Pathogenesis of food allergy

INTRODUCTION — Tolerance is the normal immune response to the food an individual eats over a lifetime [1]. Food allergy is an abnormal immune reaction consisting of hypersensitivity to food components, most commonly proteins [2,3].

This topic will focus on food allergy due to primary sensitization through the gut and will review organization of the gut immune system and factors that influence oral tolerance induction. Theories addressing the increasing prevalence of food allergy are briefly mentioned. The pathogenesis of pollen-food allergy syndrome, seen more frequently in adolescents and adults, is discussed separately. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)

PREVALENCE — The prevalence of food allergies, particularly to peanut, appears to have increased from the late 1990s to the early 2010s (figure 1) [4-9]. While there are a number of theories regarding the apparent increase in prevalence of food allergies, especially peanut allergy, definitive answers are still lacking [10-13]. Postulated hypotheses have focused on hygiene, dietary fat, antioxidants, vitamin D, and dual allergen exposure (ie, initial exposure to a food allergen via a nonoral route, such as the skin). There are some data in support of these hypotheses to explain the increasing risk of asthma and allergic rhinitis. However, there are limited data regarding the role for these hypotheses in the increased prevalence of food allergy. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Prevalence of childhood food allergy'.)

●Hygiene hypothesis – Early life exposure to infectious pathogens, as well as normal gut microbiota, may influence the development of the immune system away from a T helper type 2 (Th2) and towards a T regulatory cell (Treg) response. Better hygiene, resulting in less microbial exposure, may lead to an increase in atopic disease.

●Microbiome depletion hypothesis – This hypothesis evolved from the hygiene hypothesis. The ecosystem of the human body (the human biome) can influence immune function. Loss of species diversity from the human microbiome can result in allergy, autoimmune disease, and other disorders related to increased inflammation [14-16].

●Short-chain fatty acid hypothesis – A specific microbiome may promote a high concentration of short-chain fatty acid such as butyrate, propionate, or acetate, which may contribute to a decreased sensitization to foods [17].

●Dietary fat hypothesis – This hypothesis postulates that decreased consumption of n-3 fatty acids (eg, omega-3 fatty acids) and increased ingestion of n-6 fatty acids (eg, vegetable oils) leads to greater production of immunoglobulin E (IgE) through the influence of prostaglandin-E2.

●Antioxidant hypothesis – This hypothesis argues that antioxidants found in fresh fruits and vegetables, such as vitamin C and beta-carotene, have protective antiinflammatory effects. Dietary patterns that include more processed foods and less fresh produce may therefore increase susceptibility to allergy.

●Vitamin D hypothesis – Vitamin D has been shown to have immunomodulatory effects. Proposed but unproven theories suggest a role for both vitamin D excess and deficiency in the development of allergic disease. (See "Vitamin D and extraskeletal health".)

●Dual allergen exposure hypothesis – This theory proposes that sensitization to a food is more likely to occur in a young child if the initial exposures are low dose and via the cutaneous route rather than high dose and via the gut. (See 'Primary sensitization' below and 'Route of antigen exposure' below.)

●Food-processing hypothesis – How foods are processed may also affect allergenicity. This can lead to varying prevalence in different cultures. As an example, roasting and emulsification of peanut to make peanut butter may alter the proteins and allow them to be presented to the immune system in a manner that may be conducive to promoting allergic responses [18]. Rates of peanut allergy are lower in countries where peanuts are primarily boiled rather than roasted. (See 'Antigen form' below.)

●Other hypotheses – Staphylococcus aureus-derived enterotoxins commonly cause food contamination. Staphylococcal superantigens are also associated with atopic dermatitis. In a mouse model, oral administration of staphylococcal enterotoxin B (SEB) along with hen's egg or peanut antigen results in Th2-polarized responses [19]. Similarly, SEB may also favor sensitivity when added to a skin-sensitizing antigen [20]. Oral challenge with allergen triggers anaphylaxis. Expression of transforming growth factor (TGF) beta and Tregs is impaired. Feeding high doses of antigen restores tolerance.

