiotic fibers Some gums, exudates from plants are best known for their texturizing properties, but they may also as prebiotic dietary fibers. 2.5.1 Guar gum Guar gum is a galactomannan isolated from the seed of Cyamopsis tetragonolobus (guar). In its unmodified form, this food additive is used as a thickener in a large variety of food products. Partial enzymatic hydrolysis results in a product with a much lower viscosity that can be used as a soluble dietary fiber, particularly in clinical nutrition (Slavin & Greenberg, 2003). The physiological effects of this fiber source comply with what might be expected from a soluble fiber. It improves bowel functioning, reducing diarrhea in enterally fed patients (Homann, Kenen, F€ ussenich, Senkal, & Zuntobel, 1994) and relieves constipation (Takahashi et al., 1994). It also improves bowel habit in people suffering from IBS (Giannini, Mansi, Dulbecco, & Savarino, 2006). It shows a hypolipidemic effect in humans, lowering both serum cholesterol and triglycerides (Takahashi et al., 1993), and it reduces postprandial glycemia (Wolever, Jenkins, Nineham, & Albert, 1979). Guar gum is readily fermented by the human fecal microbiota (Salyers, West, Vercelotti, & Wilkins, 1977), and it has bifidogenic effects, at least with enteral feeding (Okubo et al., 1994) and in combination with oligofructose from chicory (Tuohy, Kolida, Lustenberger, & Gibson, 2001). 2.5.2 Acacia gum This food additive is isolated from acacia trees and its main use is as an emulsifier or thickener in a range of food products. The arabinogalactan-type molecule consists of galactose, arabinose, rhamnose and glucuronic acid in a highly complex structure that in addition contains polypeptide chains.


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Also for this material fiber and prebiotic effects have been reported, and it is applied in food for these reasons. Bifidogenic effects in healthy human volunteers have been shown in various studies (Calame, Weseler, Viebke, Flynn, & Siemensma, 2008; Cherbut, Michel, Raison, Kravtchenko, & Severine, 2003; Wyatt, Bayliss, & Holcroft, 1986), whereas Min et al. (2012) showed the improved bowel habit of this type of fiber (in combination with a probiotic strain). 2.5.3 Arabinoxylo-oligosaccharides and xylo-oligosaccharides Arabinoxylo-oligosaccharides are an example of a novel prebiotic dietary fiber. They can be isolated from wheat bran and consist of xylan chains with a variable substitution of arabinose side chains (Swennen, Courtin, Lindemans, & Delcour, 2006). The fiber properties include an improvement of bowel habit and positive change of the fermentation in the colon (Cloetens et al., 2010, 2008; Damen et al., 2012; François et al., 2012), whereas they were also shown to possess bifidogenic properties (François et al., 2012). Xylo-oligosaccharides can be produced by partial enzymatic hydrolysis of xylan from birch wood by the endo-xylanase from Trichoderma sp. (Aachary & Prapulla, 2011; Okazaki, Fujikawa, & Matsomoto, 1990) and consist of a mixture of xylose and xylo-oligosaccharides (mostly DP2 and DP 3). Human studies have shown that XOS exhibit fiber properties, as they can improve bowel habit in elderly (Chung, Hsu, Ko, & Chan, 2007) and in pregnant women (Tateyama et al., 2005). XOS have been shown to have a bifidogenic effect in humans (Chung et al., 2007; Okazaki et al., 1990), which in turn may lead to an improved colonic fermentation as suggested by the lowered blood ammonia levels in patients with liver cirrhosis upon XOS consumption (Kajihara et al., 2000). 2.5.4 Other candidates Research for the development of new prebiotic dietary fibers is still taking place all over the world and publications about new prebiotic candidate molecules emerge regularly. It is beyond the scope of this review to discuss these publications; most of them are based on data from in vitro trials, that can give indications about the prebiotic effects of these new molecules (e.g., Leijdekkers et al., 2014), but confirmation of the effects in human trials remains essential. Moreover, showing a mere bifidogenic change in the fecal microbiota may not suffice as such a shift is not considered by authorities as a beneficial physiological effect. It may be necessary to also show beneficial effects on serum lipid levels (in relation with heart health), on serum glucose levels (relevant for diabetes), on mineral absorption (for bone health), etc.

