Skip to main content Accessibility help
×
Home
Hostname: page-component-59b7f5684b-z9m8x Total loading time: 1.796 Render date: 2022-09-29T14:07:42.579Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "displayNetworkTab": true, "displayNetworkMapGraph": false, "useSa": true } hasContentIssue true

Prebiotics, immune function, infection and inflammation: a review of the evidence

Published online by Cambridge University Press:  25 September 2008

Amy R. Lomax*
Affiliation:
Institute of Human Nutrition, School of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK
Philip C. Calder
Affiliation:
Institute of Human Nutrition, School of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK
*
*Corresponding author: Miss Amy R. Lomax, fax +44 2380 795255, email arl203@soton.ac.uk
Rights & Permissions[Opens in a new window]

Abstract

β2-1 Fructans are carbohydrate molecules with prebiotic properties. Through resistance to digestion in the upper gastrointestinal tract, they reach the colon intact, where they selectively stimulate the growth and/or activity of beneficial members of the gut microbiota. Through this modification of the intestinal microbiota, and by additional mechanisms, β2-1 fructans may have beneficial effects upon immune function, ability to combat infection, and inflammatory processes and conditions. In this paper, we have collated, summarised and evaluated studies investigating these areas. Twenty-one studies in laboratory animals suggest that some aspects of innate and adaptive immunity of the gut and the systemic immune systems are modified by β2-1 fructans. In man, two studies in children and nine studies in adults indicate that the adaptive immune system may be modified by β2-1 fructans. Thirteen studies in animal models of intestinal infections conclude a beneficial effect of β2-1 fructans. Ten trials involving infants and children have mostly reported benefits on infectious outcomes; in fifteen adult trials, little effect was generally seen, although in specific situations, certain β2-1 fructans may be beneficial. Ten studies in animal models show benefit of β2-1 fructans with regard to intestinal inflammation. Human studies report some benefits regarding inflammatory bowel disease (four positive studies) and atopic dermatitis (one positive study), but findings in irritable bowel syndrome are inconsistent. Therefore, overall the results indicate that β2-1 fructans are able to modulate some aspects of immune function, to improve the host's ability to respond successfully to certain intestinal infections, and to modify some inflammatory conditions.

Type
Review Article
Copyright
Copyright © The Authors 2008

Prebiotics have been defined 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 beneficial bacteria in the colon and thus improve host health’(Reference Gibson and Roberfroid1). Research on the potential health benefits of prebiotics has occurred over the last 15 years or so, with a recent interest in the effects on the immune system, the host's ability to fight infection, and inflammatory processes and conditions. These effects have been reviewed several times(Reference Hamilton-Miller2Reference Guarner7) but to our knowledge there are no reviews that bring together all of the available studies in all of the these areas. Thus, the aim of the present article is to describe the structure and dietary sources of prebiotics, and to summarise and evaluate studies investigating the influence of prebiotics on immunity, host defence, and inflammatory processes and conditions.

Structure of prebiotics

β2-1 Fructans, which include inulin (IN) and fructo-oligosaccharides (FOS), fulfil the criteria for prebiotics(Reference Gibson, Probert, Van Loo, Rastall and Roberfroid8). Other carbohydrates including galacto-oligosaccharides (GOS), gluco-oligosaccharides, isomalto-oligosaccharides, lactulose, mannanoligosaccharides (MOS), nigero-oligosaccharides, oat β-glucans, raffinose, soyabean oligosaccharides, transgalacto-oligosaccharides and xylo-oligosaccharides are considered as candidate prebiotics. Only studies with β2-1 fructans will be considered in the present review, as these are the most widely studied with regard to potential modulation of the immune system, and relatively little information is available on the immunomodulatory properties of the other candidate prebiotics.

IN is a linear carbohydrate molecule which contains β-(2 → 1) fructosyl–fructose linkages with a terminal glucose(Reference Waterhouse, Chatterton, Suzuki and Chatterton9). IN may contain between two and sixty fructose residues (Fig. 1), with an average of twelve. Partial enzymatic hydrolysis of IN yields a FOS known as oligofructose (OF), which can have a terminal glucose or fructose residue (Fig. 1). In OF there can be two to eight (average five) fructose residues with a terminal glucose residue or a chain of three to eight (average five) fructose residues(Reference Roberfroid10). Thus IN and OF differ according to degree of polymerisation (Fig. 1). Short-chain FOS may also be derived by enzymatic addition of fructose residues to sucrose (Fig. 1); the products formed contain two to four fructose residues with a terminal glucose residue (Fig. 1). Some studies have used products containing OF-enriched IN or IN with shorter-chain FOS removed, while some studies do not specify exactly what they used, merely referring to FOS.

Fig. 1 The structures of β2-1 fructans. DP, degree of polymerisation; F, fructose; G, glucose; RF, reducing fructose.

Dietary sources of prebiotics

IN is found naturally in a variety of plant foods such as bananas, barley, chicory, garlic, Jerusalem artichoke, leeks, onions and wheat(Reference van Loo, Coussement, de, Hoebregs and Smits11). IN has been extracted from chicory roots, Jerusalem artichoke, artichoke, dahlias and dandelions(Reference Lopez-Molina, Navarro-Martinez, Rojas, Hiner, Chazarra and Rodriguez-Lopez12). Typical daily intakes of IN for adults are estimated to be between 3 and 11 g/d in Europe, and between 1 and 4 g/d in North America(Reference van Loo, Coussement, de, Hoebregs and Smits11).

Oligosaccharides, including some believed to be prebiotics, are present in human breast milk(Reference Newburg13). They can be found in concentrations of up to 12 g/l, making them the third largest component of breast milk(Reference Newburg, Ruiz-Palacios and Altaye14). The presence of oligosaccharides in large amounts in breast milk suggests that these compounds may play an important role in early infant development, perhaps of the gut, its microbiotia and the immune system. Breast milk contains many compounds and substances that influence gut and immune maturation and consequently has a protective role against infections(Reference Long, Wood and Vasquez15) and possibly allergy development(Reference Obihara, Marais and Gie16). Oligosaccharides may contribute to these protective actions. It is possible that the oligosaccharides are present in breast milk in the mix and concentrations required for optimum protection, and for the development of the immune system.

Overview of the mechanism of action of prebiotics

β2-1 Fructans fulfil the three criteria which must be met in order to be classified a prebiotic, as defined by Gibson & Roberfroid(Reference Gibson and Roberfroid1):

  1. (1) Resistance to hydrolysis or absorption in the upper gastrointestinal tract (as the β-(2 → 1) osidic bond is not hydrolysed by mammalian digestive enzymes). This was shown in early in vitro tests, where β2-1 fructans were incubated with rat pancreatic and small intestinal homogenates, and shown to be poorly digested(Reference Oku, Tokunaga and Hosoya17). Fulfilment of this criterion has also been demonstrated in man through the study of ileostomy subjects, where 87 % of dietary IN was recovered in the ileum(Reference Bach Knudsen and Hessov18), thus establishing the survival of IN through the upper gastrointestinal tract. The non-digestibility of β2-1 fructans in the small intestine has also been demonstrated in healthy volunteers(Reference Molis, Flourie and Ouarne19).

  2. (2) Fermented by the intestinal microbiota. This has been demonstrated in experiments in which β2-1 fructans were completely metabolised in microbial fermentation cultures(Reference van Loo, Coussement, de, Hoebregs and Smits11, Reference Roberfroid, Van Loo and Gibson20).

  3. (3) Selectively stimulate the growth and/or activity of beneficial intestinal bacteria, such as Lactobacillius species and Bifidobacterium species. Studies in laboratory animals and man show that prebiotics do increase the numbers of these types of bacteria in the intestinal tract(Reference Hoentjen, Welling and Harmsen21Reference Osman, Adawi, Molin, Ahrne, Berggren and Jeppsson26). Other experiments establish that β2-1 fructans are selectively fermented by most Bifidobacterium species(Reference Gibson, Beatty, Wang and Cummings27), and also by some Lactobacillius species(Reference Kaplan and Hutkins28), as these bacteria produce the intracellular fructosyl-fructofuranosidase that is needed for hydrolysis of the β-(2 → 1) osidic bond in β2-1 fructans(Reference Roberfroid10).

As a result of intestinal fermentation and promotion of growth of beneficial members of the gut microbiota, prebiotics may influence host defence (Fig. 2). Firstly, by increasing the number of bifidobacteria, there will be increased competition with pathogenic bacteria for binding sites on the intestinal epithelium and for nutrients, thus inhibiting survival of the pathogenic strains. Beneficial members of the gut microbiota bacteria may also cross the intestinal barrier into the Peyer's patches (PP), and activate immune cells there(Reference Berg29). Others suggest that it is not the beneficial bacteria themselves that cross the barrier, but microbial substances such as cell wall components and cytoplasmic antigens(Reference De, Vesely and Negri30). Bifidobacterium species and Lactobacillius species are able to produce antibacterial substances that can inhibit the growth and survival of pathogens(Reference Gibson and Wang31).

Fig. 2 Mechanisms by which β2-1 fructans may influence host defence.

Secondly, the fermentation of prebiotics by the Bifidobacterium species produces SCFA(1), which have the following effects:

Finally, prebiotics may also influence host immune function through alternative mechanisms to the modulation of beneficial bacteria in the gut. It is hypothesised that carbohydrate moieties on the prebiotic may interact with receptors on immune cells. Although a specific fructose receptor has not yet been identified, receptors for β-glucan(Reference Brown and Gordon39, Reference Herre, Gordon and Brown40) and mannose(Reference Taylor, Conary, Lennartz, Stahl and Drickamer41) have been identified on immune cells, and in vitro, fructose has been shown to alter non-opsonic phagocytosis(Reference Speert, Eftekhar and Puterman42), suggesting that a receptor for fructose on immune cells may exist. In addition, some oligosaccharides, for example OF, can bind to receptors on pathogenic bacteria and prevent them from attaching to this same sugar on the epithelial membrane, thus preventing adherence(Reference Ouwehand, Derrien, de, Tiihonen and Rautonen43).

Prebiotics and immune function

This section reviews studies in experimental animals and in man that investigate the effects of increased consumption of β2-1 fructans on aspects of immune function.

Studies in laboratory animals

Studies conducted in laboratory animals are useful because they can be highly controlled, thus eliminating sources of variation in diet and in immune response. Twenty-two studies of β2-1 fructans reporting immune outcomes were identified in mice, rats, pigs and dogs, and are summarised in Table 1. Many of these studies show benefits of β2-1 fructans to some aspects of immune function, while showing no effect on other aspects. Thus, β2-1 fructans may have specific effects upon different components of the immune system. Here, the studies are separated into those which investigate the GALT and those which investigate the systemic immune system. The GALT is made up of the mucosa-associated lymphoid tissues of the gut, and is located underneath a columnar epithelial layer and mucus layer. Within the epithelial layer, M (microfold) cells are distributed. These are antigen-presenting cells and are capable of transporting antigen from the gut lumen into the PP of the GALT. It is in the PP that antigen-presenting cells process and present the antigen to lymphocytes, which subsequently become activated. These lymphocytes then travel via the lymph to the mesenteric lymph nodes (MLN), through the thoracic duct and into the blood, where they become re-localised to the lamina propria of the intestine. Thus, the antigen-specific activated lymphocytes become distributed throughout the intestine.