TYPES OF REACTIONS — Food allergy reactions may be IgE mediated, non-IgE mediated, or both. It was previously thought that the development of food allergy was due to a skewed T helper type 2 (Th2) allergic response. However, it is now recognized that the failure of regulatory mechanisms may also play a critical role [21,22]. (See 'Effector T cells' below.)

IgE mediated — Most immediate-type reactions are mediated by food-specific IgE antibodies, eliciting acute or chronic cutaneous symptoms (ie, contributing to eczema flares) or anaphylaxis [23]. IgE-mediated reactions are more prevalent in young children and may be outgrown for some foods during childhood. Sensitization refers to the production of allergen-specific IgE, but it is not synonymous with being allergic to that allergen. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

Non-IgE mediated — Non-IgE-mediated food allergy (usually delayed Th2 cell-mediated responses) is mostly manifested by gastrointestinal symptoms and/or occasionally by chronic skin symptoms. The absence of reliable testing for non-IgE-mediated food allergy has obscured a clear view of the pathogenesis of these diseases [24]. The increased prevalence of eosinophilic gastrointestinal disorders has led to new insights into the pathogenesis of these diseases [25].

Mixed — Food allergies associated with several diseases, such as eosinophilic esophagitis, food protein-induced enterocolitis syndrome (FPIES), and atopic dermatitis, are not always attributable exclusively to IgE- or non-IgE-mediated mechanisms but may be due to mixed processes. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Role of allergy in atopic dermatitis (eczema)" and "Food protein-induced enterocolitis syndrome (FPIES)".)

THE GUT IMMUNE SYSTEM — The gut is the largest mucosal organ of the body and, as such, is at the forefront of the body's immune homeostasis [26-28]. The gut immune system is comprised of luminal barriers, gut-associated lymphoid tissue (GALT), and lymphoid organs. The gut is exposed to pathogenic and commensal microorganisms on a daily basis. In addition, it is exposed to a large amount of ingested foreign dietary proteins. The immune system in and around the gut has developed to provide a tolerogenic response to nonpathogenic proteins. Tolerance is accomplished through two primary mechanisms: preventing the uptake of intact allergens and limiting the proallergenic damaging immune responses to undegraded antigens that do enter the system [29].

Overview of components and functions

Luminal barriers — The luminal barriers of the gut include secreted factors and physical gut components comprising the epithelial layer and luminal contents [30].

●Gastric acid and intestinal proteolytic enzymes degrade potentially allergenic proteins [31,32].

●Immunoglobulin A (IgA) produced by B cells in the gut binds foreign proteins and peptides in the gut lumen, preventing their uptake. IgA in breast milk can also prevent antigen entry [33,34].

●Mucus covering the cell surface of the gastrointestinal tract is the first physical layer of protection against foreign proteins.

●The epithelium provides a physical barrier that is enhanced by the presence of inflammatory cells [35].

Gut-associated lymphoid tissue

●Intraepithelial lymphocytes (IELs) of the gut are critical to the immune response. (See 'Intraepithelial lymphocytes' below.)

●The submucosa is colonized by numerous lamina propria T lymphocytes (LPLs) that are also involved in immune homeostasis. (See 'Lamina propria lymphocytes' below.)

●Peyer's patches are collections of lymphoid tissue located predominantly in the ileum. They are organized into follicles consisting mainly of B cells. Other immune cells in the Peyer's patches include T cells, plasma cells, macrophages, mast cells, eosinophils, and basophils. (See 'Peyer's patches T cells' below.)

●Peyer's patches are lined at their apices with M cells. M cells are enterocytes expressing major histocompatibility complex (MHC) class II that endocytose particulate antigens and transport them to antigen-presenting cells (APCs) in the underlying tissue [36].

Other components

●The vasculature of the lamina propria and Peyer's patches allows inflammatory cells to circulate to other immune structures.

●Mesenteric lymph nodes are the closest lymph nodes for filtering antigens absorbed through the gut.

