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© 2007 The American Society for Nutrition J. Nutr. 137:798S-802S, March 2007

Supplement: Effects of Probiotics and Prebiotics

Intestinal Microflora: Probiotics and Autoimmunity1,2

Takeshi Matsuzaki3,*, Akimitsu Takagi3, Haruo Ikemura3, Tetsuya Matsuguchi4 and Teruo Yokokura3

3 Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-shi, Tokyo 186-8650, Japan and 4 Laboratory of Host Defense, Nagoya Graduate University School of Medicine, Nagoya 466-8550, Japan

* To whom correspondence should be addressed. E-mail: takeshi-matsuzaki{at}yakult.co.jp.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Lactobacillus casei strain Shirota (LcS) has been demonstrated to have beneficial effects in numerous murine disease models via host immune modulation. It has also been reported that LcS induced recovery of host immune responses that were decreased by treatment with carcinogens and augmented the natural killer activity and T-cell functions of host immune cells. After LcS is ingested by the host, it is incorporated into M cells in Peyer's patches (PP) and digested to form active components. In PP, macrophages or dendritic cells that phagocytosed LcS gained the ability to produce several cytokines, especially tumor necrosis factor-{alpha}. The components of LcS digested in PP were then recognized through toll-like receptor 2 in antigen-presenting cells, resulting in the production of several cytokines that elicited varied responses in host immune cells. Also, it was observed by 2D-PAGE analyses that the expression level and/or the phosphorylation of some proteins in PP and mesenteric lymph nodes were definitely altered by the ingestion of LcS, providing more evidence of cellular responses. These results suggest that some probiotic bacteria have the potential to augment or modify the host immune function through the regulation of host immune cells.

In recent years, lactic acid bacteria (LAB)5 have become of major economic importance to the food industry, and their role in maintaining gut health has also been receiving increased research attention. LAB are gram-positive nonpathogenic bacteria that are widely distributed in nature. These bacteria inhabit the intestines of humans and have long been used in food processing. In particular, the immune-stimulating effect of LAB has been investigated using several research models (1–3). In 1981, Yokokura screened 26 strains of 14 species of LAB for in vivo antitumor activity against sarcoma 180, a transplantable mouse tumor, and found that some had potent antitumor activity (4). Among them, Lactobacillus casei strain Shirota (LcS) showed especially high potency. LcS is a strain of LAB that has been selected for its specific biological activity in humans. LcS is widely used in the production of probiotic dairy products and is also used as a food ingredient in both Japan and Europe. Numerous reports have documented the safety and functional characteristics of this strain. Because this strain is not directly cytotoxic to tumor cells in vitro, it has been postulated that its antitumor action may be mediated by augmentation of the host's immune system (5). This idea stimulated further studies of the antitumor and immunoregulatory actions of LcS in various experimental models (6–8), and it has been demonstrated that oral administration of LcS has beneficial effects in both humans and animals. In this article we review some of the recent studies that have examined the immune-modulating effect of LcS as probiotics.

Effect of LcS on autoimmune disease models

Because LcS has been shown to have immune-modulating effects, we investigated the effects of LcS in autoimmune disease models using nonobese diabetic (NOD) mice. NOD mice spontaneously develop diabetes resembling human insulin-dependent diabetes mellitus (IDDM) (9,10). These mice show progressive lymphocytic infiltration of autoreactive CD8+ T cells into the islets of Langerhans, and they have been recognized as a model of autoimmune disease, with cytoplasmic antibodies to islet cells appearing in their serum during the development of insulitis (11,12). From the age of 4 wk, female NOD mice were fed a diet containing 0.05% by weight of LcS, and the onset of diabetes was recorded thereafter. The incidence of diabetes in the control group was significantly higher than that in the LcS-treated group, and pathological analysis of the LcS-treated group revealed strong inhibition of the disappearance of insulin-secreting ß-cells in Langerhans islets (Fig. 1). Moreover, the proportion of CD8+ T cells among spleen cells was decreased in the LcS-treated group, suggesting the inhibition of autoreactive T cells (13). Although the detailed mechanism of action of LcS in this model has not yet been clarified, it is postulated that LcS may alter the imbalance of Th1/Th2 cytokine production, which is thought to be the cause of the onset of IDDM. In general, it has been reported that the onset of IDDM is regulated by the subsets of autoreactive helper T cells, Th1 and Th2 cells, with Th1 promoting and Th2 suppressing autoimmune diseases. In this respect there might be a discrepancy between the idea that IDDM is prevented by Th1 cells and the fact that these cells are induced by LAB or other bacterial cells that elicit Th1 responses. However, it is speculated that LAB regulate the Th1/Th2 balance rather than augmenting the Th1 response.


