Abstract

Diet modulates immune functions in different ways and affects host resistance to infections. In addition to the essential nutrients in food, nonessential food constituents such as nondigestible carbohydrates also affect the immune system. First results from human intervention studies suggest that the intake of inulin (IN) and oligofructose (OF) has beneficial effects on the gut-associated lymphoid tissue. At the level of the systemic immune system, however, only minor effects have been observed in healthy adult human subjects. In contrast, data from studies with infants suggest that supplementation with a prebiotic mixture positively affects postnatal immune development and increases fecal secretory IgA. Animal studies confirm the observations from human trials and give more insight into the immune tissue- specific effects of IN/OF. A clear outcome of the animal studies is that the intestinal immune system and especially the immune cells associated with the Peyer's patches are responsive to a dietary supplement of IN/OF and/or their metabolites. The mechanisms of IN/OF include indirect effects such as a shift in the composition of the intestinal flora and the enhanced production of immunoregulatory SCFA and perhaps other bacterial metabolites. Few data suggest direct effects of IN/OF via carbohydrate receptors on intestinal epithelial cells and immune cells. In conclusion, prebiotic IN/OF clearly modulate immunological processes at the level of the gut-associated lymphoid tissue, which may be associated with significant health benefits in infants and patients with intestinal inflammatory diseases.

Introduction

The immune system highly depends on an adequate supply of nutrients to function properly. In addition to the essential nutrients, nondigestible carbohydrates such as inulin (IN)5 and oligofructose (OF), including their intestinal fermentation products, may modulate the gut-associated lymphoid tissue (GALT) as well as the systemic immune system. IN and OF are classified as prebiotics, which occur naturally as plant storage carbohydrates in vegetables, cereals, and fruits. Here we review the available data from human and animal studies on the immunomodulatory potential of IN/OF and discuss their underlying mechanisms.

Immunomodulatory effects of IN and OF

Human studies.

Only few studies so far have investigated the immunomodulatory effects of IN/OF in humans. Recently, 2 clinical trials reported the therapeutic outcome of a prebiotic and synbiotic treatment in subjects with ulcerative colitis and Crohn's disease. In a small randomized, double-blinded controlled trial including subjects with ulcerative colitis, the supplementation with B. longum, IN, and OF resulted in an improvement of the full clinical appearance of chronic inflammation. Further, intestinal mRNA levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α were significantly reduced in synbiotic-treated subjects, whereas no significant differences were seen for the immunoregulatory cytokine IL-10 (1). In an uncontrolled study with Crohn's disease patients, the daily intake of 15 g IN/OF significantly decreased disease activity. The percentage of IL-10-positive mucosal dendritic cells and the percentage of these cells expressing Toll-like receptors (TLR) 2 and 4 increased significantly (2). In contrast to these human intervention studies, which have focused on the gut-associated immune system, we have investigated the immunomodulatory effect of a synbiotic (L. rhamnosus GG, B. lactis Bb12, and 10 g/d IN enriched with OF) on the systemic immunity (3). The synbiotic treatment of colon cancer patients who had undergone curative resection increased ex-vivo the capacity of peripheral blood mononuclear cells to produce IFN-γ. In polypectomized patients, the synbiotic prevented the decline in IL-2 production capacity that was observed in the placebo group over time. However, no other parameter of the systemic immune system was affected by the synbiotic treatment (3).

In a randomized controlled trial with 259 infants at high risk of atopy, the ad libitum intake of a formula providing 0.8 g prebiotics/100 mL (90% short-chain galacto-oligosaccharides and 10% long-chain IN) resulted in a significantly reduced incidence of atopic dermatitis suggesting that these prebiotics altered postnatal immune development (4). Another randomized controlled study investigated the effect of the same prebiotic mixture on fecal secretory IgA (SIgA) secretion in infants. The prebiotic-supplemented infant formula resulted in an enhanced secretion of fecal SIgA (5), which is considered to be associated with a significantly faster clearance of pathogenic bacteria and viruses from the intestine (6). In a recent study with infants (aged 6–12 mo), OF (0.67 g/d) in combination with a cereal supplement had no effect on diarrhea prevalence and antibody titers to H. influenzae compared with the cereal supplement alone (7). Because 87% of the children were breast-fed, human milk may have provided adequate protection to mask the prebiotic effects in the gut.

