The intestinal mucosa, with its extensive surface area estimated at 32 m² [1], is continuously exposed to a vast range of foreign antigens—from more than 100 g of dietary proteins ingested daily to the presence of 3 × 10 ¹3 commensal bacteria within the gastrointestinal tract [2], [3]. To maintain gut homeostasis and protect the intestinal barrier from potentially harmful immune responses to these antigens, the gut immune system has evolved complex tolerogenic mechanisms [4]. This includes local secretion of Immunoglobulin A (IgA) by plasma cells in the lamina propria and the establishment of systemic and/or local immunological tolerance to prevent adverse immune reactions to antigens encountered at mucosal surfaces. The induction and maintenance of oral tolerance involve a coordinated interplay between a functional epithelial barrier, innate immunity and the microbiota, all of which shape adaptive immune responses (Fig. 1) [5]. Failure to establish oral tolerance results in adverse gastrointestinal reactions to food including celiac disease (CeD) and food allergy, which are increasingly prevalent worldwide [6], [7], [8]. Though both CeD and food allergies share similar gastrointestinal symptoms—such as abdominal pain, diarrhea, and bloating—as well as some extra-digestive manifestations, often result in tissue remodeling, and are treated by strict food avoidance, they differ significantly in terms of triggers and underlying immune mechanisms.

CeD is a unique and complex tissue specific autoimmune-like disorder whose development is controlled by the combination of genetic and environmental factor risks. CeD develops exclusively in genetically predisposed individuals who carry the major histocompatibility complex (MHC) class II variants HLA-DQ2 or HLA-DQ8, on consumption of cereal gluten proteins consisting in a mixture of gliadins and glutenins [9], [10], [11]. Upon gluten consumption, these individuals exhibit duodenal inflammation, crypt hyperplasia, intraepithelial lymphocytes accumulation, and varying degrees of villous atrophy [12], [13], [14], [15]. In addition, the disease is characterized by the production of IgA and IgG antibodies against gluten peptides and the autoantigen transglutaminase 2 (TG2) whose enzymatic activity plays a critical role in generating immunogenic gluten peptides that drive CeD. The amino acid composition of gluten explains how this food antigen can elicit a mucosal immune response. Gluten proteins have a high content of proline that make them highly resistant to degradation by intestinal proteases in the gut lumen [16]. The undigested gluten protein fragments become good substrates for the enzyme TG2 that catalyzes the conversion of certain glutamine residues into negatively charged glutamate residues through a process called deamidation [17], [18], [19]. These deamidated gluten peptides anchor with increased affinity in the positively charged pockets of HLA-DQ2 or HLA-DQ8 that are expressed on mucosal dendritic cells (DCs) [10], [20]. The uptake and presentation of deamidated peptides to HLA-DQ2 or HLA-DQ8-restricted CD4+ T cells in the highly inflammatory environment of the gut lead to the accumulation of TH1 cells and to the formation of the inflammatory celiac lesion that precedes the development of villous atrophy [17], [18], [19], [21], [22], [23], [24]. TG2 can also form complexes with gluten peptides by transamidation promoting the delivery of gluten peptides to endosomes of antigen-presenting cells including myeloid cells and B cells. TG2-specific B cells uptake of TG2-gluten complexes leads to the presentation of deamidated gluten to cognate CD4+ T cells and results in the production of anti-TG2 antibodies and in the activation and expansion of gluten-specific CD4+ T cells [9], [25], [26], [27], [28]. Amplification of the gluten-specific T cell response to a pathogenic threshold is believed to be essential for driving the destruction of intestinal tissue in CeD. [29]. Villous blunting results from the lysis of distressed epithelial cells by activated cytotoxic CD8+ intraepithelial lymphocytes (Fig. 2) [24], [29], [30], [31], [32]. While in healthy individuals, intraepithelial lymphocytes express the inhibitory natural killer cell (NK) immunoreceptor CD94–NKG2A, the C-type lectin CD161, and low levels of the activating NK receptors NKG2D and CD94–NKG2C [33], [34], [35], intraepithelial lymphocytes from CeD patients with active disease upregulate the expression of NKG2D and CD94–NKG2C, downregulate the expression of CD94/NKG2A and display a highly cytotoxic and proinflammatory profile [31], [32], [34]. Concomitant to the induction of activating NK receptors on intraepithelial lymphocytes, the expression of MICA/B [30], [31] and HLA-E [32], which are ligands for NKG2D [36] and CD94-NKG2 NK receptors [37], [38], respectively, is upregulated in intestinal epithelial cells. Strikingly, despite a well-defined antigenic driver and a good understanding of the immune mechanisms leading to intestinal tissue damage in CeD, the only available treatment remains an enduring gluten-free diet.

