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Department of Biochemistry and Food Chemistry and Functional Foods Forum, University of Turku, 20014 Turku, Finland and Danisco Innovation, 02460 Kantvik, Finland
* To whom correspondence should be addressed. E-mail: arthur.ouwehand{at}utu.fi.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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20% of the population in western countries suffers from some form of allergy. The incidence of allergy is still rising, and there are no indications that this trend will be reversed. A hereditary predisposition for allergy is thought to be involved: children who have family members with allergies have a higher risk of developing allergy as well (1). However, environmental factors appear to be required to trigger the disease. The hygiene hypothesis suggests that insufficient or aberrant exposure to environmental microbes is one of the causes of the development of allergy. Reduced family size, improved hygiene, vaccination, the use of antimicrobial medication, and the consumption of almost sterile food have reduced and changed our exposure to microbes (2). Humans have evolved in an environment with a heavy bacterial load, and our immune system has been adapted to deal with that. With the advances in medicine and food processing, our contact with microbes has changed. The absence of such an appropriate microbial exposure may pose a problem for the development a child's immune system. In infants, the immune system is still developing; this provides an opportunity to direct development away from the allergic phenotype. Avoidance of allergens has been standard treatment in the past (3). This has met with limited success; allergen avoidance relieves the symptoms but does not treat the disease. Instead of avoidance, induction of tolerance by exposure to antigens may be the appropriate method. It is obvious that for public health reasons it is not desirable to abandon current medical and hygienic practices; therefore, safe alternatives have to be sought. Probiotics may be such safe alternatives for providing necessary microbial stimulation.
The intestinal microbiota
The normal intestinal microbiota has a diverse composition; a conservative estimate is that it consists of at least 400 species (4). This estimate was made on the basis of results from culture-based techniques. Because a large part of the intestinal microbiota can not be cultured with current techniques (5), it has been suggested that the number of microbial species in the human intestine may, in fact, exceed 1000.
This microbiota has a metabolic activity that equals that of the liver, our metabolically most active organ. The microbiota contributes to the digestion of exogenous and endogenous substrates, such as fibers and mucins. This provides the host with additional energy in the form of fatty acids (6). It may, however, also expose the host to detrimental metabolic endproducts such as amines, sulfides, ammonia, etc.
Another important function of the intestinal microbiota is to provide a protective barrier against incoming bacteria, e.g., potential pathogens. This colonization resistance works through several different mechanisms: competition for nutrients and binding sites and production of antimicrobial substances (7).
The intestine is the body's largest immune organ; most of the antibody-producing cells reside in the intestine (8). A relatively recently recognized function of the intestinal microbiota is to provide stimulation of the immune system. Consumption of probiotics (and prebiotics) is, in most cases, aimed at modulating the composition and/or activity of the intestinal microbiota (9). This modulation can be expected to influence the immune system. Indeed, several probiotic strains have been observed to modulate some immune parameters after sufficient (time and amount) consumption (10–12). However, in many cases it is uncertain what the actual health benefit of this immune modulation is for the consumer, in particular the healthy consumer.
The intestinal immune system
At birth, the immune system of an infant is not fully developed and tends to be directed toward a T-helper (Th)2 phenotype3 (Fig. 1) to prevent rejection in utero. The Th2 phenotype leads, however, to the stimulated production of IgE by B cells and thus increases the risk for allergic reactions through activation of mast cells. Microbial stimulation early in life will reverse the Th2 bias and stimulate the development of a Th1 phenotype and stimulate the activity of Th3 cells (13). Their combined action will lead to the production of IgA by B cells. IgA contributes to allergen exclusion and will thereby reduce exposure of the immune system to antigens. Cytokines produced by the Th1 phenotype will also reduce inflammation and stimulate tolerance toward common antigens (14).
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In the case of allergy, the rationale for modulating the intestinal microbiota is supported by observations that allergic children have a different microbiota composition than healthy infants. Children with allergy were found to have an aberrant microbiota even before the onset of allergy; they had higher levels of clostridia and lower levels of bifidobacteria (15,16). In addition to these quantitative differences in the Bifidobacterium microbiota, qualitative differences have also been observed. Infants with atopic dermatitis have been found to have a more adult type Bifidobacterium microbiota with high prevalence of B. adolescentis. Healthy infants, on the other hand, were found to be colonized mainly by B. bifidum, typical for breast-fed infants (17,18). However, children with respiratory allergy symptoms did not exhibit an aberrant microbiota composition (18). The bifidobacteria from infants with atopic dermatitis were found to induce a higher secretion of proinflammatory cytokines in vitro, whereas the bifidobacteria from healthy infants induced the secretion of more antiinflammatory cytokines (19). Also, bifidobacteria of dairy origin stimulated more antiinflammatory and less inflammatory cytokines than bifidobacteria from allergic infants. In addition to differing in their induction of cytokines, bifidobacteria from allergic and healthy infants also exhibited different in vitro adhesion to Caco-2 tissue culture cells (20) and intestinal mucus (21). This difference in adhesion to the intestinal mucosa may result in a different or reduced stimulation of the immune system through the gut-associated lymphoid tissue.
