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,1
* Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan and
Research and Development Center, Bio Science Laboratory, Showa Sangyo, Tsukuba, Ibaraki 305-0003, Japan
1To whom correspondence should be addressed. E-mail: hiroyuki_mizubuchi{at}showa-sangyo.jp.
ABSTRACT
Isomalto-oligosaccharides (IMO) belong to a group of prebiotics that significantly increase the number of protective gut microflora. In the present study, we investigated the effects of IMO on intestinal and systemic immunity in mice. When mice were fed a diet supplemented with 20% IMO for 4 wk, the number of lactobacilli and the levels of IgA in feces were greater than those of mice fed the control diet (P < 0.05). Interferon-
(IFN-) production by intestinal intraepithelial lymphocytes (i-IEL) in response to T-cell receptor (TCR) triggering was greater in mice fed IMO than in controls (P < 0.05), indicating T helper-1 (Th1) polarization of intestinal immunity by IMO. The proportion of natural killer (NK) T cells in the liver mononuclear cells (MNC), and the production of IFN- by the liver MNC in response to TCR triggering were greater in mice fed IMO than in controls (P < 0.05), suggesting that the Th1/Th2 balance was shifted toward the Th1 lineage by IMO in systemic immunity. Furthermore, the proportion and activity of NK cells were greater in the spleens of the mice fed IMO than in the controls. Dietary IMO protected the mice from -irradiation–induced lethality, accompanied by an inhibition of the translocation of Enterobacteriaceae. Notably, when mouse macrophage-like J774.1 cells were cultured with Lactobacillus gasseri in the presence of IMO, interleukin (IL)-12 production was greater than in the absence of IMO. These results suggest that IMO, in synergy with lactobacilli, upregulate the Th1 response and beneficially modulate host defense.
KEY WORDS: • isomalto-oligosaccharides • lactobacilli • mucosal immunity • systemic immunity • mice
The mammalian intestine is inhabited by a complex and diverse microbial community that is in intimate association with the host epithelium (1). The mucosal surface of the human gastrointestinal tract is colonized by 1013–1014 bacteria of 400 different species and subspecies (1). Specific components of the intestinal commensal microflora are associated with beneficial changes such as the reduced survival of pathogens in the gut and stimulation of the immune system of the host (2,3). Live microbial feed supplements consisting of bifidobacteria and lactobacilli have been used as probiotics, which modulate systemic and intestinal immunity (2,4). There is increasing information about the underlying immunological mechanisms of probiotics. Lactobacilli were shown to stimulate monocytes/macrophages to produce interleukin (IL)2 -12 and tumor necrosis factor (TNF)-
, so-called pro-inflammatory cytokines (5,6). IL-12 plays a central role in promoting the T helper (Th)1-type immune response by stimulating natural killer (NK), NKT and Th1 cells to produce interferon (IFN)-, a cytokine that predominates during the Th1 response (7,8). Lactobacilli actually augmented the production of IFN- by lymphocytes, suggesting they promote the Th1-type immune response possibly in an IL-12–dependent manner. The Th1 immune response, characterized by the secretion of INF-, IL-2, and lymphotoxin-, is important for resistance to intracellular pathogens including viruses, bacteria, protozoa, fungi, and carcinogenesis, whereas an excessive Th1 response is involved in the pathogenesis of several inflammatory and autoimmune diseases including multiple sclerosis, diabetes, and autoimmune thyroid diseases (9,10). In contrast, the Th2 immune response, characterized by the production of IL-4, IL-5, and IL-13, is essential for antibody production and for the elimination of some viruses, extracellular pathogens including bacteria, helminths, and nematodes, whereas excessive Th2 responses play a triggering role in allergic diseases, such as rhinitis, asthma, and eczema (11). Early IL-4 production by mast cells and unique T cells such as NKT cells is important for subsequent generation of IL-4–producing Th2 cells for IgE production (12). Thus, Th cell differentiation is determined mainly by the balance between IL-12 and IL-4 (11).
