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Probiotics and down-regulation of the allergic response
Immunol Allergy Clin N Am 24 (2004) 739 – 752
Probiotics and down-regulation of the allergic response Marko A. Kalliom7ki, MD, PhDa,*, Erika Isolauri, MD, PhDb a
Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Charlestown, MA 02129, USA b Department of Pediatrics, University of Turku and Turku University Hospital, P.O. Box 52, FIN-20521, Turku, Finland
Allergy, manifested in atopic eczema, allergic rhinitis, and asthma, is the most common chronic disease in the westernized world. The prevalence of allergic diseases seems to be increasing in developing and developed countries [1,2]. The steep increase in prevalence that occurred in the 20th century has been attributed to changes in environmental factors. The hygiene hypothesis of allergy suggests that a lack of exposure to microbes early in childhood is a major factor in this trend [3]. Studies have demonstrated that certain strains of gut microbiota possess immunomodulatory properties that might be advantageous when combating allergic diseases [4]. This article focuses on probiotics and their role in regulation of allergic response.
Probiotics: rationale for use and general criteria Epidemiologic, experimental, and in vitro evidence supports the concept that the increased prevalence of atopic diseases is related to reduced exposure to
The Academy of Finland and the Finnish Pediatric Research Foundation are acknowledged for the financial support. * Corresponding author. Department of Pediatrics, University of Turku and Turku University Hospital, P.O. Box 52, FIN-20521, Turku, Finland. E-mail address: [email protected] (M.A. Kalliom7ki). 0889-8561/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2004.06.006
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microbes at an early age as a result of improved public health and living conditions [3]. The modern diet also has been estimated to contain several thousand times less bacteria than earlier diets. This drastic reduction in dietary bacteria, mainly the genera Lactobacillus and Bifidobacterium, has resulted from changes in methods of food production and preservation [5]. Because of extensive hygiene measures practiced in medicine and daily life, children may harbor less protective indigenous gut microbiota than in earlier times. Studies have demonstrated that the prevalence of atopic diseases in children from families following an anthroposophic way of life is significantly lower than in children of families not following this lifestyle [6]. This reduced risk has been connected to characteristics of the anthroposophic lifestyle, which include restrictive use of antibiotics, antipyretics, and vaccinations but ample use of an organic diet (often consisting of vegetables that spontaneously were fermented by lactobacilli) and birth at home [6,7]. These specific lifestyle features have been shown to influence the composition of the gut microbiota, suggesting the importance of gut microbiota in the development of allergy [7]. Establishment of gut microbiota is a step-wise, well-controlled process that commences after birth [8]. All infants initially are colonized by Escherichia coli and streptococci, followed by the anaerobic genera Bacteroides, Bifidobacterium, and Clostridium at the end of the first week of life [8]. Formula-fed infants harbor the mixture of these strains in their gut, whereas bifidobacteria dominate in breast-fed infants [9,10]. Breast milk, which is likely a source of lactic acid bacteria [11], promotes that dominance. After weaning, an adult-type pattern of intestinal micriobiota gradually becomes established [8]. Sepp et al [12] found that fecal microbiota differed significantly among Estonian and Swedish healthy infants. The major differences were that Estonian infants had high counts of lactobacilli and eubacteria, and Swedish infants had increased numbers of clostridia [12]. The same research group demonstrated in a subsequent study that 2-year old allergic children were colonized with lactobacilli less often than were nonallergic children, but nonallergic children had higher counts of coliforms and Staphylococcus aureus [13]. Preschool and school-aged Japanese children with atopic eczema were shown to have lower counts of fecal Bifidobacterium than did healthy subjects, and they also were colonized more often with Staphylococcus [14]. A dissection of Bifidobacterium microbiota in a Finnish study uncovered that allergic infants had an adult-like Bifidobacterium microbiota, whereas healthy infants were colonized with a typical infant Bifidobacterium microbiota [15]. In vitro, the adult-like bifidobacteria induced more proinflammatory cytokines and fewer anti-inflammatory cytokines than did the infant-like bifidobacteria, suggesting that certain Bifidobacterium species may have antiallergic properties [16]. Two prospective studies demonstrated alterations in gut microbiota in children who later developed IgE-mediated allergic hypersensitivity and atopic eczema. Using fluorescence in situ hybridization, the authors’ group showed that children who developed reactivity to skin prick tests with environmental antigens by 1 year of age had higher counts of clostridia and lower counts of bifidobacteria in
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their neonatal feces than did children who did not develop such reactivity [17]. These differences had disappeared by the age of 3 months. Using culturedependent methods, Bjfrksten et al [18] found that children who developed skin prick test reactivity or atopic eczema by 2 years of age were colonized less often with bifidobacteria during the first year of life than were children who did not develop these disorders. These groups also exhibited differences in the colonization of enterococci, clostridia, S aureus, and Bacteroides [18]. These studies suggest that certain species of gut microbiota may contribute to the development of a nonallergic immune system. Probiotics are defined as live microbial food ingredients that beneficially affect host health. They most often belong to the genera Bifidobacterium or Lactobacillus [8,19]. Certain species of these two genera have been a part of the human diet for millennia in the form of fermented food products [5,19]. Scientific interest in these bacteria was raised by the Russian Nobel laureate Elie Metchnikoff a century ago [20]. The term probiotic was introduced by Lilly and Stillwell 3 decades ago to describe any organism or substance which contributes to the intestinal microbial balance in animals [21]. Because of increased scientific data concerning probiotics, the definition of the term has evolved through the years [4]. Several criteria must be fulfilled before a bacterial strain can be regarded as a probiotic. These factors include human origin; survival in the gut; ability to adhere temporarily to the intestinal epithelium and to induce an immune response; safe use in humans; scientifically documented beneficial effects; and invariable properties during all stages of manufacturing, processing, and preservation [4,8]. The latter criterion also includes administration (ie, native beneficial strains of the gut microbiota are not probiotics unless they have been isolated, purified, characterized, evaluated, and used as probiotics) [19]. Probiotics must demonstrate measurable clinical health benefits [19]. All candidate probiotic strains should be evaluated closely, and beneficial effects of a certain strain should not be related to any other strain without indisputable proof [4,8,19]. Attachment to intestinal mucus, a critical component in a cascade leading to an immune response, reliably can be evaluated using endoscopic biopsies, which have been shown to be superior to fecal samples in this regard [22]. Because of vigorous research in the field, these criteria should be under continuous critical evaluation. Even the need of oral administration has been challenged in a study addressing the role of probiotics in prevention and treatment of experimental colitis [23]. Safety is a critical issue in the use of any potential therapeutic intervention. According to one review, oral consumption of lactobacilli and bifidobacteria by healthy people did not increase risk for bacterial diseases [24]. Even in immunocompromised patients, the risk for severe bacterial infection is low [25]. Salminen et al [25] evaluated the clinical data from 89 patients with Lactobacillus-induced bacteremia. In 11 patients, the isolated strain was identical to the probiotic Lactobacillus rhamnosus GG. Cases of Lactobacillus-induced bacteremia usually were associated with severe underlying comorbidities [25].