In a study with elderly people living in a nursing home, 3 wk of OF supplementation at a dose of twice 4 g/d increased fecal bacterial counts of bifidobacteria (8). The percentages of CD3+, CD4+, and CD8+ lymphocytes were raised compared with controls. In contrast, phagocytic activity of peripheral blood granulocytes and monocytes and the expression of IL-6 mRNA in monocytes were decreased. The authors speculated that because of a possible reduction in pathogenic bacteria induced by OF supplementation, inflammatory processes such as phagocytosis and IL-6 production were decreased. However, the study did not include a time control; therefore, the possibility that the finding arose by chance cannot be excluded. A study in free-living elderly receiving a nutritional supplement with placebo or with OF (6 g/d) for a period of 28 wk investigated the immune response to vaccination with influenza and pneumococcal vaccines (9). No differences in serum antibodies between placebo and OF plus nutrient supplement were observed after vaccination. Ex-vivo, mononuclear cells showed similar lymphocyte proliferative responses and cytokine secretion capacities (IL-4, IFN-γ). Because there was no study group that received the OF alone, it is difficult to separate the effects of the nutrient supplement that provided 50% of vitamin daily reference values from the effects of OF. In a following study, OF plus nutrient supplement combined with L. paracasei was given to healthy elderly. Although a significant stimulation in natural killer (NK) cell cytotoxicity was observed compared with controls, significant differences were already observed at baseline (10). Again, no prebiotic control was included in this study. However, elderly subjects with adequate nutrition are known to have appropriate immune functions, which cannot be further stimulated by dietary supplements (11).

In summary, only few human studies so far have investigated the effects of OF alone on the immune system. The currently available data suggest that the oral intake of IN/OF may modulate the immune system in humans. More human studies including dose-response studies with prebiotics such as IN/OF are needed, with a special focus on the GALT.

Animal studies.

Immunomodulatory effects of IN/OF on the GALT can easily be investigated in animals. Nakamura et al. (12) extensively studied the impact of OF intake (50 g/kg diet) in infant BALB/c mice on IgA. The expression of the secretory component, as well as IgA tissue concentrations, was elevated in the small and large intestinal tract. SIgA secretion into the ileal gut lumen and IgA+ plasma cell numbers in Peyer's patches (PP) were significantly enhanced, too. These findings are in line with results of another murine study (25 g OF/kg of the diet for 4 wk) where fecal IgA levels increased and cocultured PP lymphocytes of OF-fed mice produced more IgA as a response to stimulation with a bifidobacterial homogenate (13). Results from our laboratory underpin these effects: in our short-term study (4 wk) with F344 rats, supplementation with Synergy, (100 g/kg diet), a mixture of OF and high-polymer IN, stimulated SIgA production in the cecum (14). Here, we also observed an increase in immunoregulatory IL-10 secretion by ex-vivo activated PP lymphocytes compared with control animals that had been fed a high-fat/low-fiber diet. In our long-term trial (33 wk) of similar experimental design (100 g Synergy/kg diet) the development of colon cancer had been chemically induced with the carcinogen azoxymethane (AOM). In AOM-treated animals, the production of IL-10 by PP was elevated as well (15). Indeed, in the groups treated with the prebiotic, a significantly lower number of colorectal tumors (adenomas and cancers) was found (16). In addition to findings regarding immune functionality of PP, changes in PP cellularity (increased size of PP nodules, greater numbers of B lymphocytes in PP) are reported too (13,17).

Our recent investigations dealing with a porcine animal model also revealed similar antiinflammatory changes in the GALT. In contrast to rodents, the gastrointestinal tract of pigs as well as the porcine immune system bear more resemblance to those of humans (18). After supplementation with the same mixture of IN and OF (20 g Synergy/kg diet; 3 wk) as for the rats, mitogen-activated intraepithelial lymphocytes, isolated from porcine distal jejunal sites, produced significantly more IL-10 than those isolated from controls that had received maltodextrin as isocaloric replacement for the prebiotic treatment (19).

Recent investigations in rat models of inflammatory bowel disease also demonstrated that the administration of IN and OF may alleviate acute inflammation (20,21). Transgenic HLA-B27 rats develop spontaneous colitis as an immune response to the endogenous intestinal microflora. The intake of 5 g Synergy/kg body weight for 7 wk resulted in reduced levels of proinflammatory IL-1β in the cecal mucosa and diminished production of bacterially stimulated IFN-γ by mesenteric lymphocytes. Moreover, mucosal concentrations of immunoregulatory transforming growth factor-β were significantly augmented by the prebiotic treatment. These immunomodulatory effects were associated with a reduction of colitis development in prebiotic-treated animals as inflammation scores from intestinal tissues had been reduced (20). In another study, colitis was chemically induced by dextran sodium sulfate administration to Sprague-Dawley rats. The animals received IN and OF before and after colitis induction. Here, the authors reported lowered IL-1β production in the colonic tissue, which was accompanied by reduced myeloperoxidase activity in the colon and by significantly less bacterial translocation to mesenteric lymph nodes (21). Taken together, these findings build up a strong rationale for antiinflammatory effects of IN and OF on the GALT level under normal as well as inflammatory conditions.