Figure 1
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  		Figure 1  Effect of LcS on the onset of diabetes in female NOD mice. Four-wk-old NOD mice were fed a control diet (n = 12) (•) or a diet containing 0.05% LcS (n = 12) ({blacktriangleup}), and the onset of diabetes was monitored for 40 wk. Numbers in parentheses indicate the number of mice with onset-tested animals.

 
Concerning other autoimmune disease models, it has been shown that LcS prevented the onset of type II collagen (CII)-induced arthritis (CIA) in DBA/1 mice (14). CIA is considered to be a good model of rheumatoid arthritis in humans and is often used as a system to evaluate antiinflammatory drugs. Interferon-{gamma} (IFN-{gamma}) plays a critical role in the development of CIA, particularly in the initial phase of CIA. It is reported that anti-IFN-{gamma} treatment in the early phase of CIA reduced the severity of arthritis, and the injection of IFN-{gamma} caused a transient increase of CIA severity in DBA/1 mice immunized with CII (15). It has been reported that the decreases of the severity or development of CIA were accompanied by corresponding decreases of the collagen-specific IgG2a antibody and the collagen-induced secretion of IFN-{gamma} in IL-12-deficient mice. In experiments using LcS, it was demonstrated that oral administration of LcS into CII-sensitized DBA/1 mice reduced CII-induced IgG2a and IgG2b antibodies in serum and suppressed the CII-induced secretion of IFN-{gamma} from splenocytes ex vivo. These findings suggest that oral administration of LcS modifies the systemic humoral and cellular immunity and elicits alterations of the immune state in these autoimmune models.

Inhibitory effect of LcS on murine carcinogenesis

We have demonstrated that oral administration of LcS had strong antitumor effects against transplantable experimental tumors in rodents. Also, the injection of LcS exhibited marked antitumor activity against human malignant cancer cells in clinical trials (16,17). Therefore, we examined the inhibitory effect of LcS on 3-methylcholanthrene (MC)-induced carcinogenesis in mice. The MC-induced carcinogenesis model has been used in studies of host-mediated cancer control strategies (18). Various MC tumor models were also utilized such as colon, liver, lung, uterine cervix, and mammary gland cancer models (19,20). In these models, we confirmed that LcS exerted a strong inhibitory effect on carcinogenesis in mice through the regulation of host immune cells (21). MC treatment lowered the in vitro responses of spleen cells to concanavalin A, the secretion of IL-2 in spleen cell culture after stimulation of the cells with concanavalin A, and the proportion of CD3+, CD4+, and CD8+ splenic T cells (Fig. 2). However, analysis of the spleen cells obtained from mice treated with MC and fed an LcS-containing diet revealed that disrupted host immune parameters were maintained at the levels of normal controls. These results suggest that oral feeding of mice with LcS inhibits MC-induced tumorigenesis by modulating the host immune responses that are disrupted during MC carcinogenesis. Another possible mechanism of the prevention of the carcinogenesis is the activation of natural killer (NK) cells. NK cells are large granular lymphocytes derived from bone marrow, and these cells display non-MHC-restricted cytotoxicity against a variety of tumors. It is well recognized that NK cells act as cytolytic effector cells of the innate immune system. Recent studies have revealed that cells of the innate immune system, such as NK cells, NK1.1(+)T cells, and {gamma}{delta}-T cells, also regulate the development of allergic airway disease. These findings indicate that the innate immunity of the host may be critically important in relation to the development of some diseases. Oral feeding of LcS to MC-treated mice rendered their NK cells tumoricidal in terms of both quality and quantity, resulting in the suppression of tumor incidence (22). The tumor suppressive effect of LcS in MC-induced carcinogenesis was also evaluated in the beige mouse model, which is genetically deficient in NK cells. The effect of LcS completely disappeared in beige mice, although LcS delayed tumor onset and reduced tumor incidence in the background C3H/HeN mice (Fig. 3). Interestingly, the tumor onset itself in beige mice was observed earlier than that in C3H/HeN mice. These observations strongly indicate the importance of NK cells in the suppression of tumorigenesis and demonstrate that oral administration of LcS affects innate immunity and augments the natural resistance of the host. Furthermore, human trials have clearly indicated that medium and high cytotoxic activity of peripheral blood NK cells is associated with reduced cancer risk, whereas low activity is associated with increased cancer risk, suggesting a role for natural immunological host defense mechanisms against cancer (23).


Figure 2
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  		Figure 2  Reversal of methylcholanthrene (MC)-induced suppression of proliferative responses of spleen cells to concanavalin (Con) A by LcS. Spleen cells obtained from the mice at wk 16 after MC treatment were cultured with Con A, and the splenic cell proliferation (a) and the release of interleukin (IL)-2 (b) were measured. Normal-control ({circ}), normal-LcS ({square}), MC-control (•), MC-LcS ({blacksquare}). (a) P < 0.01 vs. normal-control; (b) P < 0.05 vs. MC-control.