Table 1 Effects of β2-1 fructans on immune function in laboratory animals

DTH, delayed type hypersensitivity; IFN, interferon; LTB4, leukotriene B4; MHC, major histocompatability complex; MLN, mesenteric lymph nodes; NK, natural killer; PP, Peyer's patches; TGF, transforming growth factor; ↑ , increase/increased; ↓ , decrease/decreased.

Gut-associated lymphoid tissue

Innate immune system: The effect of β2-1 fructans upon macrophage number and function has been studied, with the results suggesting that macrophage functions are enhanced by the addition of β2-1 fructans to the diet. In Clostridia difficile-challenged mice, caecal macrophage and granulocyte numbers were increased in response to antibiotic treatment when a short course of FOS was given(Reference Gaskins, Mackie, May and Garleb44). Peritoneal macrophage phagocytic activity was also increased in rodents given IN or OF for varying periods of time(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45, Reference Kelly-Quagliana, Nelson and Buddington46) and in mice vaccinated with Salmonella typhimurium (Reference Benyacoub, Rochat and Saudan47) and respiratory burst was also increased(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45). Major histocompatability complex (MHC) II molecule expression was also shown to increase on antigen-presenting cells in the MLN of rats upon OF and IN supplementation(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45). However, natural killer (NK) cell cytotoxicity in intra-epithelial lymphocytes of adult dogs was not affected by supplementation of FOS with other fermentable fibres(Reference Field, McBurney, Massimino, Hayek and Sunvold48), and NK cell activity in MLN or PP of rats was not affected by OF-enriched IN(Reference Roller, Rechkemmer and Watzl49).

Thus, from the limited number of animal studies available, it appears that the innate immune system of the gut may be improved by β2-1 fructan intake, which could result in a beneficial effect on the host's primary response to infection. However, studies measuring NK cell activity did not find any effect upon this component of the innate immune system, which plays a major role in the anti-tumour immunity and destruction of virus-infected cells. Future studies should build upon those reported here, to create a more complete picture of how β2-1 fructans affect the innate immune system.

Adaptive immune system: in healthy and endotoxaemic mice supplemented for a short time with FOS, B cell numbers were increased in the PP(Reference Manhart, Spittler, Bergmeister, Mittlbock and Roth50). Several studies report an increase in intestinal or faecal IgA levels upon supplementation with various β2-1 fructan preparations(Reference Benyacoub, Rochat and Saudan47, Reference Roller, Rechkemmer and Watzl49, Reference Hosono, Ozawa and Kato51Reference Swanson, Grieshop and Flickinger53). FOS supplementation increased total faecal IgA and IgA secretion by PP cells in young mice(Reference Hosono, Ozawa and Kato51), and increased various intestinal measures of IgA production in newborn mice, but did not alter B220+ IgM+ cell percentages in PP(Reference Nakamura, Nosaka and Suzuki52). In rats, OF-enriched IN increased caecal secretory IgA concentrations(Reference Roller, Rechkemmer and Watzl49). FOS in combination with MOS increased ileal IgA in adult dogs(Reference Swanson, Grieshop and Flickinger53), but there was no effect upon faecal IgA concentrations in this same study(Reference Swanson, Grieshop and Flickinger53). Vaccine-specific faecal IgA was increased in mice supplemented with a combination of OF and IN with shorter-chain FOS removed and vaccinated with Salmonella typhimurium, but total faecal IgA was not(Reference Benyacoub, Rochat and Saudan47). As IgA antibodies present at the mucosal surface of the gut prevent adherence of pathogens to the gut mucosa, these findings would indicate improved health of the host upon β2-1 fructan supplementation. However, several other studies do not show an effect of β2-1 fructan supplementation on intestinal or faecal IgA levels. Faecal and ileal Ig concentrations were not altered in adult dogs fed FOS in combination with MOS(Reference Swanson, Grieshop and Flickinger54). No effect of IN with shorter-chain FOS removed or OF on faecal IgA concentrations was observed in mice or hypoallergenic dogs((Reference Kelly-Quagliana, Nelson and Buddington46, Reference Verlindin, Hesta, Hermans and Janssens55), and there was no effect of FOS on IgA in the small intestine of piglets(Reference Letellier, Messier, Lessard, Chenier and Quessy56). Thus, there is some disagreement about the effects of β2-1 fructans on IgA levels in the gastrointestinal tract, with three out of the four mouse models showing an enhancement(Reference Benyacoub, Rochat and Saudan47, Reference Hosono, Ozawa and Kato51, Reference Nakamura, Nosaka and Suzuki52) and a single study reporting no effect(Reference Kelly-Quagliana, Nelson and Buddington46). These studies were all in young mice. None of the three studies that were conducted in adult dogs showed an effect upon faecal IgA concentrations(Reference Swanson, Grieshop and Flickinger53Reference Verlindin, Hesta, Hermans and Janssens55), but one did show an effect upon ileal IgA concentration(Reference Swanson, Grieshop and Flickinger53). Thus it seems that the animal used and age may be important in determining whether or not prebiotic supplementation is beneficial on this aspect of immune function. There may be a greater effect in younger animals as their gut immune system is still developing and may therefore be more susceptible to modulation. Other explanations for why there is disparity in the results reported could include (1) that faecal IgA may not be an accurate marker of what is happening inside the gut, and (2) that the level of IgA that is reported would depend, perhaps, on the site of the gut at which IgA is measured. If β2-1 fructans enhance the immune system through promotion of the growth of beneficial members of the gut microbiota, and if a prebiotic, by definition, is specific with respect to the beneficial bacteria it stimulates, then there will be parts of the gut where these beneficial bacteria are most abundant and therefore where the largest effect upon the immune response would be observed. This may partly explain why results reporting IgA at different locations vary.

β2-1 Fructan supplementation has been reported to have effects upon T cell subsets and function, but these effects vary depending upon the anatomical site of origin of the cells, and the animal model used. The number of T cells in the MLN of rats was increased upon OF or IN supplementation(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45). The proportions of CD4+ cells (expressing CD45R+) and CD5+ cells in MLN were increased in adult dogs supplemented with FOS combined with other fermentable fibres, but the proportion of intra-epithelial, PP and lamina propria CD8+ cells was increased(Reference Field, McBurney, Massimino, Hayek and Sunvold48). Thus a decrease in the CD4+/CD8+ ratio in the lamina propria cells was observed(Reference Field, McBurney, Massimino, Hayek and Sunvold48). In contrast, the CD4+/CD8+ ratio was increased in PP of endotoxaemic mice fed FOS(Reference Manhart, Spittler, Bergmeister, Mittlbock and Roth50), and there was no effect on CD4+ or CD8+T cells in the MLN of rats supplemented with OF-enriched IN(Reference Roller, Rechkemmer and Watzl49). Responses of T cells to mitogens were increased for intra-epithelial lymphocytes and MLN, but decreased for PP and lamina propria cells in dogs supplemented with FOS plus fermentable fibres(Reference Field, McBurney, Massimino, Hayek and Sunvold48), and no effect of OF-enriched IN was seen on MLN or PP lymphocyte proliferation in rats(Reference Roller, Rechkemmer and Watzl49). Enhancement of T cell cytokine production has been reported, with an increase in IL-10 and interferon (IFN)-γ production from stimulated PP CD4+T cells seen in FOS-supplemented female mice, and high levels of IL-5 and IL-6 secretion from these cells was also maintained(Reference Hosono, Ozawa and Kato51). IL-10 production from PP and MLN, and IFN-γ production from PP, was also increased in rats with OF-enriched IN supplementation(Reference Roller, Rechkemmer and Watzl49, Reference Roller, Pietro, Caderni, Rechkemmer and Watzl57); however, cytokine production in MLN was not altered(Reference Roller, Rechkemmer and Watzl49). Taken together these findings do not present a clear picture of the effects of β2-1 fructans on T cell numbers in GALT or on T cell responses. It is possible that the effects of prebiotic supplementation upon cell-mediated immunity in the GALT are dependent upon the site of origin of the cells and the animal model used.

Systemic immune system

Innate immune system: the systemic immune system has been more widely studied in the context of prebiotic supplementation than the GALT. As observed in the GALT, after OF or IN supplementation, MHCII expression was increased in antigen-presenting cells in the spleen and thymus of male rats(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45) and mean fluorescence intensity of MHCII+ cells in spleen of mice also increased, although percentage of MHCII+ cells did not change here(Reference Benyacoub, Rochat and Saudan47). No measures of macrophage activity in the systemic immune system have been recorded with β2-1 fructan supplementation. No effect upon monocyte or eosinophil numbers in the blood was reported when aged dogs were supplemented with chicory alone or in combination with MOS, although a non-significant increase in neutrophil concentrations was seen(Reference Grieshop, Flickinger, Bruce, Patil, Czarnecki-Maulden and Fahey58), and phagocytic activity of monocytes and neutrophils in the blood or spleen was not altered upon OF-enriched IN supplementation in rats(Reference Roller, Rechkemmer and Watzl49). FOS did not affect whole blood phagocyte activation in piglets infected with Salmonella typhimurium, although when given in a synbiotic (a mixture of a probiotic and a prebiotic), this marker was increased(Reference Letellier, Messier, Lessard, Chenier and Quessy56). FOS in combination with MOS did not affect blood neutrophil numbers of adult dogs in one study(Reference Swanson, Grieshop and Flickinger53) but this supplement decreased neutrophil numbers in another study(Reference Swanson, Grieshop and Flickinger54). This could be due to the use of different doses of FOS: in the later study a higher dose of FOS was given. Thus, in the systemic immune system, there seems to be little effect of β2-1 fructans upon phagocytic function.

NK cytotoxicity in the peripheral blood was not altered by FOS supplementation in adult dogs(Reference Field, McBurney, Massimino, Hayek and Sunvold48), similar to the effects seen in the GALT. However, in the spleen, a preparation of IN, with shorted-chain FOS removed, in combination with OF increased NK activity of splenocytes in female mice(Reference Kelly-Quagliana, Nelson and Buddington46), and OF-enriched IN increased NK cell-like cytotoxic function in the spleen of male rats(Reference Roller, Pietro, Caderni, Rechkemmer and Watzl57), and the same supplement non-significantly increased this function in blood mononuclear cells in another study by the same group(Reference Roller, Rechkemmer and Watzl49). Thus, in the spleen, at least, NK cell function may be enhanced by OF or IN supplementation.