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3. NUTRITION AND HEALTH CLAIMS BASED ON PREBIOTIC FIBERS 3.1. Nutrition claims Nutrition claims based on the content of certain nutrients are used worldwide. Many of the ingredients or additives discussed above do not only have nutritional functionalities, but also technical properties that are important for their applications. As an example, inulin can be used very well in a wide range of applications as low-caloric bulking agent to replace fat or sugar (Meyer, Bayarri, Ta´rrega, & Costell, 2011). With this type of use, not only nutrition claims based on dietary fiber content are possible, but also claims based on the lower fat or sugar content, etc. Table 3 Examples of nutrition claims with relevance for prebiotic dietary fibers Claim Conditions of use in the EU

Energy reduced Energy value reduced by at least 30% (with an indication of the characteristic(s) which make(s) the food reduced in energy) Low fat

Less than 3 g of fat per 100 g for solids, or 1.5 g of fat per 100 ml for liquids (1.8 g per 100 ml for semi-skimmed milk)

Low sugars

Less than 5 g of sugars per 100 g for solids or 2.5 g of sugars per 100 ml for liquids

Source of fiber

At least 3 g of fiber per 100 g

High fiber

At least 6 g of fiber per 100 g

Reduced (ingredient)

Reduction of at least 30% compared to a similar product

Conditions of use from Annex I of EU 1924/2006 (European Commission, 2006).

The regulation of nutrition claims is not essentially different in various countries: complying with the conditions of use in each country makes the use of such claims easily possible. It is important to note that the conditions for use may be different in various countries. As an example, nutrient content claims in the United States are based on the nutrient content per serving size as opposed to per 100 g or ml in the EU and many Asian countries (e.g., Malaysia, Thailand). “Good source of fiber” can be used in the United States on food that contains at least 2.5 g fiber per serving, whereas a “source of fiber” claim in the EU requires at least 3 g of total dietary fiber per 100 g of product. In Europe, the wording and conditions for use of nutrition claims are described in Annex I of Regulation 1924/2006 (European Commission, 2006) and some examples are shown in Table 3. The prebiotic fibers described above are no exception to these rules.


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Using claims on the dietary fiber content of a product is the easiest way to tell the consumer that the product is good for his or her health. Moreover, the consumer seems to understand the fiber message well and the same holds for claims on reduced fat, sugar or energy content.

3.2. Health claims for prebiotic dietary fibers In contrast to nutrition claims there are important differences between the European and American regulations on health claims. In Europe, Regulation 1924/2006 requires that health claims are based on “generally accepted scientific evidence” and that they are well understood by the “average consumer.” The European Food Safety Authority (EFSA)— Panel on Dietetic Products, Nutrition and Allergies (NDA) assesses the scientific substantiation of three types of health claims as shown in Table 4. Part of the EU claims regulation was a procedure to generate a list of approved health claims that were already used in the EU member states (Article 13.1). The evaluation process of these generic Article 13.1 claims has now been completed; resulting in a list of 222 approved generic health claims. This European-wide list of permitted health claims has been finally approved by the European Commission, and became law by mid-May 2012 (European Commission, 2012). The EC has published the complete list of both the authorized and nonauthorized health claims (EU Register of nutrition and health claims, http://ec.europa.eu/nhclaims/). Manufacturers are allowed a certain degree of flexibility in the rewording of permitted health claims from scientific terminology into messages that can be understood by the “average consumer.” The EC has left it to EU member states to decide what further flexibility will be allowed. In the EU no generic health claims for any of the health effects of any prebiotic have been approved. Also, generic health claims for other dietary Table 4 Types of health claims in EU Regulation 1924/2006 (European Commission, 2006)