Dietary tools for changing the composition and activity of commensal bacteria are very desirable. Modulation of the commensal microflora can be achieved by the ingestion of bacteria or by providing nutritional substrates, so-called prebiotics, to favor the growth of specific intestinal bacteria, such as lactobacilli and bifidobacteria (13). IMO belong to the group of prebiotics in which there is a 1–6 glucosidic linkage in the molecular structure. The ingestion of IMO by healthy adult men and senile persons significantly increased the number of fecal bifidobacteria (14). However, isomaltose is hydrolyzed by isomaltase in the jejunum (15), suggesting that a proportion of the IMO was hydrolyzed by isomaltase in the jejunum, and that the residual IMO was used by bifidobacteria in the large intestine (15). Although it is most likely that prebiotics affect host immunity through the modification of microflora, the underlying immunological mechanisms of prebiotics are generally not well defined. In this study, we examined the effects of IMO on intestinal and systemic immunity in vitro and in vivo.
MATERIALS AND METHODS
Isomalto-oligosaccharides. Commercially available isomalto-oligosaccharide (IMO; Isomalto-900, Showa sangyo), which was enzymatically produced from cornstarch on an industrial scale, was used in this study. The composition of the dry substance was: 30.4% isomaltose, 25.6% isomalto-oligosaccharides with the degree of polymerization between 4 and 7, 15.9% isomaltotriose, 11.4% panose, 6.2% kojibiose and nigerose, 4.9% maltose, 3.0% glucose, and 2.6% maltotriose.
Mice and diets. Female 4-wk-old C57BL/6 mice were purchased from Charles River Japan and housed in a room at 37°C and 55% relative humidity, with a 12-h light:dark cycle. The control diet was prepared according to the AIN-93G formulation (16). The IMO diet was modified to include IMO, 200 g/kg, replacing equal amounts of cornstarch. The energy density of IMO diet was 11.3–13.8 kJ/g, whereas that of the cornstarch diet was 16.7 kJ/g (17). Mice were fed the experimental diets for 4 wk. Body weights and food intakes of mice were monitored weekly. At the end of the experimental feeding period, mice were anesthetized with diethylether and killed by exsanguination. A notice of the Prime Minister’s Office of Japan (no. 6 of 27 March 1980) for the care and use of laboratory animals was followed.
IgA assay. Fecal samples were collected from mice (n = 5/group) fed the control or IMO diet and stored in a –80°C freezer until analysis. Fecal samples were mixed on a vortex in PBS for 15 min at room temperature until all materials were suspended and were centrifuged at 2000 x g for 10 min. The fecal IgA level was measured using the Mouse IgA ELISA Quantitation Kit (Bethyl).
Microflora analysis. Fecal samples of mice (n = 3/group) fed the control or IMO diet were freshly collected and immediately transferred to the anaerobic tube and weighted. Examinations of fecal microflora were carried out by Calpis (18). Samples were examined for the following bacteria: Enterobacteriaceae, Lactobacillus, Bacteroidaceae, and Clostridium. Bacterial counts were reported per gram of wet feces.
Cell preparation. Small intestine, spleen, and liver were obtained from mice (n = 5/group) fed the control or IMO diet. Spleen cells were prepared by gentle crushing between 2 glass slides. Intestinal intraepithelial lymphocytes (i-IEL) were isolated as described previously (19). Liver mononuclear cells (MNC) were prepared as described previously (20). The number of viable cells was counted by staining them with trypan blue or Turk’s solution.
Cell culture.
i-IEL, spleen cells, and liver MNC were cultured in 200 µL of complete RPMI medium (RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100 kU/L penicillin, 100 g/L streptomycin and 10 mmol/L HEPES) in 96-well flat-bottomed plates (Falcon, Becton Dickinson) at a density of 5 x 105 cells/well with anti-cluster of differentiation (CD) 3
(145–2C11, 50 mg/L) monoclonal antibody (mAb) that had been immobilized on the plates by prior incubation at 4°C overnight. After incubation for 48 h, the supernatant was collected to estimate cytokine production. Culture supernatants were then analyzed for the production of IFN-, IL-4, and IL-10 with the ELISA Development Kit for Mouse IFN-, IL-4, and IL-10 (GT).