Adaptive immune system: in adult dogs, the proportion of B cells in the peripheral blood was decreased when a high fermentable fibre diet including FOS was fed(Reference Field, McBurney, Massimino, Hayek and Sunvold48). The majority of studies measuring the effect of β2-1 fructans on serum Ig show no effect. This was observed in murine(Reference Vos, Haarman and Buco23, Reference Hosono, Ozawa and Kato51) and canineReference Swanson, Grieshop and Flickinger53Reference Verlindin, Hesta, Hermans and Janssens55Reference Grieshop, Flickinger, Bruce, Patil, Czarnecki-Maulden and Fahey58 models, with supplementation of FOS alone, FOS in combination with MOS, IN alone or IN in combination with GOS or MOS. Antibodies measured included total serum Ig, IgA, IgE, IgG, IgG2a, IgM and vaccine-specific antibodies to influenza vaccination (total IgG, IgG1, IgG2a). Two studies report a decrease in serum antibody concentrations upon OF supplementation. A study in dogs showed that the proportion of B cells in the peripheral blood was decreased with a high fermentable fibre diet(Reference Field, McBurney, Massimino, Hayek and Sunvold48), and a study in mice demonstrated that FOS supplementation was associated with a decrease in serum IgG1(Reference Hosono, Ozawa and Kato51). Just one study reports an increase in vaccine-specific plasma IgG levels in mice vaccinated with Salmonella typhimurium, although no effect on total serum IgG was observed(Reference Benyacoub, Rochat and Saudan47). Thus, there seems to be little effect on systemic humoral immunity by β2-1 fructan supplementation, and the studies which have shown an effect have mostly shown a suppressive effect, in contrast to the GALT where the results suggest that this aspect of immune function may be enhanced.

T cell subpopulations may be altered with β2-1 fructan supplementation. T cell numbers were increased in the spleen and thymus of rats(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45). In the blood of adult dogs supplemented with FOS, the CD4+/CD8+ ratio was increased(Reference Field, McBurney, Massimino, Hayek and Sunvold48). In contrast, supplementation with OF-enriched IN decreased the spleen CD4+/CD8+ ratio in rats(Reference Roller, Pietro, Caderni, Rechkemmer and Watzl57). In mice, IN with shorter-chain FOS removed or OF had no effect on lymphocyte subsets (CD4+ and CD8+ percentages and or CD4+/CD8+ ratio) in the spleen or thymus(Reference Kelly-Quagliana, Nelson and Buddington46). Neither was there any effect of OF-enriched IN on numbers of CD4+ or CD8+T cells in the spleen and blood of rats(Reference Roller, Rechkemmer and Watzl49), or of OF in combination with IN with shorter-chain FOS removed on the percentage of spleen cell subsets (CD4+, CD8+, B220+, CD11b+ or CD11c+) in mice(Reference Benyacoub, Rochat and Saudan47). Thus, although some studies show that β2-1 fructans may alter T cell subpopulations in the blood and spleen, other studies report no effect on these measurements in the spleen, thymus and blood.

Vaccine-induced splenocyte proliferation was not altered in mice supplemented with a combination of GOS and IN with shorter-chain FOS removed(Reference Vos, Haarman and Buco23). Neither was lymphocyte proliferation altered in the spleen of rats supplemented with OF-enriched IN(Reference Roller, Rechkemmer and Watzl49) nor splenocyte proliferation in mice vaccinated against Salmonella typhimurium and supplemented with OF in combination with IN with shorter-chain FOS removed(Reference Benyacoub, Rochat and Saudan47). Thus, lymphocyte proliferation in the spleen appears not to be susceptible to modification by β2-1 fructans.

As in the GALT, T cell cytokine production may be altered with β2-1 fructan supplementation: IFN-γ production from spleen CD4+T cells was increased in mice supplemented with FOS, although IL-5 and IL-6 production were decreased(Reference Hosono, Ozawa and Kato51), and IL-12 and IFN-γ production from splenocytes was increased upon supplementation with a combination of OF and IN with shorter-chain FOS removed in mice, although TNF-α production was not altered(Reference Benyacoub, Rochat and Saudan47). There was no effect of OF-enriched IN supplementation in rats upon IL-10 production by splenocytes(Reference Roller, Pietro, Caderni, Rechkemmer and Watzl57), or upon cytokine production in the spleen(Reference Roller, Rechkemmer and Watzl49). Blood IL-2 and IL-4 concentrations were increased upon IN or OF supplementation in rats(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45). Thus, the limited number of studies reporting T cell-derived cytokine production in animals receiving β2-1 fructans suggest that some modification occurs. Why T cell cytokine production should be altered when T cell proliferation is not affected is not clear. The delayed type hypersensitivity response represents the summation of a cell-mediated immune response to an antigenic challenge, largely representing antigen-presenting cell and T cell function. Therefore the observation that the delayed type hypersensitivity response to influenza vaccine was increased when GOS and IN with shorter-chain FOS removed were supplemented to mice(Reference Vos, Haarman and Buco23) supports the findings of improved T cell cytokine production with prebiotics.

Studies in man

Twelve studies that included supplementation with β2-1 fructans, either alone or in combination with other components, on the human immune system were identified; these have mainly measured aspects of the systemic immune system, via blood immune markers and immune cell responses, and are summarised in Table 2. Four of these studies investigated the effects of β2-1 fructans alone(Reference Guigoz, Rochat, Perruisseau-Carrier, Rochat and Schiffrin24Reference Firmansyah, Pramita, Carrie-Fassler, Haschke and Link Amster59Reference Duggan, Penny and Hibberd61) and five investigated supplements that contain β2-1 fructans combined with antioxidants, vitamins, minerals, other prebiotics and fats(Reference Langkamp-Henken, Bender and Gardner62Reference Shadid, Haarman and Knol66). Thus, it is difficult to determine whether the effects that were observed were due to β2-1 fructans, or to another component of the supplement. The remaining three studies investigated synbiotics(Reference Bunout, Barrera and Hirsch67Reference Roller, Clune, Collins, Rechkemmer and Watzl69), but did not include a prebiotic alone group, and so will be considered separately.

Table 2 Effect of β2-1 fructans on immune function in man

MCP-1, monocyte chemoattractant protein 1; NK, natural killer; TGF, transforming growth factor; ↑ , increase/increased; ↓ , decrease/decreased; MIP, macrophage inhibitory protein.

Innate immune system

A decrease in monocyte and granulocyte phagocytosis of Escherichia coli was observed when elderly adults resident in a nursing home were supplemented with OF for 3 weeks, although no control group was included in this study making it difficult to interpret the findings(Reference Guigoz, Rochat, Perruisseau-Carrier, Rochat and Schiffrin24). However, the finding of decreased phagocytosis is in contrast to what was observed in senior dogs and adult rats, where no modification of blood monocyte concentrations or phagocytosis was seen(Reference Roller, Rechkemmer and Watzl49, Reference Grieshop, Flickinger, Bruce, Patil, Czarnecki-Maulden and Fahey58) and to the findings of Seidel et al. (Reference Seidel, Boehm and Vogelsang64) of no effect on phagocytosis of E. coli by granulocytes taken from young adult males consuming bread containing IN.

Neither OF(Reference Guigoz, Rochat, Perruisseau-Carrier, Rochat and Schiffrin24) nor a bread containing IN(Reference Seidel, Boehm and Vogelsang64) affected NK cell numbers in human blood. To our knowledge there have been no reports of the effect of β2-1 fructans on human NK cell activity.

Adaptive immune system

The percentage of blood B cells (defined as CD19+) was increased in young male adults after consumption of a bread containing IN(Reference Seidel, Boehm and Vogelsang64). B cell number was increased in elderly residents of a long-term care facility supplemented with FOS(Reference Langkamp-Henken, Wood and Herlinger-Garcia63). Thus there is some consistency in findings in man regarding the effect of β2-1 fructans on B cell numbers (an increase), but this is in contrast to observations in adult dogs, where B cell numbers in the blood were decreased(Reference Field, McBurney, Massimino, Hayek and Sunvold48).

In a study of healthy free-living elderly adults, there was no effect of a combination of OF and IN upon serum Ig concentrations (IgA, IgG, IgM)(Reference Bunout, Hirsch and Pia De la60), which is agreement with several studies in laboratory animals which show no effect of β2-1 fructans on these(Reference Vos, Haarman and Buco23Reference Hosono, Ozawa and Kato51Reference Swanson, Grieshop and Flickinger53Reference Verlindin, Hesta, Hermans and Janssens55Reference Grieshop, Flickinger, Bruce, Patil, Czarnecki-Maulden and Fahey58. In the same study, there was no effect of the combination of OF and IN upon salivary secretory IgA levels(Reference Bunout, Hirsch and Pia De la60). In newborn infants supplemented with a mixture of GOS and IN with shorter-chain FOS removed in their formula, an increase in faecal secretory IgA levels was seen(Reference Bakker-Zierikzee, Tol, Kroes, Alles, Kok and Bindels65), which fits with the findings from animal studies which show an enhancement of the antibody response in the GALT by prebiotics(Reference Benyacoub, Rochat and Saudan47, Reference Roller, Rechkemmer and Watzl49, Reference Hosono, Ozawa and Kato51Reference Swanson, Grieshop and Flickinger53).

The antibody response to vaccination is considered to be the gold standard for measuring the functioning of the immune system in vivo, based on its biological relevance, sensitivity and practical feasibility(Reference Albers, Antoine and Bourdet-Sicard70). Thus several human studies use this marker, but these have generated mixed results. In healthy, free-living elderly adults, OF plus IN increased the antibody response to influenza B virus and Streptococcus pneumoniae after vaccination, yet this was also seen in the control group(Reference Bunout, Hirsch and Pia De la60). In the same study, there was no effect of the supplementation upon antibody titres against influenza A virus. In a study of elderly adults, FOS supplementation increased the number of subjects with a four-fold or greater increase in serum antibody titre, and an antibody titre of forty or more, to the A/Beijing component of the influenza vaccine 6 weeks after the vaccine was administered(Reference Langkamp-Henken, Bender and Gardner62), but this was not seen for the other components of the vaccine. In a group of elderly adults resident in long-term care facilities and vaccinated with influenza, FOS supplementation did not alter the geometric mean antibody titre, but did increase the number of subjects with an antibody titre greater than 100 to the H1N1 component 6 weeks after the vaccine was given(Reference Langkamp-Henken, Wood and Herlinger-Garcia63). A study in 8-month-old infants supplemented with OF plus IN reported an increase in post-vaccination measles IgG levels in the blood(Reference Firmansyah, Pramita, Carrie-Fassler, Haschke and Link Amster59), but in Peruvian infants given OF-enriched cereal, and immunized against influenza, there was no effect upon post-vaccination antibody titres to Haemophilus influenzae type B(Reference Duggan, Penny and Hibberd61). Taken together, these studies suggest that β2-1 fructans may increase the response to some vaccines or vaccine components but not all. This conclusion is consistent with that from animal studies(Reference Vos, Haarman and Buco23, Reference Benyacoub, Rochat and Saudan47).

The percentages of peripheral blood T cells, CD4+T cells and CD8+T cells were increased in elderly nursing home residents upon OF supplementation, although there was no effect on the number of activated T cells(Reference Guigoz, Rochat, Perruisseau-Carrier, Rochat and Schiffrin24). No effect of FOS was seen on percentages of lymphocytes, or CD4+ or CD8+T cells in elderly adults resident in long-term care facilities, although influenza-activated T cells were increased and memory cytotoxic T cells were decreased, and NK T cells were non-significantly increased(Reference Langkamp-Henken, Wood and Herlinger-Garcia63). Likewise, there was no effect of consumption of a bread containing IN on the percentage of T, activated T, CD4+ or CD8+ cells in the blood of young male adults(Reference Seidel, Boehm and Vogelsang64). However, the percentage of activated T cells (defined as CD3+HLA-DR+) increased while that of NK T cells (defined as CD3+NK+) decreased(Reference Seidel, Boehm and Vogelsang64). This mixed picture of effects of β2-1 fructans on blood lymphocyte subsets is similar to that seen in laboratory animals(Reference Field, McBurney, Massimino, Hayek and Sunvold48, Reference Roller, Rechkemmer and Watzl49).

