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Invited Review

Food Allergy and Helicobacter Pylori

Matysiak-Budnik, Tamara; Heyman, Martine

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Journal of Pediatric Gastroenterology and Nutrition: January 2002 - Volume 34 - Issue 1 - p 5-12
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Helicobacter pylori infection is a gastric infection that is common, worldwide, recognized as the main causative agent of chronic gastritis and peptic ulcer disease, and is closely associated with the development of gastric cancer. In the past decade, evidence has suggested that chronic H. pylori infection, although localized in the stomach, could be involved in the pathogenesis of some extradigestive diseases, such as short stature in children, anemia, or coronary and liver diseases. Data coming from clinical and experimental studies also indicate that H. pylori could play a role in the development of allergic diseases in some subjects. This review presents the arguments in favor of the possible association between H. pylori and food allergy. In this article, we will successively consider the disease mechanisms and the possible role of microorganisms in the development of allergy, the protective role of the gastric barrier against allergic sensitization, the role of the stomach as a potential target for allergic reactions, and the clinical and experimental data suggesting the role of H. pylori in the development of allergy.

DISEASE MECHANISMS OF FOOD ALLERGY

Adverse reactions to foods are caused by an inappropriate immune response to the ingestion of food antigens. Food allergy has to be differentiated from food intolerance, an adverse reaction to food not linked to an abnormal immune response. In contrast, true food allergy is an immunologically mediated process occurring only in susceptible individuals in response to specific food antigens. Epidemiologic surveys indicate a current increase in the prevalence of allergic diseases. In developed countries, these diseases are among the most common chronic diseases, affecting between 15% and 30% of the population (1). Multiple mechanisms are responsible for adverse immunologic response to food antigens (Fig. 1). In genetically predisposed subjects, food antigen exposure leads to the production of high amounts of immunoglobulin E (IgE). Immunoglobulin E is responsible for the rapidly occurring “immediate” hypersensitivity allergic reactions. Immunoglobulin E is produced systemically, and circulating IgE molecules bind to the high affinity receptors FcεRI, present on mast cells or on basophils, leading to the release of various mediators (histamine, serotonin, prostaglandins, leukotrienes, platelet activating factor (PAF), cytokines) that induce alterations of target organs such as the gastrointestinal tract, skin, or respiratory tract. Another mechanism, mainly involved in the so-called food-sensitive enteropathy observed in young children, is mediated through the activation of specific T cells and the release of proinflammatory cytokines such as tumor necrosis factor–α(2), which leads to alteration of the intestinal epithelial integrity. The main treatment of food allergy is avoidance of offending foods.

FIG. 1.
FIG. 1.:
Factors contributing to the development of food allergy.

The importance of genetic background in allergic diseases, including food allergy, is strongly supported by clinical observations and epidemiologic studies showing that heredity plays a significant role in the development of sensitization to food antigens, and that a higher frequency of these diseases is observed in twins (3,4) and in children of parents with allergic diseases (5,6) than in the control population. Analysis of several hundred pairs of twins shows that quantifiable traits associated with allergic diseases, such as total serum IgE levels and skin test results, show intrapairs correlation coefficients twofold higher for monozygotic than dizygotic twins (7). At least two independently segregating disease-susceptibility genes are thought to come together with environmental factors to result in allergic inflammation in a particular tissue. The genetic studies have implicated multiple regions in the human and mouse genomes that are currently being evaluated for harboring putative atopy genes (8,9). For instance, susceptibility to peanut allergy could be determined by the HLA class II genetic polymorphism (10).

It is not known why a specific antigen leads to an abnormal immune response, but environmental factors, i.e., bacterial and viral stimuli, probably also play a role. Indeed, these factors could modify the intestinal permeability to food antigens or activate the costimulatory molecules at the surface of local antigen-presenting cells, thus favoring the development of an immune response instead of the normal suppressive response, which is the basis of oral tolerance.