Article 13.1

“Generic function” claims describing the effect of a food or an ingredient on a physiological function of the body

Article 13.5

“New function” health claims, based on newly developed scientific evidence and/or claim applications that include a request for protection of proprietary data

Article 14 “Reduction of disease risk” claims; and “Children’s claims” referring to the growth and development of children

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fibers will not be allowed (with a few exceptions, such as for pectins and maintenance of blood cholesterol) and thus, such claims cannot be used for prebiotic dietary fibers. The procedure as used for approval of Article 13.1 claims is not available any longer. This means that approval of new function claims can only be obtained through an Article 13.5 procedure, which requires submission of a dossier in a prescribed format. Following this procedure, the joint European inulin industry has submitted a dossier for the effect of lowering the postprandial glycemic response with inulin and oligofructose when used as a sugar replacer. In January 2014, a positive opinion was published by EFSA (EFSA, 2014). This opinion has now to be adopted as an authorized health claim by the European Commission and the European Parliament. A similar claim has been approved for polydextrose (EFSA, 2011) as a sugar replacer to lower the glycemic response. In Japan, the physiological effects of lactulose (not a dietary fiber, but a prebiotic) are exploited in a variety of food applications (Mizota, 1994) and in the EU the improved bowel habit effect may used in an authorized health claim: lactulose contributes to an acceleration of intestinal transit (EFSA, 2010a, 2010b). The bifidogenic effect of lactulose cannot be used as a health claim in the EU. So far, these are the only health claims allowed in the EU on any of the ingredients described above. 3.2.1 Health claims in the United States In the United States, different health-related statements are permissible. The claim situation in the United States has been reviewed by Hasler (2008). In brief: apart from nutrient content claims (already discussed in Section 3.1), a distinction is made between structure-function claims and health claims. Structure-function claims are statements that describe the relation between an ingredient and the effect on a normal function or structure of the body; this type of claims is similar to the Article 13.1 and 13.5 claims in Europe. Health claims are statements that describe a relationship between a food component and reducing risk of a disease or a health-related condition. These claims are comparable to Article 14 (reduction of disease risk) claims in the EU. Structure-function claims were authorized under the Dietary Supplement Health and Education Act of 1994. These claims are allowed without premarket approval, but a dossier with the scientific evidence for the claim should be available with the manufacturer of the product. The wording


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should be chosen carefully because a direct or indirect relation with a given disease is not allowed. A disclaimer should be added that the US Food and Drug Administration (FDA) has not evaluated the claim and that the product is not intended to “diagnose, treat, cure or prevent any disease.” A notification should be submitted to FDA within 30 days after marketing the product with the claim. “Inulin consumption stimulates calcium absorption” and “Galactooligosaccharides improve the composition of the colonic microbiota” are examples of such claims. Health claims related to the reduction of disease risk were authorized under the Nutrition Labeling and Education Act of 1990. These claims are based on a very high standard of scientific evidence. First, the totality of the publicly available evidence must support the diet-disease relation that is the subject of the claim, and second, there must be significant scientific agreement (SSA) among qualified experts that the relation is valid. The FDA authorizes these types of health claims based on an extensive review of the scientific literature, generally as a result of the submission of a health claim petition. SSA claims are also allowed based on statements published by certain government authorities. The Food and Drug Administration Modernization Act of 1997 provides an expedited route to health claim approval by allowing “authoritative statements” from a scientific body of the U.S. Government or the National Academy of Sciences to be used as a health claim. Another category of health claims concerns the so-called qualified health claims that are used for describing developing relationships between components in the diet and disease. Such claims require qualifying language such as “although there is scientific evidence supporting the claim, the evidence is not conclusive.” All forms of (reduction of disease risk) health claims require approval of the FDA. The FDA has published a list of both types of approved health claims (FDA, 2013a, 2013b), but none of these claims are allowed for prebiotic dietary fibers. With qualified health claims, the FDA established a ranking system from moderate/good, “B” level, to very low, “D” level, which reflects the relative weight of the scientific evidence supporting the proposed claim. Unqualified “A” levels claims are those that meet the standard of SSA (Hasler, 2008). In conclusion, in the United States, structure-function claims describing a relationship between an ingredient such as inulin or polydextrose and an effect on a normal function or structure of the body are allowed without premarket approval (a dossier with the scientific evidence for the claim should be available). These claims have a scope similar to Article 13.1 claims