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Regulation of allergic inflammation: more than a mere Th1–Th2 paradigm A T helper cell type 2 (Th2)-skewed immune response is a hallmark of allergic immune responses and atopic disease in the gut and other target organs [26,27]. Th2 cells produce several cytokines and chemokines that amplify allergic inflammation, including interleukin 4 (IL-4) and IL-5, which increase IgE synthesis and eosinophil growth and differentiation, respectively. Mast cell differentiation, enhanced by IL-9, and airway hyperreactivity, induced by IL-13, are other cardinal features of the allergic response that is regulated by Th2 cells [26]. Initially, however, all T-cell responses to environmental antigens are Th2 oriented [28]. That kind of natural immune response is a necessity for the maintenance of successful pregnancy [29]. On postnatal microbial stimulation, a new Th1–Th2 balance is established [30]. With an inappropriate stimulus, an allergic type of immune responsiveness may ensue [30]. Cytokines produced by Th1 and Th2 cells are capable of cross-regulating each other’s development. Once either kind of response has been established firmly, the cross-regulation is more difficult [26]. Experimental studies suggested that Th1 cells may exacerbate rather than alleviate a Th2-skewed allergic inflammatory response [31]. Other T cells, in addition to those involved in the Th1–Th2 paradigm, are important in the regulation of the allergic response. These regulatory T cells include Th3 cells, T regulatory 1 cells, CD4+ CD25+ T cells, and natural killer T (NKT) cells [32]. Transforming growth factor b (TGF-b), the principal cytokine of Th3 cells, reversed allergen-induced airway hyperreactivity and inflammation in mice [33]. High concentrations of TGF-b in breast milk were associated with prevention of early atopic eczema in breast-fed infants [34]. IL-10, the most abundantly expressed cytokine of T regulatory 1 cells, prevented asthmatic inflammation and food allergy in two different mouse models [35,36]. IL-10 was induced in the latter study by enteric helminth infection. In parallel, parasite-induced IL-10 production in humans has been suggested to mediate an inhibitory effect of helminth infections on allergen skin test reactivity [37,38]. CD4+ CD25+ T cells are naturally occurring and mainly thymus-derived regulatory cells that are involved in the maintenance of self-tolerance. Depletion of these cells results in autoimmune diseases in animal models [32]. This finding also has been seen in patients with X-linked autoimmunity allergic dysregulation syndrome and immune-dysregulation, polyendocrinopathy, enteropathy X-linked syndrome [39,40]. These patients lack normal CD4+ CD25+ regulatory T cells because of genetic mutations in the transcription factor Foxp3, a critical regulator of CD4+ CD25+ T-cell development and function [39,40]. These patients also develop food allergy, severe atopic eczema, and increased amounts of IgE and eosinophils in their serum, suggesting a regulatory control of CD4+ CD25+ T cells in the development of allergic diseases [39,40]. One clinical study found that the suppressive potential of CD4+ CD25+ T cells in adults with respiratory allergies was reduced significantly, as compared with the potential in healthy adults [41]. Allergic symptoms may result from an
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inappropriate balance between regulatory CD4+ CD25+ T cells and effector Th2 cells [41]. NKT cells are a T-cell population that expresses cell surface markers characteristic of natural killer cells and T cells. Once activated, these cells produce large amounts of Th1 and Th2 cytokines that may allow the cells to exert strong regulatory activity in autoimmune and allergic diseases [32]. Two studies using three different NKT cell-deficient mouse strains with Th2-skewed immune responses have demonstrated that allergen-induced airway inflammation and hyperreactivity are dependent on IL-4 and IL-13 produced by iVa14 NKT cells [42,43]. The antigen-specific IgE response was impaired in these mice [43]. These studies suggest that Th2 responses alone are not sufficient and that NKT cell-produced cytokines are needed for the development of IgE-mediated allergic asthma. The previously mentioned findings clearly suggest that an immunologic treatment of choice for allergy should combine Th1-like and suppressive properties.
Effects of probiotics in clinical studies of allergy Randomized, placebo-controlled trials of probiotics mostly have focused on patients with atopic eczema. Majamaa and Isolauri [44] evaluated infants with atopic eczema and cow’s milk allergy. The infants were treated with an extensively hydrolyzed whey formula with or without the addition of L rhamnosus GG. The clinical score of atopic eczema improved significantly during the 1-month study period in infants receiving the formula plus the probiotic [44]. Concentrations of fecal a1-antitrypsin and tumor necrosis factor a, which are markers of intestinal inflammation, decreased significantly in this group but not in the group receiving the formula only [44]. A comparable effect on atopic eczema was found in a clinical trial in which extensively hydrolyzed whey formula was fortified with L rhamnosus GG or Bifidobacterium lactis Bb-12 [45]. These formulas were administered to infants who had manifested atopic eczema during exclusive breast-feeding. In parallel, markers of allergic inflammation and concentrations of soluble CD4 in serum and eosinophilic protein X in urine were reduced significantly in these patients, as compared with levels in patients receiving the formula only [45]. In a crossover study, Rosenfeldt et al [46] gave a combination of L rhamnosus 19070-2 and Lactobacillus reuteri DSM 122,460 to 1- to 13-year-old children with atopic eczema for 6 weeks. They found that the combination was beneficial, especially in patients with a positive skin prick test response and increased IgE concentrations [46], suggesting that probiotics may be able to control inflammatory responses beyond those in the gut. The concentration of serum eosinophil cationic protein decreased during active treatment, although the production of the cytokines IL-2, IL-4, and IL-10 and interferon g (IFN-g) by peripheral blood mononuclear cells remained unaltered [46]. In general, significant adverse effects have not been reported in studies using viable probiotic preparations in allergic patients. This finding may
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not occur in studies using nonviable probiotics, because a pilot study addressing the effect of heat-inactivated L rhamnosus GG on atopic eczema was terminated early because of adverse gastrointestinal symptoms [47]. Two randomized, placebo-controlled clinical studies have evaluated the effects of lactobacilli on respiratory allergic diseases. Wheeler et al [48] conducted a crossover trial with yogurt containing Lactobacillus acidophilus in adult patients with moderate asthma. They found that consumption of this yogurt containing tended to increase IFN- g production in stimulated lymphocytes and decrease levels of eosinophilia, although no changes in clinical asthma parameters were detected [48]. No beneficial treatment effect of L rhamnosus GG was found in teenagers and young adults who were allergic to birch pollen and had intermittent respiratory symptoms [49]. The authors previously have addressed whether probiotics might prevent early atopic disease. In one study, L rhamnosus GG was administered perinatally to mothers and infants up to 6 months of age [50]. Children had a family history of atopic disease. The administration of the probiotic halved the incidence of atopic eczema during the first 2 years of life. There were no differences in IgE-mediated allergic hypersensitivity as measured by skin prick test reactivity and serum IgE concentrations [50]. The extension of the preventive effect beyond infancy was demonstrated in the 4-year follow-up of the study cohort [51]. Consumption of L rhamnosus GG by pregnant and lactating mothers increased the amount of TGF-b in breast milk. The risk for atopic eczema during infancy was reduced among infants whose mothers consumed the probiotic strain [52].