In fact, both the quantity of antigen absorbed and the concurrent adjuvant effect of digestive infection and inflammation are thought to influence the outcome of antigen presentation to mucosal T cells that, in turn, determines the development of tolerance or allergy. During viral or bacterial infections of the digestive tract, the intestinal permeability to food antigens generally increases, because of alterations in the intestinal epithelium caused by infectious agents and by the inflammatory reaction (11). In the context of such an inflammatory environment, the local antigen-presenting cells (mainly dendritic cells) switch from a tolerogenic to an immunogenic state (12). Few studies have reported a clear link between the increase in food antigen absorption by the gut and the development of food allergy (or the breakdown of oral tolerance). Infections, by disrupting the epithelial barrier and increasing antigen absorption, also could lead to intestinal dysfunction and persistent diarrhea caused by the development of food allergy. Rotavirus infection, which is the most frequent cause of diarrhea in childhood, disturbs antigen handling by the gut (13). The frequency of persistent diarrhea in viral enteritis suggests that sensitization to food antigens may occur during infection (14) and that certain viruses may contribute to the allergic sensitization process (15). Bacterial enteric infections also lead to intestinal lesions that can alter the barrier function of the epithelium (16). However, the increased intestinal transport of macromolecules does not lead systematically to an increased allergic sensitization (17). Not only does genetic susceptibility play a role in the development of allergic responses to food antigens absorbed in the intestine, but other factors that interfere with antigen presentation also contribute, such as the type of antigen, the type and status of the antigen-presenting cell, the presence of bacterial adjuvants, the expression of costimulatory molecules at the time of presentation, or the cytokines present during T-cell activation.

MICROORGANISMS AND FOOD ALLERGY

Among environmental factors that modulate oral tolerance, the bacterial intestinal microflora is an important one. Apparently contradictory results exist concerning the effect of intestinal microorganisms on the immune response to luminal antigens. Although, the commensal microflora is necessary for full induction and maintenance of oral tolerance (18–20), including the IgE production system (21), a strong immune response to an orally administered antigen is obtained when the antigen encounters the gut-associated lymphoid tissue together with microorganisms capable of stimulating antigen presentation (22,23). This has been recently explained by the fact that dendritic cells of the intestinal mucosa play an important role in inducing oral tolerance (24) and the fact that the regulation of intestinal responses to soluble antigens through dendritic cell presentation depends on the presence or absence of inflammatory signals (12,25). It also is noteworthy that nonpathogenic enteric bacteria, interacting directly with human epithelial cells grown in vitro, have recently been shown to attenuate the synthesis of proinflammatory effector molecules (NFκB) elicited by diverse proinflammatory stimuli including pathogenic bacteria (26). The mechanism of such an inhibitory effect consists of the blockade of inhibitory κβ-α degradation, preventing subsequent nuclear translocation of the active NFκB dimer and then the transcription of genes coding for inflammatory cytokines.

PROTECTIVE ROLE OF GASTRIC BARRIER AGAINST ALLERGIC REACTIONS

The gastrointestinal tract plays an important role in protecting the host against the development of allergic reactions. Two main mechanisms seem to be important: limitation of the absorption of foreign antigens across the digestive epithelium and control of the systemic immune response to these antigens. All parts of the digestive tract play a role in this process, the intestine considered a central part. However, the role of the gastric barrier has also been recognized. This barrier has a double-layer structure, comprising the epithelial cells covered by an adherent mucus layer. The integrity of the barrier is assured by the continuity of the epithelial cell layer maintained by the intercellular tight junctions (27–29), by the integrity of the epithelial cell membranes, and by the thickness and composition of the mucus layer. In normal conditions, the gastric barrier constitutes an almost total barrier to the retrodiffusion of H + ions into the gastric wall and Na + ions into the lumen. Different agents, chemical or bacterial, may damage the barrier and may lead to increased passage of various molecules across this barrier.

The gastric epithelium constitutes an important barrier against the penetration of bacterial, viral, and food antigens into the small intestine. Several studies have shown that achlorhydria may be associated with an increased proliferation of gram-positive bacteria in the intestine, with an increased incidence of gastrointestinal infections and with hypersensitivity reactions to macromolecular antigens (30). Patients with achlorhydria also have increased circulating antibodies to bovine serum albumin (31). In rats fed with bicarbonate in conjunction with proteins, increased intestinal transport of macromolecules was demonstrated in vivo (32). This observation suggests that protein hydrolysis may affect the antigenic properties of proteins or the amount of protein antigens being absorbed.

Both intestine and stomach are potential targets for allergic sensitization. Intestine, with its largely developed immune (lymphocytic cells) system is classically considered a central organ of food sensitivity reactions. It has been shown, however, that gastric epithelium, like small intestine epithelium, is able to absorb small amounts of macromolecules (33–35) and that this antigen absorption may induce the IgE-mediated sensitivity reactions to these antigens (36).