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in the EU. The FDA distinguishes two types of reduction of disease risk claims (similar to the EU Article 14 claims): claims based on SSA—including claims with approval based on authoritative statements by certain government authorities—and qualified health claims. Both types of claims need premarket approval by the FDA.

4. FUTURE DEVELOPMENTS Above we have described the dietary fiber and prebiotic properties of wide range of food ingredients and additives. For the first we focused on the fiber properties for improved of bowel habit, improved fermentation in the colon, attenuation of serum lipid levels and blood glucose, effect on colon cancer and on weight management or control. We could show that for many of the compounds one or more of these properties are shown in trials with human volunteers. Thus, these ingredients and additives can be classified as dietary fibers. For prebiotic properties first of all the bifidogenic changes in the fecal microbiota were shown as these often are the best documented for many of the fibers. Whenever available the physiological effects arising from the changes in activity of the microbiota, i.e., becoming more saccharolytic, were presented. This description of the possible components of the prebiotic effect, the physiological effects connected with the changes in composition and activity of the colon microbiota, also shows the central role of the gut microbiota in the physiology of the host. As important as the classical fiber effects may be, the prebiotic effects, the effects based on the shift in microbial composition and in metabolic activity may have much more impact on human physiology. As depicted in Fig. 5, there is accumulating evidence that prebiotics have, in various degrees, several health-promoting properties related to enhanced mineral absorption, laxation, potential anticancer properties, lipid metabolism, effect on energy homeostasis, anti-inflammatory, and other immune effects, including atopic disease. Many of these effects have been established in various degrees for the prebiotic fibers described above and many of these phenomena can be linked to their fermentation and subsequent SCFA production by the microbiota in the large gut (Macfarlane & Macfarlane, 2011; Saulnier, Kolida, & Gibson, 2009). In fact, the gut microbiota now appears to influence the host at nearly every level and in every organ system (Sekirov, Russell, Antunes, & Finlay, 2010).

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Suppression of pathogenic microorganisms growth

Pathogenic bacteria

Ca2+

Lowering of enterostasis pH increase in beneficial microorganisms action

Minerals absordtion (Ca2+) Increase in bone density

SCFA Gpr41

Keeping of appropriate insulin level Effect on satiety

GLP-1 Usage of prebiotic fermentation products

Intestinal epithelium

Systemic effects

Figure 5 Depiction of the beneficial roles of prebiotics in the mammalian gastrointestinal tract and their systemic effects. Ca2+, calcium; GLP-1, glucagon-like peptide-1; Gpr41, G protein-coupled receptor 41; SCFA, short-chain fatty acid. Figure taken from Śliżewska et al. (2012).

From recent research, it is clear that the mere analysis of the bifidogenic effect is a far too limited approach to study the complex effects of the gut microbiota on the physiology of the host. With current techniques more data can be obtained on the functionality of the gut microbiota. For instance, with metagenomic analysis sequence information can be obtained from the collective genomes of the colonic microbiota. The combination of such diverse areas as immunology, microbiology, nutrition, epidemiology, and metabolic medicine begins to unravel the complexity of the relationships between the gut microbiota and host’s health. According to Jacobs, Gaudier, van Duynhoven, and Vaughan (2009), focusing on microbe–host mutualism has demonstrated that metabolomics is capable of detecting and tracking diverse microbial metabolites from different nondigestible food ingredients, of discriminating between phenotypes with different inherent microbiota and of potentially diagnosing infection and gastrointestinal diseases. The integration of metabolomics with other -omics techniques is a further step towards a more coherent understanding of the complex microbe-host mutualism. With respect to gut and immune