Systemic immunomodulatory effects are rare, which could be demonstrated by several studies, including those of our own laboratory (14,15,19,22). However, studies by Buddington et al. (23) reported enhanced systemic immunity in IN/OF-supplemented mice. Mice exposed to enteric and systemic pathogens or to different tumor inducers were supplemented with OF (100 g/kg diet) or IN (100 g/kg diet). Although the incidence of lung tumors after injection of B16F10 tumor cells was not affected by the prebiotic supplements, carcinogen-induced aberrant crypt foci in the distal colon were reduced in mice supplemented with OF or IN. Systemic pathogen exposure with Listeria monocytogenes in OF- and IN-supplemented mice resulted in reduced mortality compared with cellulose-supplemented controls (100 g/kg diet). The data from Buddington et al. (23) suggest that OF and IN may also enhance systemic immunity against these pathogens and against aberrant cells in the colon. In a follow-up study these authors investigated the modulatory effects of IN and OF at a similar dose on immune functions in mice (24). After a period of 6 wk with OF or IN supplementation, both prebiotics increased NK-cell activity of spleen cells and phagocytic activity of peritoneal macrophages compared with the cellulose group. Because control mice received cellulose, and intestinal cellulose degradation differs from intestinal IN/OF fermentation, it is difficult to ascribe the observed changes to a decrease in cellulose intake or to an increase in prebiotic intake.

Protective effects of IN and OF during intestinal carcinogenesis seem to be closely related to their immunomodulatory potential. Min mice, which carry a mutation in the Apc gene, are a model for human intestinal cancer. In OF-fed (58 g/kg diet) Min mice, tumor incidence in the colon was reduced, and the development of lymphoid nodules in the GALT was promoted (25). Yet, in immunocompromised animals depleted in CD4+ and CD8+ T-cells, the incidence of colonic tumors was significantly raised, alluding to an involvement of the gut-associated immune system in tumor protection (26). In our own animal study with AOM-induced colon carcinogenesis in F344 rats, intervention with IN/OF reduced tumor incidence in the colon, and the number of colorectal tumors was lowered (16). In particular, immunomodulation in PP seems to be responsible for the antitumorigenic effects of IN and OF because a depression of NK-cell activity, which had been evoked by the AOM treatment, was counteracted by prebiotic supplementation (15).

Mechanisms for the effects of IN/OF on the immune system

Human intervention studies as well as short- and long-term studies from our laboratory with Fischer F344 rats and pigs indicate that OF-enriched IN primarily modulates immune functions in the GALT. Within the GALT, immune cells isolated from PP are especially responsive to oral IN/OF intake. The underlying mechanisms of prebiotic-induced alterations of the cellular structures of PP are not yet known. Substantial experimental data suggest that IN and OF mediate immunological effects in PP as well as in other tissues of the GALT (Table 1).

TABLE 1

Potential mechanisms of prebiotic-induced immunomodulation

- Selective increase/decrease in specific intestinal bacteria that modulate local cytokine and antibody production 
- Increase in intestinal SCFA production and enhanced binding of SCFA to G-coupled protein receptors on leukocytes 
- Interaction with carbohydrate receptors on intestinal epithelial cells and immune cells 
- Partial absorption of IN/OF resulting in local and systemic contact with the immune system 
- Selective increase/decrease in specific intestinal bacteria that modulate local cytokine and antibody production 
- Increase in intestinal SCFA production and enhanced binding of SCFA to G-coupled protein receptors on leukocytes 
- Interaction with carbohydrate receptors on intestinal epithelial cells and immune cells 
- Partial absorption of IN/OF resulting in local and systemic contact with the immune system 
TABLE 1