Immune-mediated food allergies encompass a range of immunoglobulin E (IgE)-mediated diseases, non-IgE mediated diseases, and mixed IgE and cell-mediated disorders. Among IgE-mediated disorders are Immediate Gastrointestinal Hypersensitivity often associated with the most rapid and severe reactions after eating the offending food and that can lead to anaphylaxis as well as Oral Allergy Syndrome that causes a local reaction on the lips and mouth. Non-IgE mediated diseases include Food Protein-Induced Enterocolitis Syndrome (FPIES), Food Protein-Induced Proctocolitis (FPIAP), Food Protein Enteropathy (FPE), and Eosinophilic Esophagitis (EoE) primarily affecting the gastrointestinal tract rather than the skin and respiratory tracts and whose etiology is largely unknown. Finally, Non-esophageal Eosinophilic Gastrointestinal Disorders (EGIDs) that are caused by IgE as well as other components of the immune system belong to the so-called “mixed IgE- and non-IgE-mediated disorders” [8], [39], [40], [41], [42], [43]. Nine foods cause most reactions: milk, eggs, peanuts, tree nuts, soybeans, wheat, fish, shellfish, and sesame. Exposure to very small amounts of allergenic foods can result in allergic reactions ranging from swelling and urticaria to airway inflammation and life-threatening anaphylactic shock [8]. Family history is a strong risk factor for the development of peanut allergy as shown by concordance rates in disease outcome of 64.3 % for monozygotic twins and 6.8 % for dizygotic twins [44]. Variants in HLA-DRB1 and HLA-DQB1 are significantly associated with peanut allergy [45], [46]. Skin barrier dysfunction is predictive of food allergy and may contribute to cutaneous sensitization to food allergens in early life. This is supported by studies showing associations between eczema and the development of food allergies in children [47], epicutaneous exposure to food proteins or skin inflammation with type 2 allergic responses in animal models [48], [49], and topical application of Arachis oil on eczematous skin or household peanut exposure during infancy with the development of peanut allergy or increased allergy risk, respectively [50], [51], [52]. Mutations in genes involved in skin barrier function, such as filaggrin or SERPINB (serine protease inhibitor B) gene cluster are linked to eczema in humans [53], [54], [55], [56] and promote cutaneous inflammation and allergen penetration in animals models [57]. In addition, patients affected by the Netherton syndrome, a rare monogenic disorder caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding the serine protease inhibitor LEKT1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia, display a severe skin barrier dysfunction associated with the production of the pro-TH2 cytokine thymic stromal lymphopoietin (TSLP) and develop IgE-dependent food allergies and EoE [58], [59], [60], [61]. Conversely, early oral exposure to food allergens within the first year of life appears to protect against food allergy, highlighting the importance of exposure route in determining the balance between allergy and tolerance to specific food antigens [50].

In IgE-mediated food allergies, initial allergen sensitization results in the production of food allergens-specific IgE that bind to the high affinity IgE receptor (FcεRI) expressed on mast cells and basophils. Re-exposure to food allergen in individuals who have been previously exposed leads to the induction of a robust TH2 immune response with the production of the type 2 cytokines IL-4, IL-5, IL-9 and IL-13 [62], [63], [64]. Epithelial cells augment their secretion of epithelial alarmins including IL-25, IL-33 and TSLP, which stimulate type 2 innate lymphoid cells (ILC2s) to produce type 2 cytokines IL-4 and IL-13 [65] and endow DCs with a TH2 cell-promoting phenotype characterized by the upregulation of OX40L [66]. IL-4 promotes local antigen-specific B cell class switching to IgE and the generation of food allergen-specific IgE antibodies. IgE specific to food allergens-derived epitopes bind to FcεRI on the surface of basophils and mast cells triggering their degranulation and secretion of several cytokines, inflammatory mediators such as histamine, other vasoactive amines, and lipid mediators [67]. The TH2 cell associated cytokine IL-9 contributes to the expansion of mast cells [64] whose activation by IgE is required to amplify TH2 immune responses while preventing the induction of regulatory T cells (Treg cells) [68]. IL-33 enhances IgE-mediated mast cells degranulation [69]. This is followed by de novo production of leukotrienes, platelet activating factor and type 2 cytokines that contribute to the maintenance of the allergic reaction (Fig. 3) [67]. Interestingly, cysteinyl leukotrienes stimulate gut absorption of food allergens promoting anaphylactic response in mice [70], [71], and they are upregulated in the gut mucosa of CeD patients promoting NKGD lymphokine killer activity in cytotoxic intraepithelial lymphocytes [72].

Non-IgE-mediated manifestations are mediated by a TH2 immune response while eosinophilic gastrointestinal disorders, such as EoE, are caused by the eosinophilic infiltration of tissues [42], [43], [73]. EoE is characterized by esophageal dysfunction and dysmotility, massive esophageal eosinophilic infiltration and mastocytosis [74]. Increased intestinal permeability both in the small intestine and esophagus contributes to disease development [75], [76], [77]. Lastly, patients with EoE show elevated levels of food-specific IgE compared to controls; however, these antibodies do not appear to have a pathogenic role [74], [78]. EoE is initiated by IL-33 and TSLP released by the esophageal epithelium that promote the differentiation of TH2 cells producing type 2 cytokines including IL-4, IL-5, and IL-13 [79]. While IL-5 primarily drives mucosal esophageal eosinophilia, IL-13 contributes to eosinophil chemotaxis, goblet cell hyperplasia and induces tissue remodeling including collagen deposition and angiogenesis. Like CeD, food-allergen avoidance remains the primary standard of care for managing food allergies often supplemented with adrenaline administration to address systemic reactions associated with food allergies [80]. The likelihood of children outgrowing their food allergies varies significantly, depending on factors such as age, atopic comorbidities, and the specific type of allergen. For instance, allergies to egg, milk, wheat, and soy are more likely to resolve than those to peanuts, tree nuts, fish, and shellfish [81], [82], [83].

Although both CeD and food allergy have a strong hereditability pattern predisposing to disease development, genetic risk factors alone are unlikely to explain the recent increase in prevalence. It is now widely recognized that environmental factors and changes in dietary habits contribute to disease development by triggering inflammation and undermining tolerance to food antigens [5]. In this review, we explore the gut mucosal immune mechanisms that maintain homeostasis and prevent immune responses to dietary antigens, as well as the processes involved in breaking this tolerance.