STOMACH AS A TARGET FOR ALLERGIC REACTIONS

The stomach is considered a major site of involvement in food-induced hypersensitivity reactions. The susceptibility of the stomach to anaphylactic changes was described in 1910 when Schittenhelm and Weichardt (37) produced petechial hemorrhages in the gastric mucosa by injecting egg protein into sensitized dogs. Since then, many other animal and human experiments have been performed that show various manifestations of food hypersensitivity (38,39). Reiman et al. (40,41) observed the development of erythema, edema, erosions, and even petechial hemorrhages after endoscopic administration of food antigens directly on the gastric mucosa of allergic individuals. Positive challenges correlated with increased mucosal lymphocyte count, and after the challenge, decreased tissue histamine and histologic evidence of mast cell degranulation were noted.

Evidence suggests the role of anaphylactic reactions in peptic ulcer as well as in various types of gastritis. A marked increase of IgE-producing cells in the gastric mucosa in patients with peptic ulcer, varioliform gastritis, and bile reflux gastritis has been observed (42–47). Significantly higher total IgE serum levels were found in patients with peptic ulcers than were found in healthy subjects (48). Immunoglobulin E–specific for cockroach antigens were detected in serum and gastric mucosa in patients with peptic ulcers and chronic gastritis (49). These observations support the concept that gastric mucosal anaphylaxis, developed in response to antigen ingestion, could be an initial insult that alters the mucosal barrier and leads to gastric lesions or perpetuation of gastric inflammation. Finally, eosinophilic gastroenteritis, characterized by an eosinophilic invasion of the stomach, also exemplifies food hypersensitivity localized in the stomach (50,51). The disease mechanisms involved are not known, but immunomediated mechanisms including immune-complex–mediated hypersensitivity, delayed hypersensitivity, and immediate hypersensitivity to food antigens are evoked (52).

All these data indicate that the stomach is an important target for allergic reactions and possesses an important capacity to mediate these reactions.

Gastric reaction to food may be mediated by a number of mechanisms, but type I IgE-mediated reactions to food antigens have been well established in at least some cases of food allergy (53). One of these mechanisms involves mast cells. Their role in the gastric manifestations of food allergy is increasingly recognized. In atopic subjects, intragastric allergen provocation resulted in increased degranulated mast cell score within the gastric mucosa, suggesting that mast cells play an important role in the gastric reaction to allergic stimulation (54). Immediate type I hypersensitivity and mast cell degranulation were found responsible for neutrophil and mononuclear cell recruitment in mouse gastric mucosa (55). This result, however, was not confirmed by Furuta et al. (56) who found that neutrophil infiltration of the stomach occurring during systemic anaphylaxis in mice did not require participation of mast cells. Gastric anaphylaxis in immunized mice was associated with increased gastric and intestinal uptake of macromolecules and degranulation of mast cells (57). Food protein–induced IgE-mediated gastric anaphylaxis in rats was found associated with delayed gastric emptying and transient reduction in gastric antral contractions, accompanied by an increased serum levels of rat mast cell protease II, a marker specific for mucosal mast cell degranulation (58).

HELICOBACTER PYLORI AND ALLERGY

Three types of data support a possible association between H. pylori infection and food allergy: 1) rationale data show that bacteria can colonize the gastric mucosa and alter the gastric barrier; 2) experimental data show the potential capacity of H. pylori to increase the passage of intact macromolecules across the epithelial barrier; and 3) clinical data show the association between H. pylori infection and allergic reactions, food allergy, and other allergic diseases.