Potential mechanisms of prebiotic-induced immunomodulation

- Selective increase/decrease in specific intestinal bacteria that modulate local cytokine and antibody production 
- Increase in intestinal SCFA production and enhanced binding of SCFA to G-coupled protein receptors on leukocytes 
- Interaction with carbohydrate receptors on intestinal epithelial cells and immune cells 
- Partial absorption of IN/OF resulting in local and systemic contact with the immune system 
- Selective increase/decrease in specific intestinal bacteria that modulate local cytokine and antibody production 
- Increase in intestinal SCFA production and enhanced binding of SCFA to G-coupled protein receptors on leukocytes 
- Interaction with carbohydrate receptors on intestinal epithelial cells and immune cells 
- Partial absorption of IN/OF resulting in local and systemic contact with the immune system 

The IN/OF-induced shift in the intestinal microflora toward bifidobacteria and other SCFA-producing bacteria may change the presence of pathogen-associated molecular patterns in the intestinal lumen including endotoxin or lipopolysaccharides, teichoic acids, and unmethylated CpG motifs of DNA (27). Through pattern recognition receptors such as the TLR, local immune cells may respond to these molecular motifs. TLR signaling results in activation of NF-κB and the secretion of proinflammatory cytokines (28,29). Ingestion of bifidobacteria is associated with increased IgA levels in the small intestine and feces and ex-vivo IgA production by PP B-lymphocytes (3032). One study with dogs supplementing a low dose of OF (2 g/d) could not find significant effects on the number of bifidobacteria or on immunological markers (33). This outcome supports the hypothesis that changes in numbers of bifidobacteria induced by OF supplementation are a prerequisite for changes of immunological functions such as IgA production.

SCFA are produced by microbial fermentation of IN/OF in the terminal ileum and in the colon with total concentrations ranging from 70–140 mmol/L in the proximal colon and 20–70 mmol/L in the distal colon (34). SCFA are rapidly transferred from the intestinal tract to the bloodstream. Usual SCFA concentrations in the bloodstream of humans are 104–143 μmol/L for acetate, 3.8–5.4 μmol/L for propionate, and 1.0–3.1 μmol/L for butyrate (35). A recent study with growing pigs reported that up to 50% of IN [average degree of polymerization (DP) = 12] was already degraded in the jejunum, with lactate as the main fermentation product followed by acetate (36). Lactate and acetate both can be interconverted to butyrate (37). As a consequence, high SCFA concentrations in the small intestine may affect immune cell functions in PP. In addition, colonic infusion of butyrate or a combination of SCFA resulted in enhanced epithelial proliferation in distant intestinal segments (38,39), suggesting that the production of SCFA in the colon induces physiological changes throughout the intestinal tract.

In vitro butyrate is known to suppress lymphocyte proliferation, to inhibit cytokine production of Th1-lymphocytes, to induce T-lymphocyte apoptosis, and to up-regulate IL-10 production of dendritic cells (4043). In combination with other SCFA butyrate significantly stimulated rat splenic NK-cell cytotoxicity (44). Butyrate production in the rat cecum also resulted in higher numbers of CD161+ NK cells in the cecal epithelial layer (45). Intravenous application of pharmacological doses of acetate further enhanced NK-cell cytotoxicity (46). These data suggest that SCFA as fermentation products of IN/OF may affect immune cells within the GALT and throughout the host.

The signaling pathways by which intraluminal SCFA are sensed by leukocytes are not completely known. In 2003, 2 orphan G-protein-coupled receptors (GPR41 and GPR43) for SCFA have been identified. For GPR43, acetate and propionate have been found to be the most potent ligands (47,48). Butyrate and isobutyrate show strong effects on GPR41 (49). Although GPR41 is expressed in a wide range of tissues and cells including neutrophils and dendritic cells, GPR43 is highly expressed in various types of immune cells (47,49) including mucosal mast cells in the rat intestine (ileum and colon) (50).

Blood acetate concentrations are well within the active range for GPR43 (49). In contrast, normal concentrations of propionate and butyrate in blood are too low to systemically activate GPR41 or GPR43. However, a recent pig study feeding a rye-based diet measured blood butyrate concentrations of 55 μmol/L 8–10 h after feeding (51). Enhanced SCFA production in the gut after prebiotic supplementation may increase SCFA supply to immune cells located along the GALT (52) and activate these cells via these SCFA-receptors. Such local effects of SCFA could explain in part the observed differences between systemic and local immune effects in the gut in IN/OF-supplemented animals and in dogs supplemented with different types of fermentable dietary fibers (53).