Flow cytometry.
All cell suspensions in HBSS containing 2.5% Nu-serum and 0.1% NaN3 were stained with the appropriate mAbs at 4°C for 30 min. To prevent nonspecific binding of mAb, CD32/16 (2.4G2) was added before staining with labeled mAb. The mAbs used in these experiments were as follows: fluorescein isothiocyanate–conjugated anti-CD3 (145–2C11) mAb, Cy-chrome-conjugated anti-CD4 (L3T4) mAb, phycoerythrin (PE)-conjugated anti-CD8 (Lyt2) mAb, biotin-conjugated anti-CD8ß (Ly3.2) mAb, biotin-conjugated anti-TCR
mAb, PE-conjugated anti-TCRßmAb, and PE-conjugated anti-NK1.1mAb. All mAbs and streptavidin-PE-Cy5 were purchased from Pharmingen. Analysis (2- or 3-color) was performed using a FACSCalibur flow cytometer (BD Biosciences). The live lymphocytes were carefully gated by forward and side scattering. The data were analyzed using CellQuest software (BD Biosciences).
NK activity assay. Mice (n = 5/group) were injected i.p. with 150 µg polyinosinic:polycytidylic acid. After 24 h, NK activity in spleen cells was assessed by a standard 4-h 51Cr-release assay using an NK-sensitive YAC-1 cell line (21).
Irradiation.
Whole-body irradiation with 9 Gy was performed with a 60Co -ray irradiator (model RE1001, Toshiba) at a rate of 0.75 Gy/min. The irradiation dose of 9 Gy administered to the mice was 1.5 x the 50% lethal dose (6 Gy) for C57BL/6 mice; this induced lethal translocation of enteric gram-negative bacteria and resulted in death (22). Mice (n = 10/group for estimation of survival rate) were fed the control or the IMO diet for 4 wk before -irradiation (9 Gy). i-IEL were collected on d 0, 3, 7, and 9 (n = 5/group on each day) after -irradiation, and cell numbers of the i-IEL were measured.
Counting of endogenous bacterial colonies.
Numbers of bacteria in the liver and spleen (n = 5/group) on d 7 after -irradiation were determined. Cell suspensions, obtained by pressing the whole tissue through stainless steel mesh, were spread on agar medium plates to detect Enterobacteriaceae (MacConkey, Nissui Pharmaceutical,) and colonies were counted after incubation for 24 h at 37°C.
Preparation of heat-killed Lactobacillus gasseri. L. gasseri ATCC 33323 was obtained from American Type Culture Collection. Heat-killed L. gasseri was used in this study. L. gasseri was incubated in MRS Broth (Difco) at 37°C for 24 h, harvested by centrifugation at 10,000 x g for 20 min at 4°C, washed 3 times, and suspended in distilled water. L. gasseri was heated at 70°C for 10 min (1 g of heat-killed L. gasseri corresponds to 109–1010 colony-forming unit (cfu) of live bacteria).
Cell line culture. Mouse macrophage-like cells J774.1 were grown in tissue culture flasks at 37°C in 5% CO2, 95% air and passaged every 2–3 d to maintain logarithmic growth. J774.1 cells were obtained from the Institute of Physical and Chemical Research Cell Bank and maintained in complete RPMI medium. J774.1 cells were cultured with or without 1 mg/L heat-killed L. gasseri in the absence or presence of 1 mg/L IMO for 24 h. Culture supernatants were then analyzed for the production of IL-12p40 with the ELISA Development Kit for Mouse IL-12p40 (GT).
Statistical analysis. Data are expressed as means ± SD. Differences between groups in survival rate were determined by the generalized Wilcoxon’s test. For each group, the mean number of days until death was calculated using Excel software (Microsoft). Other data were analyzed by Student’s t test. Differences with P < 0.05 were considered significant. The statistical calculations were carried out using StatFlex version 5.0 (Artec).