●The spleen and the liver are lymphoid organs that are important components of the immune response to potentially harmful proteins that enter through the gut. The role of the liver as a contributor to the memory of food allergy has become apparent by reports of nonallergic recipients developing peanut allergy after transplantation of a liver from peanut-allergic individuals [37,38].

ROUTES OF ALLERGEN SENSITIZATION — Sensitization to a food may occur directly through the gut or skin. Alternatively, sensitization may first occur to homologous allergens through the respiratory route.

Primary sensitization — The gut immune system is the most common site of primary sensitization in both IgE-mediated and non-IgE-mediated food allergy in children. These food allergens are generally stable to digestion.

Sensitization to allergens may also occur through the cutaneous route [39-48]. This was first demonstrated in murine and canine models and later in humans. Epicutaneous sensitization prevents oral tolerance and induces a systemic T helper type 2 (Th2) response. Exposure to antigen through the skin may predispose to development of diseases such as atopic dermatitis and eosinophilic esophagitis.

Allergen cross-reactivity — The most frequent clinical manifestation of food allergy in older children and adults is oral allergy syndrome, or pollen-food allergy syndrome. Patients suffering from oral allergy syndrome are primarily sensitized to respiratory allergens such as birch, grass, or mugwort pollens [49]. Secondarily, they develop clinical reactivity to homologous epitopes on food proteins of plant origin. These food allergens are generally labile and are destroyed during digestion. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)

ANTIGEN UPTAKE AND PRESENTATION — Dietary proteins are degraded into small peptides and amino acids by gastric acid and intestinal and pancreatic enzymes. In most cases, the digested peptides no longer bear the potentially immunogenic epitopes of the original protein. In addition, secretory IgA molecules in the gut lumen bind proteins and block absorption. However, some intact proteins and allergenic epitopes slip through these barriers and are taken up by specialized cells in the gastrointestinal tract and transported to antigen-presenting cells (APCs).

Antigen uptake — Antigens may be taken up from the gut lumen by three cell types (figure 2) [2,3]:

●Intestinal epithelial cells – Soluble food proteins can be taken up by intestinal epithelial cells through endocytosis by the microvillus membrane. Alternatively, they may cross the epithelium through a paracellular route [2,50]. By these means, potentially harmful nondigested proteins may reach the lamina propria and enter the portal circulation.

●Dendritic cells – Dendritic cells in the lamina propria can extend dendrites between intestinal epithelial cells and into the gut lumen and sample antigen directly.

●M cells – Foreign proteins can also enter through Peyer's patches. M cells specialize in uptaking particulate antigens and delivering them to APCs.

Antigen presentation — Antigen presentation is mostly achieved by dedicated APCs, also known as professional APCs, mainly dendritic cells [51]. Dendritic cells are predominantly localized in the lamina propria of peripheral tissues, where they uptake antigens. They then migrate to effector sites, including the follicles of Peyer's patches or mesenteric lymph nodes [52]. Dendritic cells then present antigenic peptides complexed with major histocompatibility complex (MHC) to T cell receptors on CD4+ T cells. (See "Antigen-presenting cells".)

Various costimulatory molecules, such as CD80 and CD86, provide essential signals for efficient antigen presentation and initiation of the immune response [53]. Other cell surface molecules, including T cell immunoglobulin-domain and mucin-domain 4 (TIM-4, or TIMD-4) and OX40 ligand (OX40L or CD252), are expressed by dendritic cells in mouse models. These molecules also promote T helper type 2 (Th2) differentiation and may be involved in the development of Th2-mediated food hypersensitivity [54,55].

Intestinal epithelial cells constitutively express MHC II and may also act as nonprofessional APCs. They primarily present to and activate CD8+ suppressor T cells [56,57].

T CELLS — A variety of T cells are involved in the pathogenesis of food allergy and oral tolerance induction. They are found in several locations, including the epithelium, lamina propria, Peyer's patches, and peripheral blood, and have differing effector functions depending on their cytokine profiles.