 

Figure 3
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  		Figure 3  Effect of LcS on MC-carcinogenesis in NK-cell-deficient (beige) mice and C57BL/6 mice. Dietary LcS (0.05%, wt:wt) was administered to MC-injected (1.0 mg/mouse, i.d.) beige mice and background C57BL/6 mice. Tumor incidence was monitored weekly. Symbols: (•) control; ({blacksquare}) LcS. Each group consisted of 12 mice.

 
Recognition of the components of LcS after oral administration

It has been demonstrated that ingested LcS is incorporated into M cells in Peyer's patches (PP) (24). Scanning electron microscopy revealed that LcS attaches to the apical surface of M cells, where it is held by the microfolds of M cells extending toward the LcS. Transmission electron microscopy also showed that the inoculated LcS were observed in the M cells, in the intracellular spaces of lymphocytes and macrophages that are adjacent to the M cells, and in macrophages and the intracellular spaces of lymphocytes in the lymph nodules. These results suggest that the inoculated LcS are initially taken up into the M cells and transferred to the lymphocytes and macrophages and then take part in immune responses associated with PP.

After the incorporation into PP, LcS is recognized by the immune cells in PP. Recently, it was reported that the recognition of bacterial components is mediated by toll-like receptors (TLR) (25,26). Toll, first identified as a protein controlling Drosophila melanogaster (27), has been shown to participate in antimicrobial immune responses (28). We examined the stimulatory effects of 6 Lactobacillus strains on mouse immune cells to investigate the relation between TLRs and LcS in the recognition of the components of LcS. All of the 6 heat-killed Lactobacillus strains induced the secretion of TNF-{alpha} from mouse splenic mononuclear cells, albeit to various degrees (Fig. 4). When fractionated subcellular components of LcS were tested, the protoplast fraction most efficiently induced NF-{kappa}B activation and TNF-{alpha} production in RAW264.7, a mouse macrophage cell line. Purified lipoteichoic acid (LTA), a component of protoplasts, from LcS significantly induced TNF-{alpha} secretion from RAW264.7 cells and splenocytes of C57BL/6, C3H/HeN, and C3H/HeJ mice but not splenocytes of C57BL/6 TLR2–/– mice (Fig. 5). LTA of LcS also induced the activation of c-Jun N-terminal kinase (JNK) in RAW264.7 cells. Furthermore, NF-{kappa}B was activated in response to LTA of LcS in HEK293T cells, a human embryonic kidney cell line transfected with a combination of CD14 and TLR2 but not TLR4. On the other hand, it has been reported that TLR6 plays an essential role by forming heterodimers with TLR2 in recognizing gram-positive bacteria (29). To explore the possible role of TLR6 in responding to lactobacilli, TLR6 was cotransfected with TLR2 into HEK293T cells, and then the cells were treated with LTA. The results revealed that the expression of TLR6 did not further increase the NF-{kappa}B activation by LTA, indicating that TLR6 is not necessary for the recognition of LcS (Fig. 6). Taken together, these data suggest that LTA from LcS elicits proinflammatory activities through TLR2.


Figure 4
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  		Figure 4  TNF-{alpha} secretion from mouse mononuclear cells induced by various Lactobacillus strains. Mononuclear cells were isolated from spleens of 6-wk-old female BALB/c mice. The mononuclear cells (2 x 106/mL) were incubated in medium containing 1 µg of heat-killed Lactobacillus bacteria/mL. Six different strains of Lactobacillus were tested. The TNF-{alpha} concentration in the culture supernatants was measured by ELISA after a 12-h incubation.

 

Figure 5
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  		Figure 5  TLR2 is essential for TNF-{alpha} secretion induced by LTA of LcS. Splenic mononuclear cells were isolated from TLR2 gene-disrupted mice along with the control (TLR2+/–) mice. The cells (2 x 106 cells/mL) were stimulated with the indicated amounts of purified LTA from LcS, synthetic lipoprotein, or synthetic lipid A. After 12 h of incubation, the TNF-{alpha} concentration in the supernatant was measured by ELISA.

 

Figure 6
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  		Figure 6  Signal transduction induced by LcS and LTA of LcS induces JNK activation. (A) HEK293T, human embryonic kidney cells, were transiently transfected with TLR2, TLR4, or TLR6 plasmid, and 48 h after the transfection, the cells were treated with LTA of LcS or synthetic lipid A (1 mg/L) for 8 h and then lysed to measure the luciferase activities. (B) RAW 264.7 cells, a mouse macrophage cell line, were either not treated or treated with 1 µg of either LPS or purified LTA for 30 min. Cells were lysed, and the JNK1 kinase activity was measured using GST-c-Jun as the substrate.