Effects of probiotics in experimental studies of allergy The impact of probiotics on allergic diseases has been studied in a few animal models. Lactobacillus plantarum L-137 was shown to inhibit antigen-specific IgE production in DBA/2 mice that were fed a casein diet. The suppressive effect of the strain was related to enhanced production of IL-12, an inducer of the Th1 response, by peritoneal macrophages [53]. The Lactobacillus casei strain Shirota was found to suppress IgE and IgG1 responses and systemic anaphylaxis in a food allergy model with ovalbumin-specific T-cell–receptor transgenic mice. The effect was mediated by induction of IL-12 production [54]. In both of these studies, probiotics were administered by intraperitoneal injection. In two murine models, Sudo et al [55] studied the effects of antibiotic-induced alterations of gut microbiota and probiotic supplementation on the development of Th2-skewed immune response. BALB/c mice who were treated with kanamycin during the neonatal period developed a Th2-skewed immune response. The change was reversed by oral introduction of Enterococcus faecalis or L acidophilus (the latter to a lesser extent) [55]. Inoculation with Bacteroideus vulcatus increased the Th2-skewed immune response. C57BL/6 mice that genetically are biased toward Th1-immunity were resistant to kanamycin treatment [55].
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Prioult et al [56] compared the abilities of three probiotics (ie, Lactobacillus paracasei, Lactobacillus johnsonii, Bifidobacterium lactis Bb12) to induce and maintain oral tolerance to b-lactoglobulin in germfree mice. Humoral and cellular immune responses were suppressed most in L paracasei-monoassociated mice, although not as much as in conventionally colonized mice [56]. These findings suggest that probiotic intervention may help oral-tolerance induction and prevent Th2-shifted immune responses, and that genetic background contributes to immune deviation. Two experimental studies have evaluated effects of intranasal co-application of probiotics and allergen on immune responses. Kruisselbrink et al [57] constructed a recombinant L plantarum strain that expressed an immunodominant T-cell epitope of the Der p 1 allergen of the house dust mite. Intranasal application of this construct to Der p 1-immunized mice induced suppression of the Th1 and Th2 immune responses that were elicited by the antigen [57]. When intranasally co-applied with recombinant Bet v 1, the major birch pollen allergen (Lactococcus lactis and L plantarum) increased levels of IgG2a antibodies, in vitro IFN-g production, and suppression of allergen-induced basophil degranulation [58]. These studies indicate that certain probiotic strains, when combined with allergens, are potential candidates for mucosal vaccination against allergy.
Antiallergic properties of probiotics: lessons from in vitro studies Food and other orally consumed products, including probiotics, are subjected to gastrointestinal characteristics, including peristalsis, gastric juice, bile, and digestive enzymes. These factors assist in digestion and down-regulation of the immune response because without degradation unresponsiveness to dietary antigens is not achieved [59]. L rhamnosus GG has been found to enhance the degradation of dietary antigens in rats [60]. Bovine casein degraded with L rhamnosus GG-derived proteases was shown to suppress lymphocyte proliferation in a dose-dependent manner and reduce the anti-CD3–stimulated IL-4 production by peripheral blood mononuclear cells in children with atopic eczema [61,62]. In one study, homogenates derived from B lactis, L acidophilus, and Lactobacillus delbrueckii subspecies bulgarius (but not from Streptococcus thermophilus) suppressed proliferation of human mononuclear cells in vitro, although not as much as L rhamnosus GG did [63]. Bovine casein degraded with L rhamnosus GG-derived proteases suppressed T-cell activation by inhibition of protein kinase C activation [64]. Activation of protein kinase C is an indispensable stage in the nuclear factor kB (NF-kB) activation cascade in T cells, ultimately leading to the expression of gene products that mediate innate and adaptive immunity [65]. These studies suggest that certain probiotic strains may contribute to the processing of dietary antigens in the intestinal lumen in such a way as to reduce their immunogenicity by suppressing T-cell activation.