Lymphocyte proliferation to influenza vaccine components was increased in elderly adults supplemented with FOS(Reference Langkamp-Henken, Bender and Gardner62), but in another study in elderly adults, there was no effect of OF plus IN upon stimulated lymphocyte proliferation(Reference Bunout, Hirsch and Pia De la60). Regarding cytokine expression, in elderly nursing home residents, OF supplementation decreased IL-6 mRNA expression in blood mononuclear cells(Reference Guigoz, Rochat, Perruisseau-Carrier, Rochat and Schiffrin24), and in elderly adults resident in long-term care facilities, IL-6 production by stimulated blood mononuclear cells was decreased(Reference Langkamp-Henken, Wood and Herlinger-Garcia63). As an increase in IL-6 is associated with the pro-inflammatory state associated with ageing(Reference Sindermann, Kruse, Frercks, Schutz and Kirchner71), this could be considered a beneficial effect. In healthy free-living elderly adults, there was no effect of OF plus IN upon IFN-γ and IL-4 secretion by cultured mononuclear cells(Reference Bunout, Hirsch and Pia De la60). This is in contrast to a study in rats that showed an increase in blood measurements of IL-4(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45). A trend for a reduced IL-10 production from stimulated blood mononuclear cells was observed upon FOS supplementation in the elderly(Reference Langkamp-Henken, Wood and Herlinger-Garcia63).

Synbiotics and the immune system in man

In a study of adult colon cancer or polypectomised patients, OF-enriched IN was given in combination with Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12. The synbiotic prevented the increase in IL-2 secretion by mononuclear cells from polypectomised patients that was seen in control patients, and also increased IFN-γ production by mononuclear cells in colon cancer patients(Reference Rafter, Bennett and Caderni68, Reference Roller, Clune, Collins, Rechkemmer and Watzl69). However, the synbiotic had no effect on several other immune markers in either cancer or polypectomised patients, including percentages of phagocytically active neutrophils and monocytes and their phagocytic intensity, percentage of neutrophils producing reactive oxygen species and the intensity of production, lytic activity of NK cells or production of IL-10, IL-12 and TNF-α by activated blood mononuclear cells. It is interesting to note that in another population, the healthy elderly immunised with influenza and pneumococcal vaccines, some of these findings are replicated. OF and IN in combination with Lactobacillus paracasei prevented the decrease in IL-2 production by mononuclear cells seen in controls after vaccination, and there was no effect upon TNF-α production(Reference Bunout, Barrera and Hirsch67). However, other findings differ, such as an increase in NK activity and no effect on IFN-γ production with influenza virus antigen stimulation. There was no effect on IL-6 or IL-1 production by stimulated blood mononuclear cells, or on lymphocyte subpopulations(Reference Bunout, Barrera and Hirsch67). The decrease in numbers of T cells with NK activity that was seen in the control group was prevented with the supplementation(Reference Bunout, Barrera and Hirsch67). After the vaccinations were given there was no effect of the synbiotic on the magnitude of the increase in anti-influenza vaccine or anti-pneumococcus vaccine antibodies, or on the delayed type hypersensitivity response(Reference Bunout, Barrera and Hirsch67).

Prebiotics and infection

If prebiotics improve host immune defences, then it would be expected that they decrease susceptibility to and/or severity of infection. This section will review studies in experimental animals and in man that investigate the effect of increased consumption of β2-1 fructans on infectious outcomes.

Studies in laboratory animals

Seventeen animal studies of infection were identified (two of which used synbiotics), and β2-1 fructan supplementation generally appears to be beneficial in the models used (Table 3).

Table 3 Effects of β2-1 fructans on infectious outcomes in animal models

 ↑ , increase/increased; ↓ , decrease/decreased.

A series of studies using piglets infected with Oesophagostomum dentatum or Trichuris suis showed decreases in Oesophagostomum dentatum and Trichuris suis faecal egg counts, intestinal worm recovery, size of worms and the female worm's ability to reproduce after IN supplementation(Reference Petkevicius, Knudsen, Nansen, Roepstorff, Skjoth and Jensen72Reference Thomsen, Petkevicius, Bach Knudsen and Roepstorff77). Another study, in Salmonella typhimurium-infected puppies, showed that OF or IN decrease the severity of enterocyte sloughing, suggesting a reduction in epithelial damage compared to controls(Reference Apanavicius, Powell and Vester78). FOS supplementation increased survival in a hamster model of Clostridium difficile infection(Reference Wolf, Meulbroek, Jarvis, Wheeler and Garleb79) and in murine models of Listeria monocytogenes and Salmonella typhimurium infection both IN and OF increased survival(Reference Buddington, Donahoo and Buddington80). In the latter study, IN was more effective than OF at decreasing mortality. FOS in drinking water decreased the shedding of Salmonella typhimurium in the faeces of piglets infected with Salmonella typhimurium, although the effect was not significant(Reference Letellier, Messier, Lessard and Quessy81), and FOS prevented diarrhoea induced by Salmonella typhimurium in piglets(Reference Correa-Matos, Donovan, Isaacson, Gaskins, White and Tappenden82). FOS decreased diarrhoea and increased survival rates in piglets infected with E. coli (Reference Bunce, Howard, Kerley, Allee and Pace83). These studies provide a consistent picture that β2-1 fructans do improve host resistance to bacterial infections.

In contrast to the studies described earlier, a series of studies investigating OF supplementation in calcium-deficient rats suggest increased Salmonella typhimurium colonisation and translocation, and increased mucosal irritation(Reference ten Bruggencate, Bovee-Oudenhoven, Lettink-Wissink and van der84Reference ten Bruggencate, Bovee-Oudenhoven, Lettink-Wissink and van der87). These findings may be explained by the calcium-deficient state of the rats used, since a direct comparison of OF in rats fed calcium-deficient and calcium-sufficient diets showed different effects(Reference ten Bruggencate, Bovee-Oudenhoven, Lettink-Wissink, Katan and van der86). While the calcium-deficient animals displayed increased susceptibility to S. typhimurium, calcium-sufficient animals did not. Thus, the relevance of the findings to animals or man that are not calcium-deficient is limited.

Two studies have investigated the use of synbiotics in animal models of infection. A study in mice pups infected with rhesus rotavirus demonstrated that OF in combination with Bifidobacterium bifidum and Bifidobacterium infantis reduced the duration of diarrhoea, although the synbiotic was no more effective than the probiotic alone(Reference Qiao, Duffy and Griffiths88). Rotavirus infects the enterocytes of the small intestine, but prebiotics and probiotics have their effects mainly in the large intestine. Thus, although improving the health of the large intestine is likely to be useful in diarrhoea, prebiotics may not be more helpful than a probiotic alone because of limited effects in the small intestine. Although piglets infected with Salmonella typhimurium were shown to have decreased shedding of Salmonella typhimurium in faeces when supplemented with FOS, FOS given as part of a synbiotic had no effect on Salmonella typhimurium infection(Reference Letellier, Messier, Lessard and Quessy81).

Studies in man

Infants and children

Several studies have shown some benefit from β2-1 fructans on common childhood and acute diarrhoea (Table 4). Although OF-enriched cereal had no effect upon frequency or duration of common childhood diarrhoea in non-breast-fed American infants, it reduced the severity(Reference Saavedra, Tschernia and Moore89, Reference Tschernia, Moore and Abi-Hanna90). In another study episodes of common childhood diarrhoea were reported to be reduced in healthy infants supplemented with OF(Reference Waligora-Dupriet, Campeotto and Nicolis91). In Indonesian children aged 1–14 years, the duration of acute diarrhoea was reduced with FOS supplementation(Reference Juffrie92), and incidence of acute diarrhoea was also reduced in infants who received an infant formula containing GOS and FOS(Reference Bruzzese, Volpicelli and Salvini93). Incidence of upper respiratory tract infections was also reduced in the group consuming this formula(Reference Bruzzese, Volpicelli and Salvini93). Intestinal permeability was improved in infants fed with a formula containing GOS and IN as compared to a control formula(Reference Francavilla, Castellaneta and Masciale94). A trial carried out in Peruvian infants found no effect of OF on the occurrence or prevalence of diarrhoea(Reference Duggan, Penny and Hibberd61), and a trial in infants with diarrhoea showed no benefit of including IN and FOS in the rehydration solution on duration of diarrhoea(Reference Hoekstra, Szajewska and Zikri95).

Table 4 Effects of β2-1 fructans on infections in man

MBP, mechanical bowel preparation; MLN, mesenteric lymph nodes; NK, natural killer; ↑ , increase/increased; ↓ , decrease/decreased.

In infants, there was a non-significant trend for a reduction in respiratory tract infections in those receiving a formula containing a synbiotic that included a GOS–FOS mixture compared to those receiving the control formula(Reference Puccio, Cajozzo, Meli, Rochat, Grathwohl and Steenhout96). A study in Chilean children colonised with Helicobacter pylori showed a reduction in the number colonised in both synbiotic and probiotic groups, but there was no difference between these two groups(Reference Gotteland, Poliak, Cruchet and Brunser97).

Taken together data from studies using prebiotics in infants and children are suggestive of a reduction in incidence or duration of some infections.

Adults

Three out of the six studies identified show significant benefit of β2-1 fructans on infections in adult human subjects (Table 4). These studies showed a decrease in relapse rate of in-patients with Clostridium difficile-associated diarrhoea(Reference Lewis, Burmeister and Brazier98), decreased upper respiratory tract infections in older adults post-influenza vaccine(Reference Langkamp-Henken, Bender and Gardner62), and decreased respiratory, skin, gastrointestinal and genitourinary infections in older adults immunised with influenza and pneumococcal vaccines(Reference Bunout, Barrera and Hirsch67). No effect was seen when OF was supplemented to in-patients receiving broad-spectrum antibiotics on antibiotic-associated diarrhoea caused by Clostridium difficile or other causes(Reference Lewis, Burmeister, Cohen, Brazier and Awasthi99). There was no significant effect of FOS supplementation upon travellers' diarrhoea in people holidaying to areas of medium/high risk of diarrhoea, although there was a non-significant decrease in diarrhoea and an increase in feelings of well-being(Reference Cummings, Christie and Cole100). In burns patients, OF did not improve a variety of measures of the severity or duration of infections(Reference Olguin, Araya and Hirsch101). In healthy adults, OF had no effect upon faecal mucin excretion(Reference Scholtens, Alles and Willemsen102). In men consuming a diet with limited calcium, intestinal permeability did not differ between the control and OF supplement periods, although faecal mucin excretion was increased with the addition of OF to the diet(Reference ten Bruggencate, Bovee-Oudenhoven, Lettink-Wissink, Katan and van der103). In a study of patients on an enteral diet, IN had no effect upon intestinal permeability(Reference Sobotka, Bratova, Slemrova, Manak, Vizd'a and Zadak104).