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function, metabolomics combined with analysis of the gut microbiota composition is essential to correlate microbial species to their activity. Further downstream, the link between metabolomics and transcriptomics would strengthen the scientific evidence on the metabolic and immune regulation of the host. Of course, the novel hypothesis generated by the -omics approach need to be validated furthermore using targeted hypothesis testing approaches involving the measurement of relevant immune function markers. The authors concluded that holistic -omics approaches are indispensable to cover the complex interactions between the gut microbial ecosystem and the host. In particular, metabolomics, albeit in an early stage with respect to the microbe–host mutualism, holds great potential to better understand the fate of nondigestible food ingredients on gut health and immunity ( Jacobs et al., 2009). Functional metagenomics could be helpful to refine or even redefine the concept of prebiotic activity. As discussed above, this is now mostly based on an increase in bifidobacteria, but with the more complete view of the effect of prebiotics on gut microbiota composition it might be possible to target or include other groups of microorganisms with potentially other health benefits. Several in vitro and in vivo studies have shown that other bacteria also use inulin as a substrate. An in vitro study by Kovatcheva-Datchary (2010) revealed that populations of Dorea longicatena and B. adolescentis were actively involved in inulin metabolism, as analyzed by stable isotope probing in combination with diagnostic phylogenetic profiling technique. As mentioned above, others have shown an increase of F. prausnitzii next to a bifidogenic change upon inulin consumption (Dewulf et al., 2013; Ramirez-Farias et al., 2009). The butyrate-producing F. prausnitzii has been strongly implicated in anti-inflammatory activity (Sokol et al., 2008). Scott et al. (2011) showed the importance of inducible enzymes in the utilization of inulin and starch. They studied the substrate-driven gene expression in Roseburia inulinivorans, a recently identified motile representative of the Firmicutes that contributes to butyrate formation from a variety of dietary polysaccharide substrates in the human large intestine. Another study by Sonnenburg et al. (2010) indicates that genetic and functional differences between Bacteroides species are predictive of in vivo competitiveness in the presence of dietary fructans. The investigators speculate that gene sequences that distinguish species’ metabolic capacity can serve as potential biomarkers in microbiome datasets to enable rational manipulation of the microbiota via diet. As an example, Louis, Young, Holtrop, and Flint (2010) showed that inulin intake leads to an increase of butyrate-producing bacteria


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(F. prausnitzii, Eubacterium spp.) by analysis of a gene for an enzyme for butyrate production (butyryl-CoA:acetate-CoA transferase gene). This type of analysis provides a new source of information of the functionally important groups of the microbial community in the colon. Recently, Delzenne, Neyrinck, Cani, and Backhed (2011) have discussed how metagenomic and integrative metabolomic approaches could help elucidate which bacteria, among the trillions in human gut, or more specifically which activities/genes, could participate to the control of host energy metabolism, and could be relevant for future therapeutic developments. The authors expect that the -omics approach will reveal whether bifidobacteria play a (prominent) role in these effects or that other genera or species are more important. These authors speculate that the -omics approach will most likely lead to new sets of biomarkers for gut health in relation with physiological effects in the host. In the end, this will contribute to obtaining evidence for health claims.

4.1. Final remarks A tremendous research effort is going on in the area of human gut microbiota to determine the relevance for human health. Almost every day a new paper is published describing the role of the gut microbiota in human health and disease. It is to be expected that these efforts not only will contribute to our understanding of the role of the human gut microbiota in human health, but also to the development of new biomarkers to measure gut health. With this increased insight and these new biomarkers, the effect of prebiotic dietary fibers on human health will become more evident. Moreover, with such biomarkers being validated health claims for prebiotic fibers will become possible in the future. At the same time, it is also clear that we still have a long way to go from the original observations of the bifidogenic effect of FOS in the early 1980s to a full understanding of the impact of prebiotic fibers on the composition and activity of the human gut microbiota and thus on human physiology and health.