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Probiotics have been shown to amplify the gut mucosal barrier. L rhamnosus GG and L plantarum 299v, but not L acidophilus DDS-1, adhered effectively to HT 29 intestinal epithelial cells and increased expression of MUC2 and MUC3 intestinal mucins [66,67]. This up-regulation of mucins inhibited the adherence of E coli to the cell line [66,67]. This finding may be important in allergy, because total serum IgE concentration correlated directly with fecal E coli counts in infants with early onset food-allergy and atopic eczema [68]. Supplementation with B lactis Bb-12 resulted in decreased numbers of E coli, as measured by fluorescence in situ hybridization [68]. L rhamnosus GG reversed the increased intestinal permeability that was induced by cow’s milk in suckling rats [69]. The permeability was measured by absorption of horseradish peroxidase across segments containing Peyer’s patches and patch-free jejunal segments [69]. The same method was used to show that antigen transfer across the gut mucosal barrier is increased in children with atopic eczema [70]. In theory, by reducing antigen transfer to the lamina propria, probiotics might reduce the quantity and quality of the antigenic load on the gut-associated lymphatic tissue in children with atopic eczema. Beyond physical support, a single layer of epithelial cells between the intestinal lumen and lamina propria constitutes a major compartment of the gut immune system [71]. Intestinal epithelial cells possess delicate mechanisms that allow symbiotic coexistence with abundant resident luminal bacteria while maintaining alert responsiveness to enteropathogenic intruders [71–73]. Lactobacilli are likely to maintain homeostasis in intestinal epithelial cells. Treatment with L johnsonii La1, L acidophilus La10, or lipoteichoic acids from these stains did not result in a proinflammatory response in a co-culture with human intestinal HT29 cells [74]. The lipoteichoic acids, however, antagonized the proinflammatory response of HT29 cells induced by lipopolysaccharide and gram-negative bacteria [74]. L rhamnosus GG prevented cytokine-induced apoptosis in mouse and human colon cells [75]. This effect was mediated by activation of anti-apoptotic Akt and protein kinase B, a part of the phosphoinositide 3-kinase pathway, and inactivation of the pro-apoptotic p38 mitogenactivated protein kinase (p38 MAPK) signaling pathway [75]. p38 MAPK and NF-kB pathways are downstream of a common myloid differention factor 88-dependent signaling pathway [76]. p38 MAPK, a novel target of antiinflammatory therapies, has been linked to a wide range of inflammatory responses in the gut [77]. L acidophilus and L casei also stimulated Akt activation but did not inactivate the p38 MAPK pathway [75]. These findings indicate that lactobacilli may have strain-specific anti-inflammatory effects in the intestinal epithelium. Dendritic cells have a pivotal role in orchestration of the immune system [78]. In the gastrointestinal tract, they reside in the Peyer’s patches, lamina propria, and draining mesenteric lymph nodes, representing the principal stimulators of naRve T cells [79]. Intestinal dendritic cells can sample microbes and other intestinal antigens by way of M cells in Peyer’s patches, directly from the intestinal lumen by reaching between adjacent epithelial cells and indirectly by sampling
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apoptotic epithelial cells or taking up antigen-bearing exosomes. Direct contact with antigens is also possible when epithelial integrity is disrupted [79]. The fate of a naRve T cell is determined by three dendritic cell-derived signals: antigen (signal 1), co-stimulation (signal 2), and cytokines (signal 3) [78]. The expression of different toll-like receptors (TLRs) in antigen-presenting cells allows the cells to discriminate between specific patterns of microbial products found in pathogenic and nonpathogenic strains [80]. E coli LPS is recognized by TLR4, whereas TLR2 recognizes peptidoglycans of S aureus. In parallel, lipoteichoic acids from lactobacilli are recognized by TLR2 [81]. On recognition of their ligands, TLRs initiate signaling processes that lead to maturation of dendritic cells and secretion of cytokines and chemokines by the cells. These cell products influence the polarization of T helper cells and greatly regulate adaptive immune responses [78]. All of the six lactobacilli studied were capable of maturation of the bone marrow-derived murine dendritic cells in vitro [82]. L casei CHCC3139 was the most potent IL-12 (Th1) inducer, and Lactobacillus reuteri DSM12246 the weakest inducer [82]. In co-culture, however, the latter strain prevented dendritic cell maturation and the production of IL-12, IL-6 and tumor necrosis factor a that had been induced by the former strain [82]. Braat et al [83] compared the abilities of L rhamnosus GG and the intestinal commensal Klebsiella pneumoniae to induce maturation and polarization of human dendritic cells. Both bacterial strains induced dendritic cell maturation, although K pneumoniae-matured dendritic cells produced much more Th1 cytokines than did the cells matured by L rhamnosus GG [83]. In parallel, naive T cells primed with K pneumoniae-matured dendritic cells adopted a Th1 phenotype and produced also IL-10, whereas T cells generated from L rhamnosus-matured dendritic cells produce equal amounts of IL-4 and IFN-g (Th0 phenotype). These cells also produced some IL-10 [83], suggesting that they might have suppressive properties. Ingestion of L rhamnosus GG has been shown to result in elevation of serum IL-10 concentrations in children with atopic eczema, as compared with children receiving placebo [84]. The increase of mitogen-induced IL-10 production by peripheral blood mononuclear cells preceded the increase in serum IL-10 levels [84], a finding which indirectly suggests that the previously mentioned dendritic cell-driven mechanism might also function in vivo. These findings indicate that lactobacilli may be able to induce the maturation of dendritic cells that prime T cells to produce mainly Th1 and regulatory cytokines. Probiotics exert mostly proinflammatory immune responses when co-cultured with peripheral blood mononuclear cells or macrophages. Miettinen et al [85] and Hessle et al [86] studied the effects of six Lactobacillus strains in co-culture with human peripheral blood mononuclear cells. Five strains elicited strong IL-12, minor IL-10, and no IL-4 production, suggesting Th1-oriented immune responses [85,86]. L paracasei NCC2461, however, induced production of suppressive IL-10 and TGF-b in a mixed culture of murine splenocytes and CD4+ T cells [87]. L rhamnosus GG induced Th1 chemokine production in human macrophages [88], and the same strain has been shown to activate the transcription factor NFkB directly and to activate STAT1 and STAT3 indirectly by way of cytokines
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Table 1 Potential antiallergic properties of probiotics Site of action
Effects
Gastrointestinal mucus and epithelium
Processing of enteral antigens Inhibition of attachment of pathogenic bacteria Amplification of permeability barrier Suppression of proinflammatory responses elicited by pathogenic bacteria Prevention of apoptosis Maturation of dendritic cells with Th1-type and suppressive properties Production of Th1 and suppressive cytokines by myeloid-derived immune cells
Lamina propria
[89]. These chemokines were shown to stimulate Th1 cell chemotaxis [88]. Studies with murine macrophages suggest that lactobacilli induce their effect on these cells, at least partially, by way of TLR2 that is stimulated by lipoteichoic acids [81].
Summary The first clinical trials with probiotics, especially in the treatment of atopic eczema, have yielded encouraging results. Experimental studies have found that probiotics exert strain-specific effects in the intestinal lumen and on epithelial cells and immune cells with anti-allergic potential. These effects include enhancement in antigen degradation and gut barrier function and induction of regulatory and proinflammatory immune responses, the latter of which occurs more likely beyond the intestinal epithelium (Table 1). Future studies should address more accurately how these and other possible mechanisms operate in the complex gastrointestinal macroenvironment in vivo and how these mechanisms are related to the clinical effects in a dose-dependent manner.