Most trials of synbiotics and infection in human adults have been carried out in patients admitted to intensive care or surgery wards (Table 4). Synbiotics appear to exert some beneficial effects on infections in these patients(Reference Jain, McNaught, Anderson, MacFie and Mitchell105Reference Reddy, MacFie, Gatt, Larsen, Jensen and Leser107). In studies where synbiotics have been compared with prebiotics alone, synbiotics have been shown to be more beneficial in terms of reducing length of antibiotic therapy and bacterial infections in patients undergoing duodenal surgery(Reference Rayes, Seehofer and Theruvath108) and liver transplantation(Reference Rayes, Seehofer and Theruvath109). However, some of these studies report no effects of synbiotics on other outcomes measured(Reference Jain, McNaught, Anderson, MacFie and Mitchell105, Reference Reddy, MacFie, Gatt, Larsen, Jensen and Leser107). No effect of a synbiotic was seen regarding bacterial colonisation to lymph nodes or terminal ileal serosa, gastric colonisation or septic complications in adult patients undergoing elective abdominal surgery(Reference Anderson, McNaught, Jain and MacFie110).

Overall, studies of β2-1 fructans in adults are less convincing of a benefit with respect to infections compared with studies in infants and children. However, it appears that β2-1 fructans are useful in this regard in some situations(Reference Lewis, Burmeister and Brazier98) and as a component of a synbiotic.

Prebiotics and inflammation

This section will review studies in experimental animals and in man that investigate the effect of increased consumption of β2-1 fructans on inflammatory outcomes.

Studies in laboratory animals

Ten studies were identified (two using synbiotics), with mostly consistent results, showing positive effects of β2-1 fructans on inflammation in animal models (Table 5).

Table 5 Effects of β2-1 fructans on inflammation in laboratory animal models

LTB4, leukotriene B4; MLN, mesenteric lymph nodes; TGF, transforming growth factor; ↑ , increase/increased; ↓ , decrease/decreased.

Considering the reported effects of β2-1 fructans on T cell numbers and function in animal models described previously(Reference Trushina, Martynova, Nikitiuk, Mustafina and Baigarin45Reference Field, McBurney, Massimino, Hayek and Sunvold48Reference Hosono, Ozawa and Kato51Reference Roller, Pietro, Caderni, Rechkemmer and Watzl57 it is not surprising that they are effective in colitis: four out of five rodent studies of colitis report a decrease in inflammatory markers and the severity of disease when animals were supplemented with β2-1 fructans. Three studies using IN, FOS or OF-enriched IN in colitis models in rats report reductions in mucosal damage, release of a range of inflammatory mediators (such as PGE2, thromboxane B2, leukotriene B4 and pro-inflammatory cytokines) in different parts of the gut, and various other markers of inflammation(Reference Hoentjen, Welling and Harmsen21, Reference Videla, Vilaseca and Antolin25, Reference Cherbut, Michel and Lecannu111). A model of colitis in female mice showed that FOS decreased disease activity index and damage to the distal colon(Reference Winkler, Butler and Symonds112). However, OF did not have an effect on total macroscopic scores, or on caecal, proximal and distal colon histological scores in a colitis model in male rats(Reference Moreau, Martin and Toquet113). β2-1 Fructans given as part of a synbiotic have also been shown to have beneficial effects in rat models of colitis: when IN was given along with Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12, colonic inflammation was reduced(Reference Schultz, Munro and Tannock114), and OF-enriched IN given alone or in combination with Bifidobacterium infantis reduced bacterial translocation to MLN, colonic myeloperoxidase activity (an indicator of inflammatory granulocyte infiltration) and disease activity index(Reference Osman, Adawi, Molin, Ahrne, Berggren and Jeppsson26).

Neonatal necrotising enterocolitis may be in part caused by interactions between intestinal immaturity, inappropriate bacterial colonisation and infections(Reference Neu115). Thus, from the known beneficial microbiota-stimulating effects, and previously described effects of β2-1 fructans on the immune system, it is possible that β2-1 fructans could be of benefit in this disease. Indeed, in a quail model of neonatal necrotising enterocolitis, OF decreased the occurrence and severity of intestinal lesions, although the clostridial species that was used to induce the colitis had an effect on the magnitude of this effect(Reference Butel, Waligora-Dupriet and Szylit22, Reference Butel, Catala and Waligora-Dupriet116).

In a rat model of allergic airway eosinophilia, FOS provided no benefit, regarding total cell, eosinophil, macrophage or lymphocyte numbers in bronchoalveolar lavage fluid, or IL-4, IL-5 or IFN-γ mRNA levels in lung tissue(Reference Sonoyama, Watanabe and Watanabe117). The lack of effect of FOS on airway inflammation may be due to the distance of this compartment from the gastrointestinal tract.

Thus, animal studies provide fairly strong evidence of a protective effect of β2-1 fructans on colitis and necrotising enterocolitis. The consistent findings may relate to the action of prebiotics directly at the site of pathology. Effects of prebiotics on inflammatory processes distant from the intestinal tract (e.g. the lung) may not be expected or may be much smaller in magnitude.

Studies in man

Eleven studies of β2-1 fructans in human inflammatory conditions were identified (four where synbiotics were used), of which ten were conducted in adults (Table 6).

Table 6 Effects of β2-1 fructans on inflammation in human disease

 ↑ , Increase/increased; ↓ , decrease/decreased.

In accordance with findings from animal experiments, β2-1 fructans supplementation was shown to be beneficial in ulcerative colitis patients. OF-enriched IN supplementation in such patients decreased faecal calprotectin (a marker of intestinal inflammation) and perception of abdominal pain, although there was no change in the inflammatory mediators measured (PGE2 and IL-8) or on faecal excretion of human DNA (a result of the mucosal inflammation seen in ulcerative colitis)(Reference Casellas, Borruel and Torrejon118). Although IN supplementation in patients with ileal pouch–anal anastomosis did not produce any effects on clinical symptom scores, there were reductions in total endoscopic scores, mucous exudates, total histological scores and total Pouchitis Disease Activity Index(Reference Welters, Heineman, Thunnissen, van den Bogaard, Soeters and Baeten119). A trial into OF supplementation to patients with ileo-colonic Crohn's disease reported positive results: disease activity scores were reduced, and expression of toll-like receptor 4 on dendritic cells in the lamina propria was increased, while there were non-significant improvements in several other outcomes(Reference Lindsay, Whelan and Stagg120).

Most trials in irritable bowel syndrome do not report beneficial effects of β2-1 fructans on symptom scores(Reference Hunter, Tuffnell and Lee121, Reference Olesen and Gudmand-Hoyer122), perhaps due to the nature of the disease regarding the relapse and remission pattern, although there is one positive study in this disorder(Reference Astengiano, Pellicano, Terzi, Simondi and Rizzetto123).

In contrast to the single animal study that reported no benefit of FOS on allergic airway esoinophilia(Reference Sonoyama, Watanabe and Watanabe117), a study in infants at risk from atopy found a reduction in the development of atopic dermatitis in the group supplemented with FOS in combination with GOS(Reference Moro, Arslanoglu, Stahl, Jelinek, Wahn and Boehm124). Several reasons could be given to explain this inconsistency in results. In the human study, the composition of this FOS–GOS supplement was designed to closely resemble the composition of oligosaccharides of the mother's milk, but as this was not the case in the animal study it may be that the amount of prebiotic given was not appropriate. Also, the rats were at a later stage of development than the infants in the human study, and so as their immune systems would have been more developed, the prebiotics may have had less of an effect upon their immune system. Finally, the infants were at risk from allergy because of parental allergy (i.e. genetics was most likely an important factor), while in the animal model, the allergy was induced in the affected animals.

Synbiotic therapy for inflammatory bowel diseases produces mixed results. OF-enriched IN in combination with Bifidobacterium longum improved markers of inflammation in patients with active ulcerative colitis, such as decreases in TNF-α, IL-1α mRNA levels in mucosal tissue and decreased C-reactive protein levels in the blood(Reference Furrie, Macfarlane and Kennedy125). Mucosal tissue mRNA levels of the β-defensins that are up-regulated in ulcerative colitis were also reduced in this study(Reference Furrie, Macfarlane and Kennedy125). IN given in combination with other fermentable fibres and four lactic acid bacteria had no effect on relapse rates (either endoscopic or clinical) in Crohn's disease patients undergoing resection(Reference Chermesh, Tamir and Reshef126). In a study of patients with acute pancreatitis, a synbiotic supplement was found to be more beneficial than when the prebiotics were given alone regarding outcomes such as systemic inflammatory response and multi-organ failure(Reference Olah, Belagyi, Issekutz and Olgyai127). Regarding irritable bowel syndrome, a formula containing IN as well as Lactobacillius acidophilus, Lactobacillius sporogenes (this bacterium is actually Bacillus sporogenes, a soil micro-organism claimed to have probiotic properties) and Streptococcus thermophilius, amino acids and vitamins resulted in significant reductions in abdominal pain, distension and constipation(Reference Astengiano, Pellicano, Terzi, Simondi and Rizzetto123).

Conclusions

This paper has presented and evaluated results from all of the studies available, to our knowledge, of the effects of β2-1 fructans upon immune function, the host's ability to fight infection, and inflammatory processes and conditions. The results of these studies are often difficult to compare, due to inconsistencies in methodology and the heterogeneity of the subjects used. Despite this, much evidence suggests that β2-1 fructans do influence some aspects of host immunity. In laboratory animals, the innate and adaptive immune systems of both the GALT and the systemic immune system have been shown to be modified by β2-1 fructans. In man, most studies have investigated the effects of β2-1 fructans upon the systemic immune system, with little effect observed on innate immune function, but with many mixed results reported regarding the adaptive immune system, suggesting modification by β2-1 fructans on this aspect of immunity. In animal models of infections, findings are conclusive regarding the benefits of β2-1 fructans upon improving host resistance. In man there is convincing evidence that β2-1 fructans may reduce the incidence and duration of certain infections in infants and children. β2-1 Fructan supplementation in adults has not, generally, produced beneficial results, but when given as a synbiotic to critically ill or surgical patients, β2-1 fructans were shown to reduce infections. Taken together these results suggest that β2-1 fructans, especially IN and OF, may be most beneficial in those who are particularly susceptible to modifications of their immune system. In animal models of inflammation, β2-1 fructans have shown benefits in models of colitis and necrotising entercolitis, perhaps due to the pathological site of these conditions being the same as the site of action of prebiotics. This theory is supported by the observation of the lack of effect of β2-1 fructans upon a model of allergic airway eosinophilia, an inflammatory condition distant from the gut. However, in human infants, an improvement in atopic dermatitis was observed in one study. Inflammatory bowel conditions in human adults are improved upon β2-1 fructan supplementation, but findings in irritable bowel syndrome are mixed. It is important that future studies build upon the findings of the studies reported here, in order that a more complete picture of the effects of β2-1 fructans upon immune function, infections and inflammation is formed. The funding of these future studies needs to be considered carefully. The majority of studies conducted to date have been funded directly from industry or have involved academic collaboration of some sort with industry. It is not possible to identify whether studies funded by industry yield different findings than those not funded by industry, quite simply because there are so many of the former and so few of the latter and also because the extent of industry support and funding for some published studies is not readily apparent.

