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

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’(1). 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(27) 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(8). 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(9). 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(10). 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(11). IN has been extracted from chicory roots, Jerusalem artichoke, artichoke, dahlias and dandelions(12). 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(11).

Oligosaccharides, including some believed to be prebiotics, are present in human breast milk(13). They can be found in concentrations of up to 12 g/l, making them the third largest component of breast milk(14). 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(15) and possibly allergy development(16). 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(1):

  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(17). 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(18), 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(19).

  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(11, 20).

  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(2126). Other experiments establish that β2-1 fructans are selectively fermented by most Bifidobacterium species(27), and also by some Lactobacillius species(28), as these bacteria produce the intracellular fructosyl-fructofuranosidase that is needed for hydrolysis of the β-(2 → 1) osidic bond in β2-1 fructans(10).

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(29). 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(30). Bifidobacterium species and Lactobacillius species are able to produce antibacterial substances that can inhibit the growth and survival of pathogens(31).

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:

  • Acidification of the colonic environment, which is detrimental to some pathogenic strains of bacteria(32) such as some pathogenic species of bacteroides, clostridia and coliforms(31).

  • Acidification of the colon favouring mucin production(33). This is believed to improve mucosal morphology, so decreasing pathogenic bacterial colonisation and translocation.

  • Binding to SCFA receptors (G protein coupled receptors 41 and 43) on immune cells within the gut-associated lymphoid tissues (GALT)(3436).

  • Butyrate decreases the requirement of epithelial cells for glutamine, thus sparing more for GALT(37).

  • Butyrate may also alter epithelial cell gene expression, for example IL-8 and monocyte chemoattractant protein 1, and this in turn would alter the signalling of the epithelial cell to the mucosal immune system(38).

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(39, 40) and mannose(41) have been identified on immune cells, and in vitro, fructose has been shown to alter non-opsonic phagocytosis(42), 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(43).

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(44). Peritoneal macrophage phagocytic activity was also increased in rodents given IN or OF for varying periods of time(45, 46) and in mice vaccinated with Salmonella typhimurium (47) and respiratory burst was also increased(45). 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(45). However, natural killer (NK) cell cytotoxicity in intra-epithelial lymphocytes of adult dogs was not affected by supplementation of FOS with other fermentable fibres(48), and NK cell activity in MLN or PP of rats was not affected by OF-enriched IN(49).

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(50). Several studies report an increase in intestinal or faecal IgA levels upon supplementation with various β2-1 fructan preparations(47, 49, 5153). FOS supplementation increased total faecal IgA and IgA secretion by PP cells in young mice(51), and increased various intestinal measures of IgA production in newborn mice, but did not alter B220+ IgM+ cell percentages in PP(52). In rats, OF-enriched IN increased caecal secretory IgA concentrations(49). FOS in combination with MOS increased ileal IgA in adult dogs(53), but there was no effect upon faecal IgA concentrations in this same study(53). 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(47). 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(54). No effect of IN with shorter-chain FOS removed or OF on faecal IgA concentrations was observed in mice or hypoallergenic dogs((46, 55), and there was no effect of FOS on IgA in the small intestine of piglets(56). 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(47, 51, 52) and a single study reporting no effect(46). 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(5355), but one did show an effect upon ileal IgA concentration(53). 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(45). 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(48). Thus a decrease in the CD4+/CD8+ ratio in the lamina propria cells was observed(48). In contrast, the CD4+/CD8+ ratio was increased in PP of endotoxaemic mice fed FOS(50), and there was no effect on CD4+ or CD8+T cells in the MLN of rats supplemented with OF-enriched IN(49). 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(48), and no effect of OF-enriched IN was seen on MLN or PP lymphocyte proliferation in rats(49). 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(51). IL-10 production from PP and MLN, and IFN-γ production from PP, was also increased in rats with OF-enriched IN supplementation(49, 57); however, cytokine production in MLN was not altered(49). 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(45) and mean fluorescence intensity of MHCII+ cells in spleen of mice also increased, although percentage of MHCII+ cells did not change here(47). 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(58), and phagocytic activity of monocytes and neutrophils in the blood or spleen was not altered upon OF-enriched IN supplementation in rats(49). 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(56). FOS in combination with MOS did not affect blood neutrophil numbers of adult dogs in one study(53) but this supplement decreased neutrophil numbers in another study(54). 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(48), 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(46), and OF-enriched IN increased NK cell-like cytotoxic function in the spleen of male rats(57), and the same supplement non-significantly increased this function in blood mononuclear cells in another study by the same group(49). 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(48). The majority of studies measuring the effect of β2-1 fructans on serum Ig show no effect. This was observed in murine(23, 51) and canine535558 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(48), and a study in mice demonstrated that FOS supplementation was associated with a decrease in serum IgG1(51). 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(47). 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(45). In the blood of adult dogs supplemented with FOS, the CD4+/CD8+ ratio was increased(48). In contrast, supplementation with OF-enriched IN decreased the spleen CD4+/CD8+ ratio in rats(57). 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(46). Neither was there any effect of OF-enriched IN on numbers of CD4+ or CD8+T cells in the spleen and blood of rats(49), 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(47). 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(23). Neither was lymphocyte proliferation altered in the spleen of rats supplemented with OF-enriched IN(49) nor splenocyte proliferation in mice vaccinated against Salmonella typhimurium and supplemented with OF in combination with IN with shorter-chain FOS removed(47). 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(51), 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(47). There was no effect of OF-enriched IN supplementation in rats upon IL-10 production by splenocytes(57), or upon cytokine production in the spleen(49). Blood IL-2 and IL-4 concentrations were increased upon IN or OF supplementation in rats(45). 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(23) 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(245961) and five investigated supplements that contain β2-1 fructans combined with antioxidants, vitamins, minerals, other prebiotics and fats(6266). 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(6769), 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(24). 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(49, 58) and to the findings of Seidel et al. (64) of no effect on phagocytosis of E. coli by granulocytes taken from young adult males consuming bread containing IN.