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Probiotics and down-regulation of the allergic response Marko A. Kalliom7ki, MD, PhDa,*, Erika Isolauri, MD, PhDb a
Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Charlestown, MA 02129, USA b Department of Pediatrics, University of Turku and Turku University Hospital, P.O. Box 52, FIN-20521, Turku, Finland
Allergy, manifested in atopic eczema, allergic rhinitis, and asthma, is the most common chronic disease in the westernized world. The prevalence of allergic diseases seems to be increasing in developing and developed countries [1,2]. The steep increase in prevalence that occurred in the 20th century has been attributed to changes in environmental factors. The hygiene hypothesis of allergy suggests that a lack of exposure to microbes early in childhood is a major factor in this trend [3]. Studies have demonstrated that certain strains of gut microbiota possess immunomodulatory properties that might be advantageous when combating allergic diseases [4]. This article focuses on probiotics and their role in regulation of allergic response.
Probiotics: rationale for use and general criteria Epidemiologic, experimental, and in vitro evidence supports the concept that the increased prevalence of atopic diseases is related to reduced exposure to
The Academy of Finland and the Finnish Pediatric Research Foundation are acknowledged for the financial support. * Corresponding author. Department of Pediatrics, University of Turku and Turku University Hospital, P.O. Box 52, FIN-20521, Turku, Finland. E-mail address: [email protected] (M.A. Kalliom7ki). 0889-8561/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2004.06.006
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microbes at an early age as a result of improved public health and living conditions [3]. The modern diet also has been estimated to contain several thousand times less bacteria than earlier diets. This drastic reduction in dietary bacteria, mainly the genera Lactobacillus and Bifidobacterium, has resulted from changes in methods of food production and preservation [5]. Because of extensive hygiene measures practiced in medicine and daily life, children may harbor less protective indigenous gut microbiota than in earlier times. Studies have demonstrated that the prevalence of atopic diseases in children from families following an anthroposophic way of life is significantly lower than in children of families not following this lifestyle [6]. This reduced risk has been connected to characteristics of the anthroposophic lifestyle, which include restrictive use of antibiotics, antipyretics, and vaccinations but ample use of an organic diet (often consisting of vegetables that spontaneously were fermented by lactobacilli) and birth at home [6,7]. These specific lifestyle features have been shown to influence the composition of the gut microbiota, suggesting the importance of gut microbiota in the development of allergy [7]. Establishment of gut microbiota is a step-wise, well-controlled process that commences after birth [8]. All infants initially are colonized by Escherichia coli and streptococci, followed by the anaerobic genera Bacteroides, Bifidobacterium, and Clostridium at the end of the first week of life [8]. Formula-fed infants harbor the mixture of these strains in their gut, whereas bifidobacteria dominate in breast-fed infants [9,10]. Breast milk, which is likely a source of lactic acid bacteria [11], promotes that dominance. After weaning, an adult-type pattern of intestinal micriobiota gradually becomes established [8]. Sepp et al [12] found that fecal microbiota differed significantly among Estonian and Swedish healthy infants. The major differences were that Estonian infants had high counts of lactobacilli and eubacteria, and Swedish infants had increased numbers of clostridia [12]. The same research group demonstrated in a subsequent study that 2-year old allergic children were colonized with lactobacilli less often than were nonallergic children, but nonallergic children had higher counts of coliforms and Staphylococcus aureus [13]. Preschool and school-aged Japanese children with atopic eczema were shown to have lower counts of fecal Bifidobacterium than did healthy subjects, and they also were colonized more often with Staphylococcus [14]. A dissection of Bifidobacterium microbiota in a Finnish study uncovered that allergic infants had an adult-like Bifidobacterium microbiota, whereas healthy infants were colonized with a typical infant Bifidobacterium microbiota [15]. In vitro, the adult-like bifidobacteria induced more proinflammatory cytokines and fewer anti-inflammatory cytokines than did the infant-like bifidobacteria, suggesting that certain Bifidobacterium species may have antiallergic properties [16]. Two prospective studies demonstrated alterations in gut microbiota in children who later developed IgE-mediated allergic hypersensitivity and atopic eczema. Using fluorescence in situ hybridization, the authors’ group showed that children who developed reactivity to skin prick tests with environmental antigens by 1 year of age had higher counts of clostridia and lower counts of bifidobacteria in
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their neonatal feces than did children who did not develop such reactivity [17]. These differences had disappeared by the age of 3 months. Using culturedependent methods, Bjfrksten et al [18] found that children who developed skin prick test reactivity or atopic eczema by 2 years of age were colonized less often with bifidobacteria during the first year of life than were children who did not develop these disorders. These groups also exhibited differences in the colonization of enterococci, clostridia, S aureus, and Bacteroides [18]. These studies suggest that certain species of gut microbiota may contribute to the development of a nonallergic immune system. Probiotics are defined as live microbial food ingredients that beneficially affect host health. They most often belong to the genera Bifidobacterium or Lactobacillus [8,19]. Certain species of these two genera have been a part of the human diet for millennia in the form of fermented food products [5,19]. Scientific interest in these bacteria was raised by the Russian Nobel laureate Elie Metchnikoff a century ago [20]. The term probiotic was introduced by Lilly and Stillwell 3 decades ago to describe any organism or substance which contributes to the intestinal microbial balance in animals [21]. Because of increased scientific data concerning probiotics, the definition of the term has evolved through the years [4]. Several criteria must be fulfilled before a bacterial strain can be regarded as a probiotic. These factors include human origin; survival in the gut; ability to adhere temporarily to the intestinal epithelium and to induce an immune response; safe use in humans; scientifically documented beneficial effects; and invariable properties during all stages of manufacturing, processing, and preservation [4,8]. The latter criterion also includes administration (ie, native beneficial strains of the gut microbiota are not probiotics unless they have been isolated, purified, characterized, evaluated, and used as probiotics) [19]. Probiotics must demonstrate measurable clinical health benefits [19]. All candidate probiotic strains should be evaluated closely, and beneficial effects of a certain strain should not be related to any other strain without indisputable proof [4,8,19]. Attachment to intestinal mucus, a critical component in a cascade leading to an immune response, reliably can be evaluated using endoscopic biopsies, which have been shown to be superior to fecal samples in this regard [22]. Because of vigorous research in the field, these criteria should be under continuous critical evaluation. Even the need of oral administration has been challenged in a study addressing the role of probiotics in prevention and treatment of experimental colitis [23]. Safety is a critical issue in the use of any potential therapeutic intervention. According to one review, oral consumption of lactobacilli and bifidobacteria by healthy people did not increase risk for bacterial diseases [24]. Even in immunocompromised patients, the risk for severe bacterial infection is low [25]. Salminen et al [25] evaluated the clinical data from 89 patients with Lactobacillus-induced bacteremia. In 11 patients, the isolated strain was identical to the probiotic Lactobacillus rhamnosus GG. Cases of Lactobacillus-induced bacteremia usually were associated with severe underlying comorbidities [25].