Helicobacter pylori Can Damage the Gastric Barrier

Helicobacter pylori possesses the potential to damage the gastric mucosa by various mechanisms. Among the pathogenic factors involved, adherence, lipopolysaccharides, production of ammonia, and enzymatic activity, common to all strains, are the most important. The more virulent strains possess virulence factors, e.g., vacuolating cytotoxin VacA and cag pathogenicity island, the latter producing the cagA protein. The indirect factors are represented by the local and systemic, humoral and cellular, host immune responses to the infection. The anti–H. pylori immune response, which is mainly of type 1 helper T-cell (Th1) type, is characterized by polynuclear cell infiltrate and abundant production of proinflammatory cytokines, e.g., interferon γ, tumor necrosis factor–α, IL-1, and IL-8. All the bacterial factors, as well as the inflammatory mediators (59,60) may contribute to the deleterious action of the bacteria with respect to the gastric mucosa and lead to gastric mucosal damage (61). Indeed, different epithelial lesions have been described in the presence of H. pylori. The “attachment-effacement” lesions, associated with destruction of microvilli, cytoskeleton rearrangements, and pedestal formation by these cells were observed (62,63). Alterations of gastric mucus composition and decreased mucus layer thickness caused by H. pylori have been well documented (64,65). Furthermore, alterations of the barrier function have been observed in vitro and in vivo. A decrease of the epithelial barrier integrity, reflected by decreased transepithelial resistance and increased absorption of small molecules across H. pylori–infected epithelial cell monolayers (66,67) or cell monolayers treated with VacA cytotoxin (68,69), has been described. In vivo, increased gastric permeability to sucrose was found in patients who tested positive for H. pylori(70,71). All these data suggest that H. pylori can alter the structure and function of the gastric barrier.

Helicobacter Pylori Increases Passage of Intact Proteins Across Epithelium

Experimental data indicate that H. pylori can increase the passage of intact antigens across the epithelium. This phenomenon has been found in vitro, by using intestinal epithelial cell monolayers (72), in an experimental model of mice infected with H. felis, a bacterium closely related to H. pylori(73), and also in humans, in a study of human gastric biopsies obtained from patients infected with H. pylori (Matysiak-Budnik et al., 2001, unpublished data). All these studies were performed using the Ussing chamber system, which allows evaluation of the integrity of the tissue by measuring the electrical parameters—especially electrical resistance—of the tissue, and also allows measuring the passage of various permeability markers, micromolecular and macromolecular, across the tissue. Using this system, we have demonstrated that infection of the HT29 intestinal epithelial cell line with H. pylori increases the passage of intact protein (horseradish peroxidase) across these layers, and that this increase is caused by an enhanced transcellular passage of the protein (Fig. 2). The HT29 intestinal cell line has been used because gastric polarized epithelial cell lines with tight junctions, required for studying the function of the epithelial barrier, are not available. However, this model is well established and widely used in studies on the absorption of various permeability markers across the epithelial barrier. Moreover, H. pylori has been shown to adhere easily to different intestinal cell lines (74,75), and this model has been found useful in various physiopathologic studies.

FIG. 2.
FIG. 2.:
Effect of Helicobacter pylori on the macromolecular transport across the digestive epithelium in vitro (72). Infection of the HT29-19A intestinal cells with H. pylori increases, when compared with the noninfected cells, the fraction of protein that crosses the epithelial cell under intact form (25% vs. 10%).

In mice infected with H. felis, the passage of horseradish peroxidase across the gastric mucosa increased when compared with noninfected mice. In this case, both intact and degraded proteins were concerned. The final result is increased antigenic load in the gastric mucosa because proteins degraded to peptides of a size of 5 amino acids or more preserve their antigenic properties (Fig. 3). Our results obtained with gastric biopsies (2001, unpublished) confirm that the increase of transepithelial absorption of macromolecules by H. pylori also takes place in humans.

FIG. 3.
FIG. 3.:
Effect of Helicobacter pylori and associated inflammation on the macromolecular transport across the gastric mucosa in vivo in mice (73). Bacterium increases the passage of intact protein across the epithelial cells whereas the inflammation increases the captation and degradation of protein by these cells. The final result is an increased antigenic load in the gastric mucosa that may contribute, by stimulation of the local immune system, to maintenance of gastric inflammation or to development of allergic sensitization.

Increased epithelial permeability to food antigens in H. pylori–induced gastritis, by increasing the mucosal protein absorption, could explain the persistence of gastric inflammation for months and even years after eradication of the bacteria, observed in 20% to 50% of patients (76–79). Furthermore, this increased permeability to antigens could be responsible for an allergic sensitization to bystander food antigens occurring in some patients who test positive for H. pylori. Indeed, some clinical data show that H. pylori infection is often associated with the development of allergic disorders.