Neither OF(24) nor a bread containing IN(64) 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(64). B cell number was increased in elderly residents of a long-term care facility supplemented with FOS(63). 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(48).

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)(60), which is agreement with several studies in laboratory animals which show no effect of β2-1 fructans on these(2351535558. In the same study, there was no effect of the combination of OF and IN upon salivary secretory IgA levels(60). 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(65), which fits with the findings from animal studies which show an enhancement of the antibody response in the GALT by prebiotics(47, 49, 5153).

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(70). 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(60). 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(62), 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(63). A study in 8-month-old infants supplemented with OF plus IN reported an increase in post-vaccination measles IgG levels in the blood(59), 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(61). 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(23, 47).

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(24). 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(63). 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(64). However, the percentage of activated T cells (defined as CD3+HLA-DR+) increased while that of NK T cells (defined as CD3+NK+) decreased(64). This mixed picture of effects of β2-1 fructans on blood lymphocyte subsets is similar to that seen in laboratory animals(48, 49).

Lymphocyte proliferation to influenza vaccine components was increased in elderly adults supplemented with FOS(62), but in another study in elderly adults, there was no effect of OF plus IN upon stimulated lymphocyte proliferation(60). Regarding cytokine expression, in elderly nursing home residents, OF supplementation decreased IL-6 mRNA expression in blood mononuclear cells(24), and in elderly adults resident in long-term care facilities, IL-6 production by stimulated blood mononuclear cells was decreased(63). As an increase in IL-6 is associated with the pro-inflammatory state associated with ageing(71), 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(60). This is in contrast to a study in rats that showed an increase in blood measurements of IL-4(45). A trend for a reduced IL-10 production from stimulated blood mononuclear cells was observed upon FOS supplementation in the elderly(63).

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(68, 69). 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(67). 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(67). The decrease in numbers of T cells with NK activity that was seen in the control group was prevented with the supplementation(67). 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(67).

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(7277). 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(78). FOS supplementation increased survival in a hamster model of Clostridium difficile infection(79) and in murine models of Listeria monocytogenes and Salmonella typhimurium infection both IN and OF increased survival(80). 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(81), and FOS prevented diarrhoea induced by Salmonella typhimurium in piglets(82). FOS decreased diarrhoea and increased survival rates in piglets infected with E. coli (83). 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(8487). 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(86). 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(88). 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(81).

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(89, 90). In another study episodes of common childhood diarrhoea were reported to be reduced in healthy infants supplemented with OF(91). In Indonesian children aged 1–14 years, the duration of acute diarrhoea was reduced with FOS supplementation(92), and incidence of acute diarrhoea was also reduced in infants who received an infant formula containing GOS and FOS(93). Incidence of upper respiratory tract infections was also reduced in the group consuming this formula(93). Intestinal permeability was improved in infants fed with a formula containing GOS and IN as compared to a control formula(94). A trial carried out in Peruvian infants found no effect of OF on the occurrence or prevalence of diarrhoea(61), and a trial in infants with diarrhoea showed no benefit of including IN and FOS in the rehydration solution on duration of diarrhoea(95).

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(96). 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(97).

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


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(98), decreased upper respiratory tract infections in older adults post-influenza vaccine(62), and decreased respiratory, skin, gastrointestinal and genitourinary infections in older adults immunised with influenza and pneumococcal vaccines(67). 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(99). 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(100). In burns patients, OF did not improve a variety of measures of the severity or duration of infections(101). In healthy adults, OF had no effect upon faecal mucin excretion(102). 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(103). In a study of patients on an enteral diet, IN had no effect upon intestinal permeability(104).

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(105107). 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(108) and liver transplantation(109). However, some of these studies report no effects of synbiotics on other outcomes measured(105, 107). 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(110).

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(98) 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(45485157 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(21, 25, 111). A model of colitis in female mice showed that FOS decreased disease activity index and damage to the distal colon(112). 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(113). 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(114), 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(26).

Neonatal necrotising enterocolitis may be in part caused by interactions between intestinal immaturity, inappropriate bacterial colonisation and infections(115). 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(22, 116).

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(117). 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)(118). 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(119). 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(120).

Most trials in irritable bowel syndrome do not report beneficial effects of β2-1 fructans on symptom scores(121, 122), perhaps due to the nature of the disease regarding the relapse and remission pattern, although there is one positive study in this disorder(123).

In contrast to the single animal study that reported no benefit of FOS on allergic airway esoinophilia(117), 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(124). 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(125). Mucosal tissue mRNA levels of the β-defensins that are up-regulated in ulcerative colitis were also reduced in this study(125). 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(126). 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(127). 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(123).


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.


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


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