RESULTS
Body weights and food intakes. The initial body weights of the mice were 13.6 ± 0.7 and 13.6 ± 1.0 g in the control and IMO groups, respectively and the final weights at 4 wk were 16.1 ± 0.7 and 16.3 ± 0.7 g, respectively. The body weights did not differ between groups throughout the experiment. Food intake in the IMO group (1.66 ± 0.08 g/d) tended to be greater (P = 0.16) than that in the control group (1.58 ± 0.16 g/d). Energy intake did not differ between the control (25.02 ± 2.53 kJ/d) and IMO groups (24.47 ± 1.18–25.31 ± 1.22 kJ/d).
Fecal IgA levels and microflora. Fecal output did not differ between groups (data not shown). The concentration of IgA in the feces in the IMO group was higher 2 and 4 wk after oral administration, compared with the control group (Fig. 1, P < 0.05). The number of Lactobacillus in the IMO group was greater (Table 1, P < 0.05) than in the control group. Numbers of other bacteria did not differ between the groups (Table 1).
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and ß or TCRß and did not differ between the groups (data not shown). However, mice fed the IMO diet had greater ratios of NK (NK1.1+CD3–) cells in spleen (6.90 ± 1.07%) compared with mice fed the control diet (5.97 ± 0.57%, P < 0.05). In addition, mice fed the IMO diet had greater ratios of NKT (NK1.1+CD3+) cells in liver MNC (38.73 ± 5.61%) compared with mice fed the control diet (27.11 ± 3.39%, P < 0.05).
Cytokine production.
IFN- production by i-IEL in the IMO group (8.019 ± 1.336 g/L) was greater than that in the control group (3.558 ± 2.082 g/L, P < 0.05), whereas the levels of IL-4 and IL-10 in the IMO group did not differ from those in the control group (data not shown). Similarly, IFN- production by liver MNC in the IMO group (2.095 ± 0.257 g/L) was higher than that in the control group (1.416 ± 0.223 g/L, P < 0.05), whereas the level of IL-4 in the IMO group (62.9 ± 23.0 mg/L) was lower than that in the control group (95.1 ± 22.7 mg/L, P < 0.05). Cytokine production by the spleen cells did not differ between the groups (data not shown).
NK activity of spleen cells. The NK cell activity of spleen cells in the IMO group was higher at a 100:1 effector:target ratio than that in the control group (Fig. 2, P < 0.05).
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-irradiation was longer than that in the control group (8.10 ± 0.99 d) (P < 0.05; Fig. 3A). The numbers of bacteria in liver of the IMO group were lower than in the control group on d 7 after -irradiation (Fig. 3B, P < 0.05). The i-IEL cell numbers in the IMO group were greater than in the control group on d 9 after -irradiation (Fig. 4, P < 0.05).
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DISCUSSION
The objective of the present study was to investigate the effects of IMO as a prebiotic on the immune system. Results of this study indicate that IMO may be useful as a prophylactic approach to control infectious diseases by inducing Th1-dominant immunity.
In the present study, IMO enhanced IL-12 production by macrophages stimulated with L. gasseri in vitro, and dietary IMO significantly increased lactobacilli in the intestinal microflora. Because IL-12 is produced by monocytes/macrophages and dendritic cells, IMO affects primarily these cells and promotes the Th1-type immune response. It was shown that Lactobacillus strains, such as L. paracasei and L. casei, increase IL-12 production, and lipoteichoic acids from Lactobacillus strains induce production of proinflammatory cytokines through toll-like receptor (TLR)2 (23,24). From these studies, we suggest that the synergistic effect of IMO on lactobacilli-induced IL-12 production is not limited to L. gasseri, and IMO can synergistically enhance the ability of other Lactobacillus strains to induce IL-12 production. Additionally, dietary IMO may augment the production of IFN- by i-IEL, possibly by lactobacilli-induced IL-12 production.