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Regulation of allergic inflammation: more than a mere Th1–Th2 paradigm A T helper cell type 2 (Th2)-skewed immune response is a hallmark of allergic immune responses and atopic disease in the gut and other target organs [26,27]. Th2 cells produce several cytokines and chemokines that amplify allergic inflammation, including interleukin 4 (IL-4) and IL-5, which increase IgE synthesis and eosinophil growth and differentiation, respectively. Mast cell differentiation, enhanced by IL-9, and airway hyperreactivity, induced by IL-13, are other cardinal features of the allergic response that is regulated by Th2 cells [26]. Initially, however, all T-cell responses to environmental antigens are Th2 oriented [28]. That kind of natural immune response is a necessity for the maintenance of successful pregnancy [29]. On postnatal microbial stimulation, a new Th1–Th2 balance is established [30]. With an inappropriate stimulus, an allergic type of immune responsiveness may ensue [30]. Cytokines produced by Th1 and Th2 cells are capable of cross-regulating each other’s development. Once either kind of response has been established firmly, the cross-regulation is more difficult [26]. Experimental studies suggested that Th1 cells may exacerbate rather than alleviate a Th2-skewed allergic inflammatory response [31]. Other T cells, in addition to those involved in the Th1–Th2 paradigm, are important in the regulation of the allergic response. These regulatory T cells include Th3 cells, T regulatory 1 cells, CD4+ CD25+ T cells, and natural killer T (NKT) cells [32]. Transforming growth factor b (TGF-b), the principal cytokine of Th3 cells, reversed allergen-induced airway hyperreactivity and inflammation in mice [33]. High concentrations of TGF-b in breast milk were associated with prevention of early atopic eczema in breast-fed infants [34]. IL-10, the most abundantly expressed cytokine of T regulatory 1 cells, prevented asthmatic inflammation and food allergy in two different mouse models [35,36]. IL-10 was induced in the latter study by enteric helminth infection. In parallel, parasite-induced IL-10 production in humans has been suggested to mediate an inhibitory effect of helminth infections on allergen skin test reactivity [37,38]. CD4+ CD25+ T cells are naturally occurring and mainly thymus-derived regulatory cells that are involved in the maintenance of self-tolerance. Depletion of these cells results in autoimmune diseases in animal models [32]. This finding also has been seen in patients with X-linked autoimmunity allergic dysregulation syndrome and immune-dysregulation, polyendocrinopathy, enteropathy X-linked syndrome [39,40]. These patients lack normal CD4+ CD25+ regulatory T cells because of genetic mutations in the transcription factor Foxp3, a critical regulator of CD4+ CD25+ T-cell development and function [39,40]. These patients also develop food allergy, severe atopic eczema, and increased amounts of IgE and eosinophils in their serum, suggesting a regulatory control of CD4+ CD25+ T cells in the development of allergic diseases [39,40]. One clinical study found that the suppressive potential of CD4+ CD25+ T cells in adults with respiratory allergies was reduced significantly, as compared with the potential in healthy adults [41]. Allergic symptoms may result from an
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inappropriate balance between regulatory CD4+ CD25+ T cells and effector Th2 cells [41]. NKT cells are a T-cell population that expresses cell surface markers characteristic of natural killer cells and T cells. Once activated, these cells produce large amounts of Th1 and Th2 cytokines that may allow the cells to exert strong regulatory activity in autoimmune and allergic diseases [32]. Two studies using three different NKT cell-deficient mouse strains with Th2-skewed immune responses have demonstrated that allergen-induced airway inflammation and hyperreactivity are dependent on IL-4 and IL-13 produced by iVa14 NKT cells [42,43]. The antigen-specific IgE response was impaired in these mice [43]. These studies suggest that Th2 responses alone are not sufficient and that NKT cell-produced cytokines are needed for the development of IgE-mediated allergic asthma. The previously mentioned findings clearly suggest that an immunologic treatment of choice for allergy should combine Th1-like and suppressive properties.
Effects of probiotics in clinical studies of allergy Randomized, placebo-controlled trials of probiotics mostly have focused on patients with atopic eczema. Majamaa and Isolauri [44] evaluated infants with atopic eczema and cow’s milk allergy. The infants were treated with an extensively hydrolyzed whey formula with or without the addition of L rhamnosus GG. The clinical score of atopic eczema improved significantly during the 1-month study period in infants receiving the formula plus the probiotic [44]. Concentrations of fecal a1-antitrypsin and tumor necrosis factor a, which are markers of intestinal inflammation, decreased significantly in this group but not in the group receiving the formula only [44]. A comparable effect on atopic eczema was found in a clinical trial in which extensively hydrolyzed whey formula was fortified with L rhamnosus GG or Bifidobacterium lactis Bb-12 [45]. These formulas were administered to infants who had manifested atopic eczema during exclusive breast-feeding. In parallel, markers of allergic inflammation and concentrations of soluble CD4 in serum and eosinophilic protein X in urine were reduced significantly in these patients, as compared with levels in patients receiving the formula only [45]. In a crossover study, Rosenfeldt et al [46] gave a combination of L rhamnosus 19070-2 and Lactobacillus reuteri DSM 122,460 to 1- to 13-year-old children with atopic eczema for 6 weeks. They found that the combination was beneficial, especially in patients with a positive skin prick test response and increased IgE concentrations [46], suggesting that probiotics may be able to control inflammatory responses beyond those in the gut. The concentration of serum eosinophil cationic protein decreased during active treatment, although the production of the cytokines IL-2, IL-4, and IL-10 and interferon g (IFN-g) by peripheral blood mononuclear cells remained unaltered [46]. In general, significant adverse effects have not been reported in studies using viable probiotic preparations in allergic patients. This finding may
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not occur in studies using nonviable probiotics, because a pilot study addressing the effect of heat-inactivated L rhamnosus GG on atopic eczema was terminated early because of adverse gastrointestinal symptoms [47]. Two randomized, placebo-controlled clinical studies have evaluated the effects of lactobacilli on respiratory allergic diseases. Wheeler et al [48] conducted a crossover trial with yogurt containing Lactobacillus acidophilus in adult patients with moderate asthma. They found that consumption of this yogurt containing tended to increase IFN- g production in stimulated lymphocytes and decrease levels of eosinophilia, although no changes in clinical asthma parameters were detected [48]. No beneficial treatment effect of L rhamnosus GG was found in teenagers and young adults who were allergic to birch pollen and had intermittent respiratory symptoms [49]. The authors previously have addressed whether probiotics might prevent early atopic disease. In one study, L rhamnosus GG was administered perinatally to mothers and infants up to 6 months of age [50]. Children had a family history of atopic disease. The administration of the probiotic halved the incidence of atopic eczema during the first 2 years of life. There were no differences in IgE-mediated allergic hypersensitivity as measured by skin prick test reactivity and serum IgE concentrations [50]. The extension of the preventive effect beyond infancy was demonstrated in the 4-year follow-up of the study cohort [51]. Consumption of L rhamnosus GG by pregnant and lactating mothers increased the amount of TGF-b in breast milk. The risk for atopic eczema during infancy was reduced among infants whose mothers consumed the probiotic strain [52].