Intraepithelial lymphocytes — Intraepithelial lymphocytes (IELs) are mostly anergic to usual antigenic stimulation, suggesting a tolerogenic role for these types of T cells [58]. Their specific characteristics are most likely due to their proximity to the strong immunogenic stimuli of the gut microbiota [59].

IELs constitute a unique population of T cells. A higher percentage of IELs are CD8+ (75 to 80 percent) and CD8 alpha/alpha+ (80 percent) than other T cell populations, and one-half express the gamma-delta chains of the T cell receptor [60-62]. Both CD8 alpha-alpha+ and gamma-delta T cells recognize antigen independently of major histocompatibility complex (MHC) I. The exact function of these cells is still unknown. It is suspected that their major roles include immune surveillance and maintenance of immune homeostasis since they are predominantly found at internal/external interfaces such as the gut. IELs may also act as antigen-presenting cells (APCs) [63].

IELs can also be characterized by their cell surface expression of alpha E beta 7 integrin, which is involved in homing and adhesion [64]. IELs predominantly produced T helper type 1 (Th1) cytokines (eg, interferon [IFN] gamma, interleukin [IL] 12) in the activated state in mice [65]. They can also produce T helper type 2 (Th2) cytokines (eg, IL-4, IL-5) and antiinflammatory/regulatory cytokines such as IL-10 and transforming growth factor (TGF) beta. Galectin 9, a lectin with known immunomodulatory effects, in particular on eosinophils, has been found upregulated on IELs from patients with food allergy and might contribute to the sustained sensitization to foods [66].

Lamina propria lymphocytes — Lamina propria lymphocytes (LPLs) are thought to be memory T cells. They are exposed to soluble antigens crossing the epithelial barrier of the gut. Once activated, they migrate to gut-associated lymphoid structures, such as mesenteric lymph nodes. In these nodes, they regulate other lymphoid and nonlymphoid cells involved in the immune response. One of their primary functions is inducing terminal differentiation of B cells into IgA-secreting plasma cells [67]. They also promote differentiation of intestinal epithelial cells [68].

Characterization of LPLs has shown that the ratio of CD4+ to CD8+ cells (65 percent and 35 percent, respectively) is similar to T cell populations in other lymphoid structures and to circulating T cells [69]. Furthermore, a majority of LPLs have an alpha-beta T cell receptor. In mice, LPLs produce both Th1 and Th2 cytokines (eg, IFN-gamma and IL-4, respectively), but the Th2 phenotype predominates in humans [70-72].

Peyer's patches T cells — Peyer's patches T cells recirculate to other lymphoid structures of the gut and are therefore considered central to orchestrating tolerant/allergic immune responses [73,74]. T cells found in Peyer's patches have similar characteristics to LPLs and circulating T cells but also have unique features. Peyer's patches T cells secrete tolerogenic cytokines such as IL-10 and TGF-beta upon exposure to common food allergens in a mouse model [75].

Peripheral T cells — Circulating T cells are the most studied cell population in the pathogenesis of food allergy. However, only a small fraction of circulating T cells is definitively involved in the regulation of the immune response to foods.

Food allergen-specific memory T cells are found both in individuals tolerant or allergic to foods [76]. Thus, antigen-activated lymphocyte proliferation tests of circulating T cells have low specificity and are not generally used in the diagnosis of food allergy [77-79]. However, cytokine profiles of peanut-specific lymphocytes differ between peanut-allergic patients and those who are nonallergic or have outgrown their allergy [80,81]. Lymphocytes from peanut-allergic children show a Th2 cytokine profile (low IFN-gamma and tumor necrosis factor [TNF] alpha and high IL-4, IL-5, and IL-13). The reverse, Th1-skewed cytokine profile is seen in children without peanut allergy (nonallergic or resolved allergy).

Effector T cells — Activated T cells are phenotypically polarized in relation to their specific cytokine production profile. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)

●Th1 T cells secrete mostly IFN-gamma and are classically involved in the response to intracellular microbes. The role of the Th1 response in the prevention of allergy has been debated [82]. Several studies have shown that T cells from individuals with food allergies also secrete IFN-gamma after antigen-specific activation [83].