Another mechanism points to interactions of prebiotic carbohydrates with carbohydrate receptors on immune cells. Phagocytic cells, minor subsets of T and B lymphocytes, and NK cells express the complement receptor 3 (CD11b/CD18) (54). This receptor mediates cellular cytotoxic reactions against target cells bearing specific carbohydrate structures. Soluble β-glucan derived from the yeast cell wall is a particularly potent stimulator of this receptor. Recently, the β-glucan receptor dectin-1 has been identified on immune cells including neutrophils, monocytes, macrophages, and a subset of T cells (55,56). This C-type lectin receptor belongs to the pattern recognition receptor, is widely expressed in thymus, spleen, and the small intestine, and recognizes a variety of β-1,3-linked and β-1,6-linked glucans (DP > 7) from fungi and plants. In vitro, the nondigestible oligosaccharides nigerooligosaccharides stimulated NK-cell cytotoxicity, pointing to a direct effect of this oligosaccharide on NK cells via specific lectin-type receptors (57). It is presently not known whether specific fructose receptors exist on immune cells, although mannose receptors have been identified on immune cells (55). However, in vitro studies have shown that fructose modulates nonopsonic phagocytosis and production of reactive oxygen species by phagocytes (58,59).

To bind to such carbohydrate receptors outside the intestinal tract, prebiotic carbohydrates have to be bioavailable. Data from human studies suggest that human milk oligosaccharides are partially absorbed intact in the infant's intestine and excreted in the urine of breast-fed infants (60). This indirectly proves that these prebiotic carbohydrates were systemically available. For the trisaccharide raffinose, peak plasma concentrations of 60 μmol/L were observed in rats within 60 min after supplementation (61), suggesting that OF with a lower DP may also be absorbed intact in the gastrointestinal tract. Oral administration of water-soluble, highly purified glucan molecules (laminarin and scleroglucan) to rats resulted in bioavailabilities of 4.9% and 4.0%, respectively (62). Fluorescence labeling of these glucans induced fluorescence in cells isolated from PP 24 h after oral administration. However, a highly purified water-insoluble glucan was not present in plasma. This demonstrates that, depending on the physical state, such complex carbohydrates pass the intestinal barrier intact and that GALT cells are capable of recognizing and binding these carbohydrates (62). Additional evidence supporting the permeation of low-DP OF is the clinical use of mannitol, lactulose, and other low-molecular-weight, nondigestible carbohydrates to evaluate intestinal permeability.

Besides SCFA other bacterial metabolites and compounds produced by intestinal bacteria metabolizing IN/OF could also be important immunomodulatory signals.

First data from human intervention studies and the results from recent animal studies clearly suggest that IN/OF have a strong impact on the immune system. Immune cells of the GALT including PP are primarily responsive to the oral administration of such prebiotics.

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Abbreviations

     
  • AOM

    azoxymethane

  •  
  • DP

    degree of polymerization

  •  
  • GALT

    gut-associated lymphoid tissue

  •  
  • IN

    inulin

  •  
  • NK

    natural killer

  •  
  • OF

    oligofructose

  •  
  • PP

    Peyer's patches

  •  
  • SIgA

    secretory immunoglobulin A

  •  
  • TLR

    Toll-like receptors

Footnotes

1

Published in a supplement to The Journal of Nutrition. Presented at the conference “5th ORAFTI Research Conference: Inulin and Oligofructose: Proven Health Benefits and Claims” held at Harvard Medical School, Boston, MA, September 28–29, 2006. This conference was organized and sponsored by ORAFTI, Belgium. Guest Editors for the supplement publication were Marcel Roberfroid, Catholique University of Louvain, Brussels, Belgium and Randal Buddington, Mississippi State University, USA. Guest Editor disclosure: M. Roberfroid and R. Buddington, support for travel to conference provided by ORAFTI.

3

In these proceedings, the term inulin-type fructan shall be used as a generic term to cover all β–(2←1) linear fructans. In any other circumstances that justify the identification of the oligomers vs. the polymers, the terms oligofructose and/or inulin or eventually long-chain or high-molecular-weight inulin will be used, respectively. Even though the oligomers obtained by partial hydrolysis of inulin or by enzymatic synthesis have a slightly different DPav (4 and 3.6, respectively), the term oligofructose shall be used to identify both. Synergy will be used to identify the 30/70 mixture (wt:wt) of oligofructose and inulin HP, otherwise named oligofructose-enriched inulin.

4

Supported by the Commission of the European Communities, project No. QLRT-1999-00346, by the Deutsche Forschungsgemeinschaft DFG Re592/10-1 and Re592/10-2, and by the Federal Ministry for Food, Agriculture and Consumer Protection.