Effects of probiotics in experimental studies of allergy The impact of probiotics on allergic diseases has been studied in a few animal models. Lactobacillus plantarum L-137 was shown to inhibit antigen-specific IgE production in DBA/2 mice that were fed a casein diet. The suppressive effect of the strain was related to enhanced production of IL-12, an inducer of the Th1 response, by peritoneal macrophages [53]. The Lactobacillus casei strain Shirota was found to suppress IgE and IgG1 responses and systemic anaphylaxis in a food allergy model with ovalbumin-specific T-cell–receptor transgenic mice. The effect was mediated by induction of IL-12 production [54]. In both of these studies, probiotics were administered by intraperitoneal injection. In two murine models, Sudo et al [55] studied the effects of antibiotic-induced alterations of gut microbiota and probiotic supplementation on the development of Th2-skewed immune response. BALB/c mice who were treated with kanamycin during the neonatal period developed a Th2-skewed immune response. The change was reversed by oral introduction of Enterococcus faecalis or L acidophilus (the latter to a lesser extent) [55]. Inoculation with Bacteroideus vulcatus increased the Th2-skewed immune response. C57BL/6 mice that genetically are biased toward Th1-immunity were resistant to kanamycin treatment [55].
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Prioult et al [56] compared the abilities of three probiotics (ie, Lactobacillus paracasei, Lactobacillus johnsonii, Bifidobacterium lactis Bb12) to induce and maintain oral tolerance to b-lactoglobulin in germfree mice. Humoral and cellular immune responses were suppressed most in L paracasei-monoassociated mice, although not as much as in conventionally colonized mice [56]. These findings suggest that probiotic intervention may help oral-tolerance induction and prevent Th2-shifted immune responses, and that genetic background contributes to immune deviation. Two experimental studies have evaluated effects of intranasal co-application of probiotics and allergen on immune responses. Kruisselbrink et al [57] constructed a recombinant L plantarum strain that expressed an immunodominant T-cell epitope of the Der p 1 allergen of the house dust mite. Intranasal application of this construct to Der p 1-immunized mice induced suppression of the Th1 and Th2 immune responses that were elicited by the antigen [57]. When intranasally co-applied with recombinant Bet v 1, the major birch pollen allergen (Lactococcus lactis and L plantarum) increased levels of IgG2a antibodies, in vitro IFN-g production, and suppression of allergen-induced basophil degranulation [58]. These studies indicate that certain probiotic strains, when combined with allergens, are potential candidates for mucosal vaccination against allergy.
Antiallergic properties of probiotics: lessons from in vitro studies Food and other orally consumed products, including probiotics, are subjected to gastrointestinal characteristics, including peristalsis, gastric juice, bile, and digestive enzymes. These factors assist in digestion and down-regulation of the immune response because without degradation unresponsiveness to dietary antigens is not achieved [59]. L rhamnosus GG has been found to enhance the degradation of dietary antigens in rats [60]. Bovine casein degraded with L rhamnosus GG-derived proteases was shown to suppress lymphocyte proliferation in a dose-dependent manner and reduce the anti-CD3–stimulated IL-4 production by peripheral blood mononuclear cells in children with atopic eczema [61,62]. In one study, homogenates derived from B lactis, L acidophilus, and Lactobacillus delbrueckii subspecies bulgarius (but not from Streptococcus thermophilus) suppressed proliferation of human mononuclear cells in vitro, although not as much as L rhamnosus GG did [63]. Bovine casein degraded with L rhamnosus GG-derived proteases suppressed T-cell activation by inhibition of protein kinase C activation [64]. Activation of protein kinase C is an indispensable stage in the nuclear factor kB (NF-kB) activation cascade in T cells, ultimately leading to the expression of gene products that mediate innate and adaptive immunity [65]. These studies suggest that certain probiotic strains may contribute to the processing of dietary antigens in the intestinal lumen in such a way as to reduce their immunogenicity by suppressing T-cell activation.