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Delzenne, N. M., Neyrinck, A. M., Cani, P. D., & Backhed, F. (2011). Targeting gut microbiota in obesity: Effects of prebiotics and probiotics. Nature Reviews Endocrinology, 7, 639–646. Den Hond, E., Geypens, B., & Ghoos, Y. (2000). Effect of high performance chicory inulin on constipation. Nutrition Research, 20, 731–736. Depeint, F., Tzortzis, G., Vulevic, J., l’Anson, K., & Gibson, G. R. (2008). Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB 41171, in healthy humans : A randomized, double-blind, cross-over, placebo-controlled intervention study. American Journal of Clinical Nutrition, 87, 785–791. Dewulf, E. M., Cani, P. D., Claus, S. P., Fuentes, S., Puylaert, P. G., Neyrinck, A. M., et al. (2013). Insight into the prebiotic concept: Lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut, 62, 1112–1121. Dinoto, A., Marques, T. M., Sakamoto, K., Fukiya, S., Watanabe, J., Susumu, I., et al. (2006). Population dynamics of bifidobacterium species in human feces during raffinose administration monitored by fluorescence in situ hybridization-flow cytometry. Applied and Environmental Microbiology, 72, 7739–7747. Drakoularakou, A., Tzortzis, G., Rastall, R. A., & Gibson, G. R. (2010). A double-blind, placebo-controlled, randomized human study assessing the capacity of a novel galactooligosaccharide mixture in reducing travellers’ diarrhea. European Journal of Clinical Nutrition, 64, 146–152. EFSA. (2010a). EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Scientific opinion on the substantiation of health claims related to lactulose and decreasing potentially pathogenic gastro-intestinal microorganisms (ID 806) and reduction in intestinal transit time (ID 807) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA Journal, 8(10), 1806. http://dx.doi.org/10.2903/j.efsa.2010.1806. EFSA. (2010b). Outcome of the public consultation on the draft opinion of the scientific panel on dietetic products, nutrition, and allergies (NDA) on dietary reference values for carbohydrates and dietary fibre. EFSA Journal, 8(5), 1508. http://dx.doi.org/ 10.2903/j.efsa.2010.1508. EFSA. (2011). EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Scientific Opinion on the substantiation of health claims related to the sugar replacers xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, D-tagatose, isomaltulose, sucralose and polydextrose and maintenance of tooth mineralisation by decreasing tooth demineralisation (ID 463, 464, 563, 618, 647, 1182, 1591, 2907, 2921, 4300), and reduction of post-prandial glycaemic responses (ID 617, 619, 669, 1590, 1762, 2903, 2908, 2920) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA Journal, 9(4), 2076. http://dx.doi.org/10.2903/j.efsa.2011.2076. EFSA. (2014). Scientific Opinion on the substantiation of a health claim related to nondigestible carbohydrates and reduction of post-prandial glycaemic responses pursuant to Article 13(5) of Regulation (EC) No 1924/2006. EFSA Journal, 12(1), 3513. http://dx.doi.org/10.2903/j.efsa.2014.3513. European Commission. (2006). Regulation (EC) No 1924/2006 of the European parliament and of the council of 20 December 2006 on nutrition and health claims made on foods. Official Journal of the European Union, L 404, 9–25. European Commission. (2008). Directive 2008/100/EC of 28 October 2008 amending Council Directive 90/496/EEC on nutrition labelling for foodstuffs as regards recommended daily allowances, energy conversion factors and definitions. Official Journal of the European Union, L285, 9–12. European Commission. (2012). Regulation (EU) No 432/2012 establishing a list of permitted health claims made on foods, other than those referring to a reduction of disease risk or to children’s development and health. Official Journal of the European Union, L136, 1–40.

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