Acknowledgements

A. R. L. is supported by BENEO-Orafti (member of the BENEO-Group). P. C. C. has research funding from BENEO-Orafti.

References

1Gibson, GR & Roberfroid, MB (1995) Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 125, 14011412.Google ScholarPubMed
2Hamilton-Miller, JM (2004) Probiotics and prebiotics in the elderly. Postgrad Med J 80, 447451.CrossRefGoogle ScholarPubMed
3Schley, PD & Field, CJ (2002) The immune-enhancing effects of dietary fibres and prebiotics. Br J Nutr 87, Suppl. 2, S221S230.CrossRefGoogle ScholarPubMed
4Watzl, B, Girrbach, S & Roller, M (2005) Inulin, oligofructose and immunomodulation. Br J Nutr 93, Suppl. 1, S49S55.CrossRefGoogle ScholarPubMed
5Seifert, S & Watzl, B (2007) Inulin and oligofructose: review of experimental data on immune modulation. J Nutr 137, Suppl. 11, 2563S2567S.CrossRefGoogle ScholarPubMed
6Leenen, CH & Dieleman, LA (2007) Inulin and oligofructose in chronic inflammatory bowel disease. J Nutr 137, Suppl. 11, 2572S2575S.CrossRefGoogle ScholarPubMed
7Guarner, F (2007) Studies with inulin-type fructans on intestinal infections, permeability, and inflammation. J Nutr 137, Suppl. 11, 2568S2571S.CrossRefGoogle ScholarPubMed
8Gibson, GR, Probert, HM, Van Loo, J, Rastall, RA & Roberfroid, MB (2004) Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 17, 259275.CrossRefGoogle ScholarPubMed
9Waterhouse, A & Chatterton, N (1993) Glossary of fructan terms. In Science and Technology of Fructans, pp. 27 [Suzuki, M and Chatterton, N, editors]. Boca Raton, FL: CRC Press.Google Scholar
10Roberfroid, MB (2005) Introducing inulin-type fructans. Br J Nutr 93, Suppl. 1, S13S25.CrossRefGoogle ScholarPubMed
11van Loo, J, Coussement, P, de, LL, Hoebregs, H & Smits, G (1995) On the presence of inulin and oligofructose as natural ingredients in the western diet. Crit Rev Food Sci Nutr 35, 525552.CrossRefGoogle ScholarPubMed
12Lopez-Molina, D, Navarro-Martinez, MD, Rojas, MF, Hiner, AN, Chazarra, S & Rodriguez-Lopez, JN (2005) Molecular properties and prebiotic effect of inulin obtained from artichoke (Cynara scolymus L.). Phytochemistry 66, 14761484.CrossRefGoogle Scholar
13Newburg, DS (2000) Oligosaccharides in human milk and bacterial colonization. J Pediatr Gastroenterol Nutr 30, Suppl. 2, S8S17.CrossRefGoogle ScholarPubMed
14Newburg, DS, Ruiz-Palacios, GML, Altaye, M et al. (2004) Innate protection conferred by fucosylated oligosaccharides of human milk against diarrhea in breastfed infants. Glycobiology 14, 253263.CrossRefGoogle ScholarPubMed
15Long, KZ, Wood, JW, Vasquez, GE et al. (1994) Proportional hazards analysis of diarrhea due to enterotoxigenic Escherichia coli and breast feeding in a cohort of urban Mexican children. Am J Epidemiol 139, 193205.CrossRefGoogle Scholar
16Obihara, CC, Marais, BJ, Gie, RP et al. (2005) The association of prolonged breastfeeding and allergic disease in poor urban children. Eur Respir J 25, 970977.CrossRefGoogle ScholarPubMed
17Oku, T, Tokunaga, T & Hosoya, N (1984) Nondigestibility of a new sweetener, ‘Neosugar,’ in the rat. J Nutr 114, 15741581.CrossRefGoogle Scholar
18Bach Knudsen, KE & Hessov, I (1995) Recovery of inulin from Jerusalem artichoke (Helianthus tuberosus L.) in the small intestine of man. Br J Nutr 74, 101113.CrossRefGoogle Scholar
19Molis, C, Flourie, B, Ouarne, F, et al. (1996) Digestion, excretion, and energy value of fructooligosaccharides in healthy humans. Am J Clin Nutr 64, 324328.CrossRefGoogle ScholarPubMed
20Roberfroid, MB, Van Loo, JA & Gibson, GR (1998) The bifidogenic nature of chicory inulin and its hydrolysis products. J Nutr 128, 1119.CrossRefGoogle ScholarPubMed
21Hoentjen, F, Welling, GW, Harmsen, HJ, et al. (2005) Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis 11, 977985.CrossRefGoogle ScholarPubMed
22Butel, MJ, Waligora-Dupriet, AJ & Szylit, O (2002) Oligofructose and experimental model of neonatal necrotising enterocolitis. Br J Nutr 87, Suppl. 2, S213S219.CrossRefGoogle ScholarPubMed
23Vos, AP, Haarman, M, Buco, A, et al. (2006) A specific prebiotic oligosaccharide mixture stimulates delayed-type hypersensitivity in a murine influenza vaccination model. Int Immunopharmacol 6, 12771286.CrossRefGoogle Scholar
24Guigoz, Y, Rochat, F, Perruisseau-Carrier, G, Rochat, I & Schiffrin, E (2002) Effects of oligosaccharide on the faecal flora and non-specific immune system in elderly people. Nutr Res 22, 1325.CrossRefGoogle Scholar
25Videla, S, Vilaseca, J, Antolin, M, et al. (2001) Dietary inulin improves distal colitis induced by dextran sodium sulfate in the rat. Am J Gastroenterol 96, 14861493.CrossRefGoogle ScholarPubMed
26Osman, N, Adawi, D, Molin, G, Ahrne, S, Berggren, A & Jeppsson, B (2006) Bifidobacterium infantis strains with and without a combination of oligofructose and inulin (OFI) attenuate inflammation in DSS-induced colitis in rats. BMC Gastroenterol 6, 31.CrossRefGoogle ScholarPubMed
27Gibson, GR, Beatty, ER, Wang, X & Cummings, JH (1995) Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 108, 975982.CrossRefGoogle ScholarPubMed
28Kaplan, H & Hutkins, RW (2000) Fermentation of fructooligosaccharides by lactic acid bacteria and bifidobacteria. Appl Environ Microbiol 66, 26822684.CrossRefGoogle ScholarPubMed
29Berg, RD (1985) Indigenous intestinal microflora and the host immune response. EOS J Immunol Immunopharmacol 4, 161168.Google Scholar
30De, Simone C, Vesely, R, Negri, R, et al. (1987) Enhancement of immune response of murine Peyer's patches by a diet supplemented with yogurt. Immunopharmacol Immunotoxicol 9, 87100.Google Scholar
31Gibson, GR & Wang, X (1994) Enrichment of bifidobacteria from human gut contents by oligofructose using continuous culture. FEMS Microbiol Lett 118, 121127.CrossRefGoogle ScholarPubMed
32Blaut, M (2002) Relationship of prebiotics and food to intestinal microflora. Eur J Nutr 41, Suppl. 1, I11I16.CrossRefGoogle ScholarPubMed
33Barcelo, A, Claustre, J, Moro, F, Chayvialle, JA, Cuber, JC & Plaisancie, P (2000) Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46, 218224.CrossRefGoogle ScholarPubMed
34Brown, AJ, Goldsworthy, SM, Barnes, AA, et al. (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278, 1131211319.CrossRefGoogle ScholarPubMed
35Le, Poul E, Loison, C & Struyf, S (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278, 2548125489.Google Scholar
36Nilsson, NE, Kotarsky, K, Owman, C & Olde, B (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun 303, 10471052.CrossRefGoogle ScholarPubMed
37Jenkins, DJ, Kendall, CW & Vuksan, V (1999) Inulin, oligofructose and intestinal function. J Nutr 129, Suppl. 7, 1431S1433S.CrossRefGoogle ScholarPubMed
38Sanderson, IR (2007) Dietary modulation of GALT. J Nutr 137, Suppl. 11, 2557S2562S.CrossRefGoogle ScholarPubMed
39Brown, GD & Gordon, S (2001) Immune recognition. A new receptor for beta-glucans. Nature 413, Suppl. 6851, 3637.CrossRefGoogle ScholarPubMed
40Herre, J, Gordon, S & Brown, GD (2004) Dectin-1 and its role in the recognition of beta-glucans by macrophages. Mol Immunol 40, 869876.CrossRefGoogle ScholarPubMed
41Taylor, ME, Conary, JT, Lennartz, MR, Stahl, PD & Drickamer, K (1990) Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains. J Biol Chem 265, 1215612162.Google ScholarPubMed
42Speert, DP, Eftekhar, F & Puterman, ML (1984) Nonopsonic phagocytosis of strains of Pseudomonas aeruginosa from cystic fibrosis patients. Infect Immun 43, 10061011.Google ScholarPubMed
43Ouwehand, AC, Derrien, M, de, VW, Tiihonen, K & Rautonen, N (2005) Prebiotics and other microbial substrates for gut functionality. Curr Opin Biotechnol 16, 212217.CrossRefGoogle ScholarPubMed
44Gaskins, H, Mackie, R, May, T & Garleb, K (1996) Dietary fructo-oligosaccharide modulates large intestinal inflammatory responses to Clostridium difficile in antibiotic-compromosed mice. Microbial Ecol Health Dis 9, 157166.CrossRefGoogle Scholar
45Trushina, EN, Martynova, EA, Nikitiuk, DB, Mustafina, OK & Baigarin, EK (2005) The influence of dietary inulin and oligofructose on the cell-mediated and humoral immunity in rats. Vopr Pitan 74, 2227.Google ScholarPubMed
46Kelly-Quagliana, K, Nelson, P & Buddington, R (2003) Dietary oligofructose and inulin modulate immune functions in mice. Nutr Res 23, 257267.CrossRefGoogle Scholar
47Benyacoub, J, Rochat, F, Saudan, KY et al. (2008) Feeding a diet containing a fructooligosaccharide mix can enhance Salmonella vaccine efficacy in mice. J Nutr 138, 123129.CrossRefGoogle ScholarPubMed
48Field, CJ, McBurney, MI, Massimino, S, Hayek, MG & Sunvold, GD (1999) The fermentable fiber content of the diet alters the function and composition of canine gut associated lymphoid tissue. Vet Immunol Immunopathol 72, 325341.CrossRefGoogle ScholarPubMed
49Roller, M, Rechkemmer, G & Watzl, B (2004) Prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis modulates intestinal immune functions in rats. J Nutr 134, 153156.CrossRefGoogle ScholarPubMed
50Manhart, N, Spittler, A, Bergmeister, H, Mittlbock, M & Roth, E (2003) Influence of fructooligosaccharides on Peyer's patch lymphocyte numbers in healthy and endotoxemic mice. Nutrition 19, 657660.CrossRefGoogle ScholarPubMed
51Hosono, A, Ozawa, A, Kato, R, et al. (2003) Dietary fructooligosaccharides induce immunoregulation of intestinal IgA secretion by murine Peyer's patch cells. Biosci Biotechnol Biochem 67, 758764.CrossRefGoogle ScholarPubMed
52Nakamura, Y, Nosaka, S, Suzuki, M, et al. (2004) Dietary fructooligosaccharides up-regulate immunoglobulin A response and polymeric immunoglobulin receptor expression in intestines of infant mice. Clin Exp Immunol 137, 5258.CrossRefGoogle ScholarPubMed