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Probiotics have been shown to amplify the gut mucosal barrier. L rhamnosus GG and L plantarum 299v, but not L acidophilus DDS-1, adhered effectively to HT 29 intestinal epithelial cells and increased expression of MUC2 and MUC3 intestinal mucins [66,67]. This up-regulation of mucins inhibited the adherence of E coli to the cell line [66,67]. This finding may be important in allergy, because total serum IgE concentration correlated directly with fecal E coli counts in infants with early onset food-allergy and atopic eczema [68]. Supplementation with B lactis Bb-12 resulted in decreased numbers of E coli, as measured by fluorescence in situ hybridization [68]. L rhamnosus GG reversed the increased intestinal permeability that was induced by cow’s milk in suckling rats [69]. The permeability was measured by absorption of horseradish peroxidase across segments containing Peyer’s patches and patch-free jejunal segments [69]. The same method was used to show that antigen transfer across the gut mucosal barrier is increased in children with atopic eczema [70]. In theory, by reducing antigen transfer to the lamina propria, probiotics might reduce the quantity and quality of the antigenic load on the gut-associated lymphatic tissue in children with atopic eczema. Beyond physical support, a single layer of epithelial cells between the intestinal lumen and lamina propria constitutes a major compartment of the gut immune system [71]. Intestinal epithelial cells possess delicate mechanisms that allow symbiotic coexistence with abundant resident luminal bacteria while maintaining alert responsiveness to enteropathogenic intruders [71–73]. Lactobacilli are likely to maintain homeostasis in intestinal epithelial cells. Treatment with L johnsonii La1, L acidophilus La10, or lipoteichoic acids from these stains did not result in a proinflammatory response in a co-culture with human intestinal HT29 cells [74]. The lipoteichoic acids, however, antagonized the proinflammatory response of HT29 cells induced by lipopolysaccharide and gram-negative bacteria [74]. L rhamnosus GG prevented cytokine-induced apoptosis in mouse and human colon cells [75]. This effect was mediated by activation of anti-apoptotic Akt and protein kinase B, a part of the phosphoinositide 3-kinase pathway, and inactivation of the pro-apoptotic p38 mitogenactivated protein kinase (p38 MAPK) signaling pathway [75]. p38 MAPK and NF-kB pathways are downstream of a common myloid differention factor 88-dependent signaling pathway [76]. p38 MAPK, a novel target of antiinflammatory therapies, has been linked to a wide range of inflammatory responses in the gut [77]. L acidophilus and L casei also stimulated Akt activation but did not inactivate the p38 MAPK pathway [75]. These findings indicate that lactobacilli may have strain-specific anti-inflammatory effects in the intestinal epithelium. Dendritic cells have a pivotal role in orchestration of the immune system [78]. In the gastrointestinal tract, they reside in the Peyer’s patches, lamina propria, and draining mesenteric lymph nodes, representing the principal stimulators of naRve T cells [79]. Intestinal dendritic cells can sample microbes and other intestinal antigens by way of M cells in Peyer’s patches, directly from the intestinal lumen by reaching between adjacent epithelial cells and indirectly by sampling
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apoptotic epithelial cells or taking up antigen-bearing exosomes. Direct contact with antigens is also possible when epithelial integrity is disrupted [79]. The fate of a naRve T cell is determined by three dendritic cell-derived signals: antigen (signal 1), co-stimulation (signal 2), and cytokines (signal 3) [78]. The expression of different toll-like receptors (TLRs) in antigen-presenting cells allows the cells to discriminate between specific patterns of microbial products found in pathogenic and nonpathogenic strains [80]. E coli LPS is recognized by TLR4, whereas TLR2 recognizes peptidoglycans of S aureus. In parallel, lipoteichoic acids from lactobacilli are recognized by TLR2 [81]. On recognition of their ligands, TLRs initiate signaling processes that lead to maturation of dendritic cells and secretion of cytokines and chemokines by the cells. These cell products influence the polarization of T helper cells and greatly regulate adaptive immune responses [78]. All of the six lactobacilli studied were capable of maturation of the bone marrow-derived murine dendritic cells in vitro [82]. L casei CHCC3139 was the most potent IL-12 (Th1) inducer, and Lactobacillus reuteri DSM12246 the weakest inducer [82]. In co-culture, however, the latter strain prevented dendritic cell maturation and the production of IL-12, IL-6 and tumor necrosis factor a that had been induced by the former strain [82]. Braat et al [83] compared the abilities of L rhamnosus GG and the intestinal commensal Klebsiella pneumoniae to induce maturation and polarization of human dendritic cells. Both bacterial strains induced dendritic cell maturation, although K pneumoniae-matured dendritic cells produced much more Th1 cytokines than did the cells matured by L rhamnosus GG [83]. In parallel, naive T cells primed with K pneumoniae-matured dendritic cells adopted a Th1 phenotype and produced also IL-10, whereas T cells generated from L rhamnosus-matured dendritic cells produce equal amounts of IL-4 and IFN-g (Th0 phenotype). These cells also produced some IL-10 [83], suggesting that they might have suppressive properties. Ingestion of L rhamnosus GG has been shown to result in elevation of serum IL-10 concentrations in children with atopic eczema, as compared with children receiving placebo [84]. The increase of mitogen-induced IL-10 production by peripheral blood mononuclear cells preceded the increase in serum IL-10 levels [84], a finding which indirectly suggests that the previously mentioned dendritic cell-driven mechanism might also function in vivo. These findings indicate that lactobacilli may be able to induce the maturation of dendritic cells that prime T cells to produce mainly Th1 and regulatory cytokines. Probiotics exert mostly proinflammatory immune responses when co-cultured with peripheral blood mononuclear cells or macrophages. Miettinen et al [85] and Hessle et al [86] studied the effects of six Lactobacillus strains in co-culture with human peripheral blood mononuclear cells. Five strains elicited strong IL-12, minor IL-10, and no IL-4 production, suggesting Th1-oriented immune responses [85,86]. L paracasei NCC2461, however, induced production of suppressive IL-10 and TGF-b in a mixed culture of murine splenocytes and CD4+ T cells [87]. L rhamnosus GG induced Th1 chemokine production in human macrophages [88], and the same strain has been shown to activate the transcription factor NFkB directly and to activate STAT1 and STAT3 indirectly by way of cytokines
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Table 1 Potential antiallergic properties of probiotics Site of action
Effects
Gastrointestinal mucus and epithelium
Processing of enteral antigens Inhibition of attachment of pathogenic bacteria Amplification of permeability barrier Suppression of proinflammatory responses elicited by pathogenic bacteria Prevention of apoptosis Maturation of dendritic cells with Th1-type and suppressive properties Production of Th1 and suppressive cytokines by myeloid-derived immune cells
Lamina propria
[89]. These chemokines were shown to stimulate Th1 cell chemotaxis [88]. Studies with murine macrophages suggest that lactobacilli induce their effect on these cells, at least partially, by way of TLR2 that is stimulated by lipoteichoic acids [81].
Summary The first clinical trials with probiotics, especially in the treatment of atopic eczema, have yielded encouraging results. Experimental studies have found that probiotics exert strain-specific effects in the intestinal lumen and on epithelial cells and immune cells with anti-allergic potential. These effects include enhancement in antigen degradation and gut barrier function and induction of regulatory and proinflammatory immune responses, the latter of which occurs more likely beyond the intestinal epithelium (Table 1). Future studies should address more accurately how these and other possible mechanisms operate in the complex gastrointestinal macroenvironment in vivo and how these mechanisms are related to the clinical effects in a dose-dependent manner.
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