●Th2 T cells are classically linked to an allergic response. These cells secrete IL-4 and IL-13, two cytokines known to facilitate IgE production. In addition, Th2 cells also secrete cytokine IL-5, which activates eosinophils.

●In addition to the classically described Th1 and Th2 cells in allergic inflammation, IL-17-secreting Th17 cells have been described [84]. IL-17 and IL-23 secreted by these cells contribute to various inflammatory phenomena in the gut, and increasing evidence links them to hypersensitivity reaction to food allergens.

●Various populations of T cells involved in tolerance have been characterized [2,3,85-88]. These regulatory T cells (Tregs) include T helper type 3 (Th3), type 1 regulatory T cells (Tr1), and CD4+CD25+ cells. Th3 cells secrete primarily TGF-beta, and Tr1 cells produce IL-10. TGF-beta and IL-10 are both major cytokines that promote oral tolerance. CD4+CD25+ Tregs express Foxp3, a transcription factor that is thought to suppress Th1 and Th2 polarization.

CD4+CD25+ Tregs from cord blood in children who develop hen's egg allergy in the first year of life are normal in number but have impaired suppression of IFN-gamma production and effector T cell responses [89]. Functional milk-specific suppressive Foxp3+CD4+CD25+ Tregs are found in higher numbers in children with cow's milk allergy (CMA) who are tolerant to heated milk than in children allergic to all forms of milk or nonallergic controls [90]. CD25+ milk-specific T cell clones from children with a history of CMA who are now tolerant produce higher levels of IL-10 and, to a lesser extent, IFN-gamma compared with milk-specific T cell clones from children with persistent CMA [91]. Supporting the role of IL-10 producing Treg cells in food allergy, a single nucleotide polymorphism (SNP) in the IL-10 gene is associated with an increased risk of food allergy in atopic Japanese children [92].

Cytokine mediators — Cytokines secreted by antigen-specific T cells or other immune cells provide key stimuli for the development of tolerance or allergy.

●Oral tolerance is characterized by the secretion of IL-10 and TGF-beta by T lymphocytes. IL-10 is a regulatory cytokine that favors T cell anergy and also activates antigen-specific secretory IgA antibody production [93]. TGF-beta has an immunosuppressive effect on B and T cells, maintaining immune nonresponsiveness to commensal bacterial and food antigens. It is also a switch factor for secretory IgA production [73].

●Th2 cytokines, IL-4 and IL-13, induce the production of antigen-specific IgE antibodies.

●IL-5 provides a signal for eosinophil maturation and migration.

●IL-12 favors a Th1 response, which is characterized by IFN-gamma secretion [94]. IFN-gamma is believed to be an allergy protective cytokine, although it has been shown in several studies that cells activated by food antigen produce IFN-gamma [83,95].

●IL-25 favors sensitization to foods. Increased IL-25 is observed in animal models of food allergy, and transgenic mice lacking expression of the IL-25 receptor are resistant to sensitization to foods [96,97].

●IL-33 is an additional Th2-inducing cytokine. It is upregulated on human skin keratinocytes after exposure to peanut antigen and drives a Th2-type response [20]. In an experimental mouse model, IL-4 production by IL-33 activated innate lymphoid cells inhibits allergen-specific Treg cells and favors food allergy [98].

●Thymic stromal lymphopoietin (TSLP) can promote sensitization to food antigens, and TSLP-receptor negative mice are less prone to develop food allergy [99].

Homing receptors — T cells exhibit specific surface receptors that link them to particular organs. Patients who have food-induced atopic dermatitis have increased expression of cutaneous lymphocyte antigen (CLA) on allergen-specific T cells [100]. Similarly, patients with IgE-mediated food allergy show increased expression of alpha 4 beta 7 integrin on the surface of their T cells [101]. These surface receptors are activated during the initial sensitization phase and redirect effector T cells to specific target organs that exhibit the clinical response.