Not only the composition of the intestinal microbiota but also the metabolic activity of the microbiota may be different. Swedish children, who are at high risk to develop allergy, were found to have significantly higher levels of fecal butyrate, isovalerate, and caproate then Estonian children, who have a low risk for developing allergies (22).
Treatment of atopic disease
A limited number of strains have been tested for their efficacy in the treatment and prevention of allergy in infants. Allergy may manifest in infants even when they are exclusively breast-fed. Standard treatment involves the feeding of extensively hydrolyzed formula (3). Supplementation of this type of formula with Bifidobacterium lactis Bb-12 or Lactobacillus rhamnosus GG has been found to lead to an earlier recovery than standard treatment alone, 2 mo vs. 6 mo (23). A combination of 2 Lactobacillus strains, L. rhamnosus 19070–2 and L. reuteri DSM 122460, was found to significantly reduce the clinical scoring of atopic dermatitis (SCORAD) in 1- to 13-y-old children with a positive skin prick test. But the SCORAD of children with no positive skin prick test remained unchanged. Interestingly, more than half of the subjects reported an improvement in their eczema, whereas only 15% in the placebo group reported improvement (24).
The 2 studies discussed used different probiotics preparations; this may explain the observed differences in outcome. But the differences may also relate to the differences in age of the patients studied. In young infants, the immune system is still developing. There is still a possibility to direct it toward tolerance. In older children, the allergic phenotype is already established, and here one may only be able to relieve the symptoms. Similarly, probiotics have not been very successful in alleviating symptoms of respiratory allergy. L. rhamnosus GG was not able to reduce the symptoms of birch pollen allergy in adults (25) despite its effectiveness in children. Similarly, L. acidophilus L-92 was reported only to relieve the subjective symptoms of cedar pollen allergy in adults (26).
Prevention of allergic disease
In addition to treatment of allergy, it has been observed that selected probiotics can reduce the risk for the development of allergy. One of the earliest studies was performed with a nonpathogenic Escherichia coli administered to term and preterm infants. At 10 and 20 y of age, children treated with E. coli suffered significantly fewer allergic diseases than the subjects in the control group (27). In a recent study, the efficacy of L. rhamnosus GG on at-risk infants was studied; children of allergic mothers have 50% risk of developing allergy. Pregnant allergic mothers were given L. rhamnosus GG or placebo from 2 to 4 wk before the calculated date of delivery in a randomized double-blind trial. After delivery, the children received L. rhamnosus GG for 6 mo. After 4 y, 46% of the children in the placebo group had developed atopic eczema, whereas in the probiotics group this was 26% (28). Surprisingly, the serum IgE levels did not differ between the 2 groups. This is in contrast to observations in mice, where L. casei Shirota was able to suppress the production of IgE (29).
Mechanisms of antiallergic probiotic action
The precise mechanisms behind the favorable effects of probiotics on allergy are not entirely known. Several mechanisms have been observed in vitro and in animal studies (Fig. 2). In addition to modulation of the intestinal microbiota, probiotics have been observed to improve the barrier function of the intestinal mucosa (30), reducing leakage of antigens through the mucosa and thereby exposure to them. Direct modulation of the immune system may be through the induction of antiinflammatory cytokines or through increased production of secretory IgA (31). IgA will contribute to an exclusion of antigens from the intestinal mucosa. Further, enzymatic degradation of dietary antigens by enzymes from probiotics will reduce the load of and exposure to antigens (32). These and other mechanisms contribute to reduced exposure of the immune system to dietary antigens.
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Thus, although probiotic therapy appears to be a promising approach in the treatment and prevention of allergy, there are still a substantial number of questions that remain to be answered.
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FOOTNOTES |
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2 Author disclosure: The author is currently employed by Danisco Finland.
3 Abbreviations used: Ig, immunoglobulin; SCORAD, clinical scoring of atopic dermatitis; Th, helper T cells.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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