H. pylori is Associated With Allergic Reactions and Allergic Diseases

Two studies have reported an association of H. pylori infection with food allergy. In the first study, of children with food allergy, the anti–H. pylori IgG titers were significantly higher than in children with atopic asthma or with inflammatory bowel disease (80). In the second study, of an adult population, patients with symptomatic food allergy had similar prevalence of H. pylori infection to nonallergic controls. However, anti-cagA antibodies were detected in 62% of patients with food allergy versus 28% of controls. Furthermore, the mean IgE level to the most common food antigens increased in patients with cagA-positive strains as compared with the patients with cagA-negative strains. This study highlights a possible role of the cag pathogenicity island food allergy development (81).

Helicobacter pylori has been also implicated in the pathogenesis of chronic urticaria, a skin disorder characterized by recurrent, transitory itchy wheals. The clinical symptoms are caused by the release of histamine and other vasoactive mediators that allow the allergen to bind to its specific mast cell receptor. In most cases, the allergen that triggers this reaction cannot be identified and the urticaria is considered idiopathic. In several studies, H. pylori infection was more common in patients with chronic urticaria than in controls (82,83). Moreover, a beneficial effect of H. pylori eradication on clinical symptoms was reported in some cases of this disease (84–86). These results, however, have not been confirmed in all the studies (87–89); thus, the association between H. pylori infection and chronic urticaria is not established.

Atopic dermatitis, another skin disease of allergic origin, also has been associated with H. pylori infection. In one case report, after successful eradication of the bacteria in a 14-year-old girl, the skin symptoms of dermatitis gradually disappeared, accompanied by decreased blood eosinophils and IgE levels (90).

Other arguments support the role of H. pylori in allergy. The histologic picture of H. pylori–associated gastritis is often consistent with that observed in allergic reactions. Indeed, biopsy specimens containing the bacterium are characterized by the presence of a neutrophilic infiltrate and eosinophils (91,92). A significant correlation between positivity for antibodies against cow milk protein and anti–H. pylori antibodies has been found in diabetic patients (93). The ability of H. pylori to induce a specific IgE immune response to bacterial antigens has been demonstrated in patients with chronic gastritis (94). Mast cells, which are implicated in IgE-mediated reactions, have been proposed as a trigger of inflammation in H. pylori infection. Degranulation of rat mast cells in vitro was induced by water extract of H. pylori(95). An increased number of degranulated mast cells was found in the gastric mucosa in children (96) and in adults (97,98) infected with H. pylori when compared with noninfected subjects.

THE TH1/TH2 PARADOX

T cells can be classified as Th1 or type 2 helper cells (Th2) according to their profile of cytokine secretion. Type 1 helper cells produce interferon γ, IL2, and tumor necrosis factor–β, which activate macrophages and are responsible for cell-mediated immunity. Type 2 helper cells produce IL4, IL5, IL10, and IL13, which are responsible for antibody production, eosinophil activation, and inhibition of several macrophage functions. Helicobacter pylori infection, virtually in all cases, is associated with gastric inflammation and the release of cytokines, mainly of the Th1 phenotype. Type 1 helper cells are mainly associated with bacterial or viral infections, whereas Th2 cells predominate in response to nematode infection or in allergic disorders. Theoretically, a Th1 response can protect against the development of allergic diseases because Th1 and Th2 responses are considered mutually inhibitory. This aspect has been recently addressed in an experimental model in mice, in which a concurrent enteric helminth infection modulated the inflammation and the gastric immune response, and reduced Helicobacter-induced gastric atrophy (99). It is possible, however, that allergic sensitization rises during the initial phase of infection, when the local Th1 response is not yet fully developed.

In developed countries, the incidence of food allergy is increasing. Allergic diseases are certainly related to the genetic susceptibility of the individuals, but their expression may be modulated by environmental (including bacterial) factors. The prevalence of H. pylori infection in the world is decreasing, following improvement of the socioeconomic conditions in many countries, whereas the prevalence of food allergy seems to increase. These two opposite trends, however, do not exclude the possibility that in some subjects, chronic infection with H. pylori may play a role in the development of allergic sensitization to food antigens.

Chronic gastric infection with H. pylori could favor development of food allergy by increasing the passage of intact proteins across the gastric epithelial barrier in some subsets of patients. It remains, however, to be established whether this increased gastric antigen absorption by H. pylori may have clinical consequences, i.e., be responsible for the development of allergic sensitization in susceptible individuals.

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