INNATE IMMUNITY — Innate immunity is increasingly cited for contributing to the pathogenesis of allergy [102]. In particular, innate lymphoid cells type 2 (ILC2) are a group of innate immune cells that produce T helper type 2 (Th2) cytokines [103]. In a mouse model of food allergy, ILC2 cells contributed to interleukin (IL) 13-dependent eosinophilic inflammation [104]. ILC2 also increase the sensitivity to mast cell mediators released during food-induced anaphylaxis [105].

OTHER EFFECTOR CELLS — Other effector cells involved in the pathogenesis of food allergy include eosinophils and mast cells. Natural killer (NK) T cells may also be involved in oral tolerance induction [106,107].

Eosinophils — Eosinophils are found mainly in peripheral organs. Their maturation is strongly induced by interleukin (IL) 5. Eosinophils are clearly linked to the classic manifestations of IgE-mediated allergy, including allergic rhinitis and asthma. Several studies have also shown that eosinophils present in large numbers in parts of the gut are linked to clinical manifestations of food allergy (eg, eosinophilic esophagitis) [25]. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

Mast cells — Mast cells are present in most organs. They play a major role as effector cells in IgE-mediated food allergy. Food-specific IgE antibodies bound to Fc (fragment, crystallizable) epsilon receptors on mast cells initiate degranulation upon activation by food antigen. Vasoactive amines are released, resulting in the common clinical reactions of food allergy. Measurement of mast cell mediators, such as tryptase, can be helpful in the diagnosis of food-related anaphylaxis. In addition, adoptive transfer of regulatory T cells (Tregs) was shown to inhibit mast cell-dependent anaphylaxis in a mouse model of food allergy [108].

FACTORS INFLUENCING SENSITIZATION OR TOLERANCE — Several factors related to the antigen or host influence whether an individual becomes sensitized or tolerized to a food antigen [109].

Antigen dose — Mouse models show that tolerance is mediated through different mechanisms, depending upon the antigen dose [2]. A low dose of antigen leads to induction of regulatory T cells (Tregs), including suppressor CD8+ cells, T helper type 3 cells (Th3), type 1 regulatory T cells (Tr1), and CD4+CD25+ cells [110-112]. The last three cell types are thought to induce tolerance through the secretion of suppressive cytokines, interleukin (IL) 10 and transforming growth factor (TGF) beta. A high antigen dose induces oral tolerance through lymphocyte anergy or deletion (figure 3) [113,114].

Antigen form — Exposure to soluble antigen is more likely to result in tolerance, while exposure to particulate antigen is more likely to lead to sensitization [115,116]. Processing of foods can affect allergenicity [117]. For example:

●Roasted peanuts are more allergenic than raw peanuts. Roasted peanut proteins are less soluble and have a higher IgE-binding capacity [116].

●Cooked hen's egg is less allergenic than raw or incompletely cooked egg. Most patients with hen's egg allergy tolerate egg in cooked form, particularly baked or extensively heated egg [118]. (See "Egg allergy: Clinical features and diagnosis", section on 'Pathogenesis' and "Egg allergy: Management", section on 'Avoidance'.)

Timing of antigen exposure — For decades, allergy prevention guidelines emphasized that late exposure to foods helps prevent food allergy. In consequence, introduction of allergenic foods, such as peanuts, were delayed into childhood. However, an increase in the prevalence of food allergy was seen during this same time period. In addition, studies support the existence of a critical time early in infancy during which the genetically predisposed atopic infant is at higher risk for developing allergic sensitization. A protective effect has been demonstrated with early introduction of peanut in high-risk infants; similar studies with hen's egg, although suggestive, are less convincing [119-121]. In the general population, prospective birth cohorts have not supported delaying the introduction of solid foods beyond four to six months for the prevention of allergic disease [122-132] and, for cow's milk protein, suggest that an even earlier introduction with ongoing exposure may be beneficial [133-136]. The timing of allergen introduction is discussed in greater detail separately. (See "Introducing highly allergenic foods to infants and children" and "Introducing formula to infants at risk for allergic disease" and 'Prevalence' above and 'Antigen dose' above.)