53Swanson, KS, Grieshop, CM, Flickinger, EA, et al. (2002) Supplemental fructooligosaccharides and mannanoligosaccharides influence immune function, ileal and total tract nutrient digestibilities, microbial populations and concentrations of protein catabolites in the large bowel of dogs. J Nutr 132, 980989.CrossRefGoogle ScholarPubMed
54Swanson, KS, Grieshop, CM, Flickinger, EA, et al. (2002) Effects of supplemental fructooligosaccharides plus mannanoligosaccharides on immune function and ileal and fecal microbial populations in adult dogs. Arch Tierernahr 56, 309318.CrossRefGoogle ScholarPubMed
55Verlindin, A, Hesta, M, Hermans, J & Janssens, G (2006) The effects of inulin supplementation of diets with or without protein sources on digestibility, faecal characterisitcs, haematology and immunoglobulins in dogs. Br J Nutr 96, 936944.Google Scholar
56Letellier, A, Messier, S, Lessard, L, Chenier, S & Quessy, S (2001) Host response to various treatments to reduce Salmonella infections in swine. Can J Vet Res 65, 168172.Google ScholarPubMed
57Roller, M, Pietro, FA, Caderni, G, Rechkemmer, G & Watzl, B (2004) Intestinal immunity of rats with colon cancer is modulated by oligofructose-enriched inulin combined with Lactobacillus rhamnosus and Bifidobacterium lactis. Br J Nutr 92, 931938.CrossRefGoogle ScholarPubMed
58Grieshop, CM, Flickinger, EA, Bruce, KJ, Patil, AR, Czarnecki-Maulden, GL & Fahey, GC Jr (2004) Gastrointestinal and immunological responses of senior dogs to chicory and mannan-oligosaccharides. Arch Anim Nutr 58, 483493.CrossRefGoogle ScholarPubMed
59Firmansyah, A, Pramita, G, Carrie-Fassler, A, Haschke, F & Link Amster, H (2001) Improved humoral immune response to measles vaccine in infants recieving infant cereal with fructooligosaccharides. J Paediatr Gastroenterol Nutr 31, A521.Google Scholar
60Bunout, D, Hirsch, S, Pia De la, MM, et al. (2002) Effects of prebiotics on the immune response to vaccination in the elderly. JPEN J Parenter Enteral Nutr 26, 372376.CrossRefGoogle ScholarPubMed
61Duggan, C, Penny, ME, Hibberd, P et al. (2003) Oligofructose-supplemented infant cereal: 2 randomized, blinded, community-based trials in Peruvian infants. Am J Clin Nutr 77, 937942.CrossRefGoogle ScholarPubMed
62Langkamp-Henken, B, Bender, BS & Gardner, EM (2004) Nutritional formula enhanced immune function and reduced days of symptoms of upper respiratory tract infection in seniors. J Am Geriatr Soc 52, 312.CrossRefGoogle ScholarPubMed
63Langkamp-Henken, B, Wood, SM, Herlinger-Garcia, KA, et al. (2006) Nutritional formula improved immune profiles of seniors living in nursing homes. J Am Geriatr Soc 54, 18611870.CrossRefGoogle ScholarPubMed
64Seidel, C, Boehm, V, Vogelsang, H, et al. (2007) Influence of prebiotics and antioxidants in bread on the immune system, antioxidative status and antioxidative capacity in male smokers and non-smokers. Br J Nutr 97, 349356.CrossRefGoogle ScholarPubMed
65Bakker-Zierikzee, AM, Tol, EA, Kroes, H, Alles, MS, Kok, FJ & Bindels, JG (2006) Faecal SIgA secretion in infants fed on pre- or probiotic infant formula. Pediatr Allergy Immunol 17, 134140.CrossRefGoogle ScholarPubMed
66Shadid, R, Haarman, M, Knol, J et al. (2007) Effects of galactooligosaccharide and long-chain fructooligosaccharide supplementation during pregnancy on maternal and neonatal microbiota and immunity – a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 86, 14261437.CrossRefGoogle ScholarPubMed
67Bunout, D, Barrera, G, Hirsch, S, et al. (2004) Effects of a nutritional supplement on the immune response and cytokine production in free-living Chilean elderly. JPEN J Parenter Enteral Nutr 28, 348354.CrossRefGoogle ScholarPubMed
68Rafter, J, Bennett, M, Caderni, G, et al. (2007) Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am J Clin Nutr 85, 488496.CrossRefGoogle ScholarPubMed
69Roller, M, Clune, Y, Collins, K, Rechkemmer, G & Watzl, B (2007) Consumption of prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis has minor effects on selected immune parameters in polypectomised and colon cancer patients. Br J Nutr 97, 676684.CrossRefGoogle ScholarPubMed
70Albers, R, Antoine, JM, Bourdet-Sicard, R, et al. (2005) Markers to measure immunomodulation in human nutrition intervention studies. Br J Nutr 94, 452481.CrossRefGoogle ScholarPubMed
71Sindermann, J, Kruse, A, Frercks, HJ, Schutz, RM & Kirchner, H (1993) Investigations of the lymphokine system in elderly individuals. Mech Ageing Dev 70, 149159.CrossRefGoogle ScholarPubMed
72Petkevicius, S, Knudsen, KE, Nansen, P, Roepstorff, A, Skjoth, F & Jensen, K (1997) The impact of diets varying in carbohydrates resistant to endogenous enzymes and lignin on populations of Ascaris suum and Oesophagostomum dentatum in pigs. Parasitology 114, Pt555568.Google ScholarPubMed
73Petkevicius, S, Knudsen, KE, Nansen, P & Murrell, KD (2001) The effect of dietary carbohydrates with different digestibility on the populations of Oesophagostomum dentatum in the intestinal tract of pigs. Parasitology 123, 315324.CrossRefGoogle ScholarPubMed
74Petkevicius, S, Bach Knudsen, KE & Murrell, KD (2003) Effects of Oesophagostomum dentatum and dietary carbohydrates on morphology of the large intestine of pigs. Vet Parasitol 116, 125138.CrossRefGoogle ScholarPubMed
75Petkevicius, S, Bach Knudsen, KE, Murrell, KD & Wachmann, H (2003) The effect of inulin and sugar beet fibre on Oesophagostomum dentatum infection in pigs. Parasitology 127, 6168.CrossRefGoogle ScholarPubMed
76Petkevicius, S, Thomsen, LE, Bach Knudsen, KE, Murrell, KD, Roepstorff, A & Boes, J (2007) The effect of inulin on new and on patent infections of Trichuris suis in growing pigs. Parasitology 134, Suppl. 1, 121127.CrossRefGoogle ScholarPubMed
77Thomsen, LE, Petkevicius, S, Bach Knudsen, KE & Roepstorff, A (2005) The influence of dietary carbohydrates on experimental infection with Trichuris suis in pigs. Parasitology 131, 857865.CrossRefGoogle ScholarPubMed
78Apanavicius, CJ, Powell, KL, Vester, BM et al. (2007) Fructan supplementation and infection affect food intake, fever, and epithelial sloughing from Salmonella challenge in weanling puppies. J Nutr 137, 19231930.CrossRefGoogle ScholarPubMed
79Wolf, B, Meulbroek, J, Jarvis, K, Wheeler, K & Garleb, K (1997) Dietary supplementation with fruoctooligosaccharides increase survival time in a hamster model of Clostridium difficile-colitis. Biosci Microflora 16, 5964.CrossRefGoogle Scholar
80Buddington, KK, Donahoo, JB & Buddington, RK (2002) Dietary oligofructose and inulin protect mice from enteric and systemic pathogens and tumor inducers. J Nutr 132, 472477.CrossRefGoogle ScholarPubMed
81Letellier, A, Messier, S, Lessard, L & Quessy, S (2000) Assessment of various treatments to reduce carriage of Salmonella in swine. Can J Vet Res 64, 2731.Google ScholarPubMed
82Correa-Matos, NJ, Donovan, SM, Isaacson, RE, Gaskins, HR, White, BA & Tappenden, KA (2003) Fermentable fiber reduces recovery time and improves intestinal function in piglets following Salmonella typhimurium infection. J Nutr 133, 18451852.CrossRefGoogle ScholarPubMed
83Bunce, T, Howard, MD, Kerley, MS, Allee, GL & Pace, LW (1995) Protective effect of fructooligosaccharides (FOS) in prevention of mortality and morbidity from infectious E. coli. J Anim Sci 71, Suppl. 1, 69.Google Scholar
84ten Bruggencate, SJ, Bovee-Oudenhoven, IM, Lettink-Wissink, ML & van der, Meer R (2003) Dietary fructo-oligosaccharides dose-dependently increase translocation of salmonella in rats. J Nutr 133, 23132318.CrossRefGoogle ScholarPubMed
85Bovee-Oudenhoven, IM, ten Bruggencate, SJ, Lettink-Wissink, ML & van der, Meer R (2003) Dietary fructo-oligosaccharides and lactulose inhibit intestinal colonisation but stimulate translocation of salmonella in rats. Gut 52, 15721578.CrossRefGoogle ScholarPubMed
86ten Bruggencate, SJ, Bovee-Oudenhoven, IM, Lettink-Wissink, ML, Katan, MB & van der, Meer R (2004) Dietary fructo-oligosaccharides and inulin decrease resistance of rats to salmonella: protective role of calcium. Gut 53, 530535.CrossRefGoogle Scholar
87ten Bruggencate, SJ, Bovee-Oudenhoven, IM, Lettink-Wissink, ML & van der, Meer R (2005) Dietary fructooligosaccharides increase intestinal permeability in rats. J Nutr 135, 837842.CrossRefGoogle ScholarPubMed
88Qiao, H, Duffy, LC, Griffiths, E et al. (2002) Immune responses in rhesus rotavirus-challenged BALB/c mice treated with bifidobacteria and prebiotic supplements. Pediatr Res 51, 750755.CrossRefGoogle ScholarPubMed
89Saavedra, J, Tschernia, A, Moore, N et al. (1999) Gastrointestinal function in infants consuming a weaing food supplemented with oligofructose, a prebiotic. J Pediatr Gastroenterol Nutr 29, A95.CrossRefGoogle Scholar
90Tschernia, A, Moore, N, Abi-Hanna, A, et al. (1999) Effects of long-term supplementation of a weaning food supplemented with oligofructose, a prebiotic, on general infant health status. J Pediatr Gastroenterol Nutr 29, A58.CrossRefGoogle Scholar
91Waligora-Dupriet, AJ, Campeotto, F, Nicolis, I, et al. (2007) Effect of oligofructose supplementation on gut microflora and well-being in young children attending a day care centre. Int J Food Microbiol 113, 108113.CrossRefGoogle ScholarPubMed
92Juffrie, M (2002) Fructooligosaccharide and diarrhea. Biosci Microflora 21, 3134.CrossRefGoogle Scholar
93Bruzzese, E, Volpicelli, M, Salvini, F, et al. (2006) Early administration of GOS/FOS prevents intestinal and respiratory infections in infants. J Pediatr Gastroenterol Nutr 42, Suppl. 5, E95.Google Scholar
94Francavilla, R, Castellaneta, S, Masciale, A, et al. (2006) Intestinal permeability and faecal flora of infants fed with a prebiotic supplemented formula: a double blind placebo controlled study. J Pediatr Gastroenterol Nutr 42, Suppl. 5, E96.Google Scholar