 
With respect to quantification of LcS inoculated into hosts, mRNA of LcS was observed in PP 1 h after oral administration of LcS but not in mesenteric lymph nodes (MLN) or other organs. However, effects of LcS on biological activities such as NK and cytotoxic activities were shown at this time in spleen and other organs, indicating that some signals were definitely transmitted to other organs from PP. We therefore conducted 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) analysis of PP and MLN to search for some proteins involved in the signal transduction. These 2D-PAGE analyses revealed that the expression level and/or the phosphorylation of some proteins in PP and MLN were definitely altered after ingestion of LcS, providing more evidence about possible cellular signaling responses.

Possible mechanism of action of LcS

Other possible effector cells that may respond to LcS are dendritic cells (DCs). DCs are thought to be 1 of the most important types of cells involved in the presentation of several antigens and in the production of cytokines (30,31). DCs are found in most tissues and test the environment by capturing and processing antigens. Once activated by inflammatory stimuli involving the intake of bacteria and infectious agents, DCs first produce chemokines that in turn recruit macrophages, neutrophils, NK cells, and immature DCs at the inflammatory site and then migrate to lymphoid organs in search of antigen-specific T cells. These actions clearly indicate that DCs take part in the activation or regulation of immune cells at the local site of inflammation. Therefore, we also speculate that DCs that have phagocytosed the components of LcS will migrate to the MLN, spleen, or other organs and then will present antigens to immune cells at that site, resulting in the local augmentation of immune responses in the local site. In particular, the liver will be 1 of the most crucial organs because it contains a high proportion of NK T cells that express NK1.1 antigen and produce large amounts of IL-4 and IFN-{gamma} (32). The initial production of IL-4, which promotes the Th2 response, plays an important role in the inhibition of autoimmune disease. It has been reported that overexpression of NK T cells protects mice against diabetes (33). It as also been shown that decreases in the number of NK T cells and the amount of IL-4 are associated with diabetes in NOD mice (34). These reports suggest that IL-4 produced by NK T cells probably participates in the subsequent immune responses leading to a Th2-dominant reaction. Further experiments concerning this point will be needed to show the impact of LcS on the protection against autoimmune disease in which the Th2 reaction is dominant.

We summarized here the biological activities of LcS, especially focusing on the recognition mechanisms of host immune cells. It has been demonstrated that LcS is initially incorporated into M cells in PP after ingestion and that LTA, a component of LcS, is then recognized through TLR2, resulting in the initiation of the subsequent immune responses. After the recognition and the presentation of antigens of LcS, some signals or cytokines produced in PP appear to be transmitted into the MLN, spleen, or other effector organs following the activation of several types of immune cells in the host. In this way, a series of downstream immune responses are induced by LcS. Further experiments will be required to elucidate the detailed mechanisms of action of LcS in the activation of immune cells after the transmission of LcS to the MLN and other organs, particularly focusing on NK T cells.


   FOOTNOTES
 
1 Published as a supplement to The Journal of Nutrition. The articles included in this supplement are derived from presentations and discussions at the World Dairy Summit 2003 of the International Dairy Federation (IDF) in a joint IDF/FAO symposium entitled "Effects of Probiotics and Prebiotics on Health Maintenance—Critical Evaluation of the Evidence," held in Bruges, Belgium. The articles in this publication were revised in April 2006 to include additional relevant and timely information, including citations to recent research on the topics discussed. The guest editors for the supplement publication are Michael de Vrese and J. Schrezenmeir. Guest Editor disclosure: M. de Vrese and J. Schrezenmeir have no conflict of interest in terms of finances or current grants received from the IDF. J. Schrezenmeir is the IDF observer for Codex Alimentarius without financial interest. The editors have received grants or compensation for services, such as lectures, from the following companies that market pro- and prebiotics: Bauer, Danone, Danisco, Ch. Hansen, Merck, Müller Milch, Morinaga, Nestec, Nutricia, Orafti, Valio, and Yakult. Back

2 Author disclosure: T. Matsuzaki, A. Takagi, H. Ikemura, and T. Yokokura are employed by Yakult Honsha Co., Ltd. Back

5 Abbreviations used: CIA, collagen-induced arthritis; CII, type-II collagen; DC, dendritic cells; IDDM, insulin-dependent diabetes mellitus; IFN, interferon; JNK, c-Jun N-terminal kinase; LAB, lactic acid bacilli; LcS, Lactobacillus casei strain Shirota; LTA, lipoteichoic acid; MC, 3-methylcholanthrene; MLN, mesenteric lymph nodes; NK, natural killer; NOD, nonobese diabetic; PP, Peyer's patches; TLR, Toll-like receptors; 2D-PAGE, 2-dimensional polyacrylamide gel electrophoresis. Back


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