Route of antigen exposure — Initial exposure to a food antigen through an extraintestinal route is more likely to lead to sensitization. This can occur through cutaneous exposure [137], especially in children with atopic dermatitis. Both food allergy and atopic dermatitis are associated with an impaired epithelial barrier [138,139]. However, regular emollient use for several months starting in early infancy, including in infants at high risk for atopic disease, was not effective in decreasing the risk of eczema (relative risk [RR] 1.03, 95% CI 0.81-1.31) and was associated with an increased risk of food allergy (RR 2.53, 95% CI 0.99-6.47) by one to three years of age [140]. Sensitization to food allergens may also occur by sensitization to homologous pollen antigens through the respiratory route. (See 'Primary sensitization' above and 'Allergen cross-reactivity' above and "Treatment of atopic dermatitis (eczema)", section on 'Skin barrier enhancement'.)

Sensitization to allergens does not appear to occur in utero [141].

T helper type 2 adjuvants — Adjuvants can increase the immunogenicity of antigens by increasing solubility, slowing antigen release, or enhancing activation of antigen-presenting cells (APCs) [142]. Postulated adjuvants that may play a role in food allergy include glycans, lectins, and chitin.

Gut and skin microbiota — The microbial environment of the gut (microbiota) provides a major stimulus to the gut immune system [28,143-145]. Specific patterns of microbiota colonization, such as colonization in large number by probiotics or greater microbial diversity, may favor tolerance, possibly through increased production of IgA and IL-10 [146-152]. Similarly, skin commensal bacteria have been recognized as significant factors imprinting the immune system [153], possibly also influencing food allergy.

Cesarean delivery is postulated to increase the risk of IgE-mediated sensitization to food allergens as a result of alterations in the gut microbiota [154,155]. Data on the impact of cesarean delivery on the rate of clinical food allergy are inconsistent, although most studies show an increased risk [154,156-159]. One study showed that treatment with probiotics during the last month of pregnancy and first six months of infancy may decrease IgE-associated allergic disease, particularly eczema, and sensitization to food allergens in children at high risk for atopic disease born by cesarean delivery [160]. However, another study found that only emergency cesarean section, not planned cesarean section with less exposure to maternal vaginal and fecal microflora, was associated with an increased risk of food allergy, suggesting that other factors not associated with early-life microbial transfer are playing a role [161].

Children with food allergy have a dysbiotic gut microbiota that fails to protect against the development of food allergy when transferred to mice. Therapy with a consortium of protective clostridial species suppresses food allergy in mice [162], suggesting that gut microbiota dysbiosis is a potential target for future treatment of food allergy if these findings are replicated in humans.

In a mouse model of induced food allergy by skin sensitization, feeding mice a high-fat diet prior to skin sensitization and subsequent gastrointestinal challenge to a food allergen was associated with development of obesity, decreased intestinal bacterial diversity, and increased food allergy susceptibility [163]. Transfer of the gut microbiome from these mice to germ-free recipient mice on a normal diet led to decreased intestinal bacterial diversity and increased food allergy susceptibility but not obesity. Translation of these observations to humans requires further study.

Skin colonization with S. aureus, a marker for more severe eczema, is also associated with sensitization to food allergens [164]. Independent of eczema severity, skin S. aureus colonization was associated with hen's egg and peanut sensitization and persistent allergy, with a weaker association seen for cow's milk, in a study that followed children from infancy to six years of age [165].

Breastfeeding — Exclusive breastfeeding for the first four to six months of life may help prevent the development of food allergies. Breast milk decreases intestinal permeability, colonizes the infant gut with probiotics, and supplies numerous cellular and secreted components that enhance immunocompetence and cell growth and repair [166]. However, exclusive breastfeeding for the first four to six months of life does not contribute to the prevention of food allergy. Breastfeeding and its relation to food allergies are discussed more extensively in several other topic reviews. (See "The impact of breastfeeding on the development of allergic disease" and "Introducing formula to infants at risk for allergic disease" and "Primary prevention of allergic disease: Maternal diet in pregnancy and lactation".)