95Hoekstra, JH, Szajewska, H & Zikri, MA (2004) Oral rehydration solution containing a mixture of non-digestible carbohydrates in the treatment of acute diarrhea: a multicenter randomized placebo controlled study on behalf of the ESPGHAN working group on intestinal infections. J Pediatr Gastroenterol Nutr 39, 239245.CrossRefGoogle Scholar
96Puccio, G, Cajozzo, C, Meli, F, Rochat, F, Grathwohl, D & Steenhout, P (2007) Clinical evaluation of a new starter formula for infants containing live Bifidobacterium longum BL999 and prebiotics. Nutrition 23, 18.CrossRefGoogle ScholarPubMed
97Gotteland, M, Poliak, L, Cruchet, S & Brunser, O (2005) Effect of regular ingestion of Saccharomyces boulardii plus inulin or Lactobacillus acidophilus LB in children colonized by Helicobacter pylori. Acta Paediatr 94, 17471751.CrossRefGoogle ScholarPubMed
98Lewis, S, Burmeister, S & Brazier, J (2005) Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhoea: a randomized, controlled study. Clin Gastroenterol Hepatol 3, 442448.CrossRefGoogle ScholarPubMed
99Lewis, S, Burmeister, S, Cohen, S, Brazier, J & Awasthi, A (2005) Failure of dietary oligofructose to prevent antibiotic-associated diarrhoea. Aliment Pharmacol Ther 21, 469477.CrossRefGoogle ScholarPubMed
100Cummings, JH, Christie, S & Cole, TJ (2001) A study of fructo oligosaccharides in the prevention of travellers' diarrhoea. Aliment Pharmacol Ther 15, 11391145.CrossRefGoogle ScholarPubMed
101Olguin, F, Araya, M, Hirsch, S, et al. (2005) Prebiotic ingestion does not improve gastrointestinal barrier function in burn patients. Burns 31, 482488.CrossRefGoogle Scholar
102Scholtens, PA, Alles, MS, Willemsen, LE, et al. (2006) Dietary fructo-oligosaccharides in healthy adults do not negatively affect faecal cytotoxicity: a randomised, double-blind, placebo-controlled crossover trial. Br J Nutr 95, 11431149.CrossRefGoogle Scholar
103ten Bruggencate, SJ, Bovee-Oudenhoven, IM, Lettink-Wissink, ML, Katan, MB & van der, MR (2006) Dietary fructooligosaccharides affect intestinal barrier function in healthy men. J Nutr 136, 7074.CrossRefGoogle ScholarPubMed
104Sobotka, L, Bratova, M, Slemrova, M, Manak, J, Vizd'a, J & Zadak, Z (1997) Inulin as the soluble fiber in liquid enteral nutrition. Nutrition 13, 2125.CrossRefGoogle ScholarPubMed
105Jain, PK, McNaught, CE, Anderson, AD, MacFie, J & Mitchell, CJ (2004) Influence of synbiotic containing Lactobacillus acidophilus La5, Bifidobacterium lactis Bb 12, Streptococcus thermophilus, Lactobacillus bulgaricus and oligofructose on gut barrier function and sepsis in critically ill patients: a randomised controlled trial. Clin Nutr 23, 467475.CrossRefGoogle ScholarPubMed
106Kotzampassi, K, Giamarellos-Bourboulis, EJ, Voudouris, A, Kazamias, P & Eleftheriadis, E (2006) Benefits of a synbiotic formula (Synbiotic 2000Forte) in critically ill trauma patients: early results of a randomized controlled trial. World J Surg 30, 18481855.CrossRefGoogle ScholarPubMed
107Reddy, BS, MacFie, J, Gatt, M, Larsen, CN, Jensen, SS & Leser, TD (2007) Randomized clinical trial of effect of synbiotics, neomycin and mechanical bowel preparation on intestinal barrier function in patients undergoing colectomy. Br J Surg 94, 546554.CrossRefGoogle ScholarPubMed
108Rayes, N, Seehofer, D, Theruvath, T, et al. (2007) Effect of enteral nutrition and synbiotics on bacterial infection rates after pylorus-preserving pancreatoduodenectomy: a randomized, double-blind trial. Ann Surg 246, 3641.CrossRefGoogle ScholarPubMed
109Rayes, N, Seehofer, D, Theruvath, T, et al. (2005) Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation – a randomized, double-blind trial. Am J Transplant 5, 125130.CrossRefGoogle ScholarPubMed
110Anderson, AD, McNaught, CE, Jain, PK & MacFie, J (2004) Randomised clinical trial of synbiotic therapy in elective surgical patients. Gut 53, 241245.CrossRefGoogle ScholarPubMed
111Cherbut, C, Michel, C & Lecannu, G (2003) The prebiotic characteristics of fructooligosaccharides are necessary for reduction of TNBS-induced colitis in rats. J Nutr 133, 2127.CrossRefGoogle ScholarPubMed
112Winkler, J, Butler, R & Symonds, E (2007) Fructo-oligosaccharide reduces inflammation in a dextran sodium sulphate mouse model of colitis. Dig Dis Sci 52, 5258.CrossRefGoogle Scholar
113Moreau, NM, Martin, LJ, Toquet, CS et al. (2003) Restoration of the integrity of rat caeco-colonic mucosa by resistant starch, but not by fructo-oligosaccharides, in dextran sulfate sodium-induced experimental colitis. Br J Nutr 90, 7585.CrossRefGoogle Scholar
114Schultz, M, Munro, K, Tannock, GW et al. (2004) Effects of feeding a probiotic preparation (SIM) containing inulin on the severity of colitis and on the composition of the intestinal microflora in HLA-B27 transgenic rats. Clin Diagn Lab Immunol 11, 581587.Google ScholarPubMed
115Neu, J (2005) Neonatal necrotizing enterocolitis: an update. Acta Paediatr Suppl 94, Suppl. 449, 100105.CrossRefGoogle ScholarPubMed
116Butel, MJ, Catala, I & Waligora-Dupriet, AJ (2001) Protective effect of dietary oligofructose against cecitis induced by clostridia in gnotobiotic quails. Microbial Ecol Health Dis 13, 166172.Google Scholar
117Sonoyama, K, Watanabe, H, Watanabe, J, et al. (2005) Allergic airway eosinophilia is suppressed in ovalbumin-sensitized Brown Norway rats fed raffinose and alpha-linked galactooligosaccharide. J Nutr 135, 538543.CrossRefGoogle ScholarPubMed
118Casellas, F, Borruel, N, Torrejon, A, et al. (2007) Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin. Aliment Pharmacol Ther 25, 10611067.CrossRefGoogle ScholarPubMed
119Welters, CF, Heineman, E, Thunnissen, FB, van den Bogaard, AE, Soeters, PB & Baeten, CG (2002) Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum 45, 621627.CrossRefGoogle ScholarPubMed
120Lindsay, JO, Whelan, K & Stagg, AJ (2006) Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn's disease. Gut 55, 348355.CrossRefGoogle ScholarPubMed
121Hunter, JO, Tuffnell, Q & Lee, AJ (1999) Controlled trial of oligofructose in the management of irritable bowel syndrome. J Nutr 129, Suppl. 7, 1451S1453S.CrossRefGoogle ScholarPubMed
122Olesen, M & Gudmand-Hoyer, E (2000) Efficacy, safety, and tolerability of fructooligosaccharides in the treatment of irritable bowel syndrome. Am J Clin Nutr 72, 15701575.CrossRefGoogle ScholarPubMed
123Astengiano, M, Pellicano, R, Terzi, E, Simondi, D & Rizzetto, M (2006) Treatment of irritable bowel syndrome: a case-control experience. Minerva Gastroenterol Dietol 52, 359363.Google Scholar
124Moro, G, Arslanoglu, S, Stahl, B, Jelinek, J, Wahn, U & Boehm, G (2006) A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 91, 814819.CrossRefGoogle ScholarPubMed
125Furrie, E, Macfarlane, S, Kennedy, A, et al. (2005) Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 54, 242249.CrossRefGoogle ScholarPubMed
126Chermesh, I, Tamir, A, Reshef, R, et al. (2007) Failure of Synbiotic 2000 to prevent postoperative recurrence of Crohn's disease. Dig Dis Sci 52, 385389.CrossRefGoogle ScholarPubMed
127Olah, A, Belagyi, T, Issekutz, A & Olgyai, G (2005) Combination of early nasojejunal feeding with modern synbiotic therapy in the treatment of severe acute pancreatitis (prospective, randomized, double-blind study). Magy Seb 58, 173178.Google Scholar
128Pierre, F, Perrin, P, Champ, M, Bornet, F, Meflah, K & Menanteau, J (1997) Short-chain fructo-oligosaccharides reduce the occurrence of colon tumors and develop gut-associated lymphoid tissue in Min mice. Cancer Res 57, 225228.Google ScholarPubMed
129Herich, R, Revajova, V, Levkut, M, et al. (2002) The effect of Lactobacillus paracasei and Raftilose P95 upon the non-specific immune response of piglets. Food Agric Immunol 14, 171179.CrossRefGoogle Scholar
130Stillie, RM, Bell, RC & Field, CJ (2005) Diabetes-prone BioBreeding rats do not have a normal immune response when weaned to a diet containing fermentable fibre. Br J Nutr 93, 645653.CrossRefGoogle Scholar
131Adogony, V, Respondek, F, Biourge, V, et al. (2007) Effects of dietary scFOS on immunoglobulins in colostrums and milk of bitches. J Anim Physiol Anim Nutr (Berl) 91, 169174.CrossRefGoogle ScholarPubMed
132Agustina, R, Lukito, W, Firmansyah, A, Suhardjo, HN, Murniati, D & Bindels, J (2007) The effect of early nutritional supplementation with a mixture of probiotic, prebiotic, fiber and micronutrients in infants with acute diarrhea in Indonesia. Asia Pac J Clin Nutr 16, 435442.Google ScholarPubMed
133Fujitani, S, Ueno, K, Kamiya, T, et al. (2007) Increased number of CCR4-positive cells in the duodenum of ovalbumin-induced food allergy model Nc/jic mice and antiallergic activity of fructooligosaccharides. Allergol Int 56, 131138.CrossRefGoogle ScholarPubMed
134Paineau, D, Payen, F, Panserieu, S, et al. (2008) The effects of regular consumption of short-chain fructo-oligosaccharides on digestive comfort of subjects with minor functional bowel disorders. Br J Nutr 99, 311318.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1 The structures of β2-1 fructans. DP, degree of polymerisation; F, fructose; G, glucose; RF, reducing fructose.

Figure 1

Fig. 2 Mechanisms by which β2-1 fructans may influence host defence.

Figure 2

Table 1 Effects of β2-1 fructans on immune function in laboratory animals

Figure 3

Table 2 Effect of β2-1 fructans on immune function in man

Figure 4

Table 3 Effects of β2-1 fructans on infectious outcomes in animal models

Figure 5

Table 4 Effects of β2-1 fructans on infections in man

Figure 6

Table 5 Effects of β2-1 fructans on inflammation in laboratory animal models

Figure 7

Table 6 Effects of β2-1 fructans on inflammation in human disease

You have Access
162
Cited by