The numbers of NK cells in the spleen and NKT cells in the liver increased significantly in mice fed IMO, but the mechanism underlying this increase is not clear. IL-15 is an important cytokine for the proliferation and development of NK and NKT cells (25). IL-15 production was induced by nuclear factor-
B and interferon regulatory factor (IRF)1 or IRF3, which were activated mainly by TLR signaling (26,27). Thus, it is possible that IMO increases the number of NK and NKT cells via augmented production of such growth factors by macrophages in the spleen and liver through accelerated TLR signaling. There was increased NK activity in the spleen of mice fed IMO. Both an increased ratio and the activities of NK cells may be due to increased IL-15 and IL-12 production by accelerated TLR signaling.
IL-4 production by liver MNC in response to immobilized TCR/CD3 mAb was mediated mainly by NKT cells (28). IL-4 production was significantly decreased, but IFN- production was increased by liver MNC of mice fed IMO in response to immobilized CD3 mAb. Oligosaccharides were reported to be detected in the portal blood at higher concentrations than in the peripheral blood in rats orally administered oligosaccharide, indicating that a small amount of oligosaccharide was absorbed by the small intestine into the body (29). It was previously reported that oral treatment with nigero-oligosaccharides enabled mice to increase IL-12 production in response to a potent IL-12 inducer, L. plantarum L-137 (30). Ligands for TLR such as lactobacilli, a strong IL-12 inducer, could be detected easily in the portal blood (31,32). Therefore, orally administered IMO may act on hepatic NKT cells through increased IL-12 production locally from Kupffer cells stimulated with TLR ligands.
In this study, dietary IMO protected mice from the endogenous infection induced by -irradiation. There are several possible underlying mechanisms. i-IEL have a predominant role in excluding pathogens in the intestine through their cytolytic activity and production of inflammatory cytokines such as IFN- (33–35). Therefore, it is possible that the increase in IFN- production in i-IEL due to dietary IMO may contribute to protection against invasion by enteric Enterobacteriaceae. Dietary IMO accelerated the recovery of i-IEL after -irradiation. i-IEL was reported to promote epithelial wound healing via the production of fibroblast growth factors, such as keratinocyte growth factors, and to regulate the maturation and homeostasis of the gut (36). Intestinal epithelial cell–derived cytokines, such as stem cell factor, IL-7, and IL-15 are required for the development of i-IEL (36,37). Therefore, it is possible that IMO induced the production of such cytokines in intestinal epithelial cells and promoted the proliferation of i-IEL, especially TCR+ i-IEL. i-IEL activated by IMO may facilitate the regeneration of the epithelium, resulting in protection against invasion by enteric bacteria.
Secretory IgA prevents bacterial translocation by enhancing gut mucosal barrier function (38,39). IFN- increases the release of a secretory component, which is the polymeric IgA (pIgA)-binding segment of the pIgA receptor, by the intestinal epithelial cells (40). Therefore, it is also possible that the increase in IFN- production in i-IEL due to dietary IMO may contribute in part to IgA production, resulting in inhibition of bacterial translocation. On the other hand, we found that fecal IgA levels in both groups were the lowest at 2 wk. It was reported that a large proportion of the intestinal IgA against cell wall antigens and proteins of commensal bacteria is specifically induced in response to their presence within the microflora (41). Therefore, we speculate that reduction of IgA levels in both groups may be due to an alteration in the number of microflora.
In conclusion, IMO stimulate intestinal and systemic immunity via a shift in the Th1/Th2 balance toward Th1-dominant immunity. These effects of IMO may be due at least in part to the increase of lactobacilli numbers in the gut microflora.
ACKNOWLEDGMENTS
We thank Y. Kobayashi and K. Kaneda for their excellent technical assistance.
FOOTNOTES
2 Abbreviations used: CD, cluster of differentiation; cfu, colony-forming unit; IFN-, interferon-; i-IEL, intestinal-intraepithelial lymphocytes; IL, interleukin; IMO, isomalto-oligosaccharide; IRF, interferon regulatory factor; mAb, monoclonal antibodies; MNC, mononuclear cells; NK, natural killer; PE, phycoerythrin; pIgA, polymeric IgA; TCR, T-cell receptor; Th, T helper; TLR, toll-like receptor; TNF, tumor necrosis factor. 
Manuscript received 8 March 2005. Initial review completed 29 March 2005. Revision accepted 12 September 2005.
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