Acid blockade — The use of acid-suppressing medication increases susceptibility to the development of food allergy [31,167]. This is thought to be related to decreased protein breakdown in the stomach due to acid suppression [168]. Food proteins therefore remain in a more intact form and thus are more allergenic.

Cyclooxygenase 2 inhibitors — Treatment of mice with the selective cyclooxygenase 2 (COX-2) inhibitor NS-398 resulted in loss of tolerance to fed proteins [169]. This loss of tolerance was associated with increased IL-4 production and defective Treg induction. Similarly, mice receiving COX-2 inhibitors simultaneously with food proteins developed pathologic changes resembling human celiac disease [170]. These experiments suggest that COX-2-dependent metabolites might be essential in establishing and/or maintaining oral tolerance to food proteins.

Age — Sensitization to food antigens is more prevalent at a young age. The immune system of the newborn and young infant is continually exposed to new antigens in the gut, either from microorganisms or food. Food sensitization may be due to a delayed maturation of protective mechanisms in the gut, including the mucus layer, gastric acid production, protease secretion, and IgA production [171,172].

Genetics — Genetic susceptibility plays a role in the development of food allergy. This has been demonstrated in mouse models by the strain-dependent variability in induction of oral tolerance or hypersensitivity [173,174].

An atopic predisposition is associated with an increased risk for food allergy. There is a significant familial aggregation of food allergy and food allergen sensitization [175]. The association is strongest among siblings: A child is over two-and-a-half times more likely to develop a food allergy if a sibling has a food allergy. Regarding inheritance of allergy to specific foods, peanut allergy is the only specific food allergy definitively associated with familial inheritance, but other foods have not been extensively studied [176-179].

SUMMARY

●Gut immune system – The gut is the largest mucosal organ of the body and is at the forefront of immune homeostasis. The gut immune system is comprised of luminal barriers, gut-associated lymphoid tissue (GALT), and lymphoid organs. (See 'Overview of components and functions' above.)

●Possible causes of increased prevalence of food allergy – While there are several theories regarding the increasing prevalence of food allergies, definitive answers are still lacking. Postulated hypotheses have focused on hygiene, dietary fat, antioxidants, vitamin D, how a food is processed, and dual allergen exposure. (See 'Prevalence' above.)

●Routes of allergen sensitization – Sensitization to a food may occur directly through the gut or skin. Alternatively, sensitization may first occur to homologous allergens through the respiratory route. (See 'Routes of allergen sensitization' above.)

●Antigen uptake and presentation – Antigens may be taken up from the gut lumen by intestinal epithelial cells, dendritic cells, or M cells. Antigens are then presented to effector cells (eg, T cells) by antigen-presenting cells (APCs; eg, dendritic cells). (See 'Antigen uptake and presentation' above.)

●Role of T cells and other effector cells – T cells are found in the epithelium, lamina propria, Peyer's patches, and peripheral blood. Their function varies depending on their cytokine profile. Other effector cells include eosinophils and mast cells. (See 'T cells' above and 'Other effector cells' above.)

●Types of food allergy – Food allergy is an abnormal immune reaction driven by a T helper type 2 (Th2) skewed response and failure of regulatory mechanisms. Food allergy may or may not involve production of food-specific immunoglobulin E (IgE). (See 'Introduction' above and 'Types of reactions' above.)

●Factors influencing sensitization or tolerance – Tolerance is the normal response to food antigens. Sensitization refers to the production of allergen-specific IgE, but it is not synonymous with being allergic to that allergen. Several factors influence whether a person becomes sensitized or tolerized to a food antigen. These factors include antigen form and dose, route of antigen exposure, microbiota, age and genetics of the host, and exposures that may affect the gut milieu, such as breastfeeding and treatment with acid-suppressing medications. (See 'Factors influencing sensitization or tolerance' above.)