According to the different causes, food allergy can generally be divided into two broad categories: immunoglobulin (Ig) E-mediated food allergy and non-IgE-mediated food allergy. In most cases, the immune mechanism of allergic reactions involves an adaptive T helper 2 (Th2)-type response, which subsequently leads to the production of allergens-specific IgE antibodies. The mechanisms of food allergic reaction are shown in Figure 1. The chain of events that occurs in an allergic reaction begins when the allergens are presented to the gastrointestinal immune system, resulting in the production of specific IgE antibodies and damage to the intestinal epithelium. When food allergens pass through the intestinal epithelium again, their infiltration is enhanced. Cytokines such as thymic stromal lymphopoietin, interleukin (IL)-25, and IL-33, which are generated by intestinal epithelial cells, induce OX40L expression in CD103⁺ dendritic cells (DCs) after injury, infection, and immunoactivation, which is beneficial for Th2 cells differentiation. In response, activated Th2 cells release cytokines, including IL-4, IL-5, and IL-13, thus promoting the immunoglobulin class switch of B cells and differentiating into IgE-secreting plasma cells ^[1][8].

Through the intestinal epithelium of allergic patients, food allergens are exposed to immune cells mainly located in the mucosa and blood vessels, such as mast cells and basophils, and bind to IgE and its high-affinity immunoglobulin gamma Fc receptor (FcεRI). These interactions lead to the activation of effector T cells and differentiation into Th0 cells, which are stimulated by IL-4 secreted by DCs and further differentiate into Th2 cells. On the surface of mast cells, FcεRI cross-linking triggers a signaling cascade starting from the tyrosine-protein kinase SYK and induces the extracellular secretion of hypersensitive mediators containing histamine, trypsin, and chymosin. These small molecules can induce physiological allergic reactions such as vascular dilatation, increased vascular permeability, pruritus, and synovial contraction, which manifest in the gastrointestinal tract as vascular edema, intestinal congestion, increased intestinal contractility and mucus secretion, acute diarrhea, etc. The factors that result in a deviation in the immune response may include symbiotic microbiota, intestinal epithelial damage, and allergens exposure in other body parts, especially the skin. For instance, many of the receptors that are reported to activate pathogen-associated molecular patterns (PAMPs), including Toll-like receptor 2 (TLR2), TLR5, TLR7, and TLR8, enhance the capacity of DCs to activate Th2 cells ^[2][9].

Despite high exposure to food allergens, only a few people experience adverse immunological reactions. The body’s immune failure to respond to food allergens is called immune tolerance. In general, oral tolerance is mainly mediated by CD103⁺ DC_S, which can present allergens to primary T cells and induce Treg cells to differentiate and proliferate. Meanwhile, CD103⁺DCs can secrete IL-5 and IL-6 to promote the differentiation of B cells into IgA-producing plasma cells ^[3][10]. Notably, IgA enhances the barrier function of the intestinal mucosa and maintains the body’s tolerance.

2. Effect of Intestinal Microbiota on Mucosal Immune System

The intestinal mucosal barrier comprises the mucous layer, gut microbiota, and intestinal immune system, and is affected by the integrity of intestinal epithelial cells. The interaction between the intestinal microbiota and the gut barrier maintains relative stability. Notably, the intestinal microbiota establishes the gut immune response and natural defense system, with the latter playing an important role in maintaining the dynamic balance of the gut immune system. Previous studies have confirmed that the microbiota and its community structure affect human health and disease by acting on mucosal barriers. Jakobsson et al. (2015) found that the number of mucus-secreting goblet cells in the cecum of germ-free mice was significantly lower than that of normal mice, and the mucus layer was more unstable ^[4][15]. Subsequent studies showed that germ-free mice have abnormal gut morphology and structure, such as decreased total gut area, shortened ileum villi, and a decrease in the number of gut crypts, due to the lack of gut microbiota ^[5][16]. Additionally, intestinal microbiota can affect the expression levels of microRNAs in intestinal epithelial cells; however, the relevant mechanism remains unclear. Under normal physiological conditions, the intestinal microbiota promotes the development of the host immune system through specific components such as lipopolysaccharides (LPS), lipoproteins, and metabolites, which form a biological gut barrier ^[6][17]. Lactobacillus acidophilus mainly parasitizes the gastrointestinal tract of animals, adheres to intestinal epithelial cells, and forms a biological barrier on their surface. Moreover, it reduces the pH of the gut cavity by secreting lactic acid, acetic acid, propionic acid, and other metabolites to prevent the adhesion and reproduction of pathogenic bacteria. Additionally, sodium butyrate (a gut microbial derivative) significantly improved epithelial barrier function of the HT29-MTX-E12 human colonic cell line by increasing mucin 2 (MUC2) levels at concentrations of 1–10 mM. However, sodium butyrate has no positive effect on MUC2 expression at 50–100 mM, probably due to the induction of apoptosis by higher sodium butyrate concentrations ^[7][18]. Importantly, ingestion of a butyrate-rich diet increased the expression levels of MUC2 and occludin in the colon, confirming that butyrate facilitates intestinal barrier function ^[8][19]. Treatment with butyrate also results in the down-regulation of IL-1β levels, further suggesting that it may help protect against inflammation-induced intestinal barrier damage ^[9][20]. Tryptophan metabolites of the intestinal microbiota activate the transcription factor aromatic hydrocarbon receptor (AHR), which promotes immune-cell maturation, and inhibits pathogen colonization in the intestinal tract through IL-22 ^[10][21]. The synthesis of AHR ligands oragonists or dietary supplementation of bacterial strains enhances gut barrier function by inducing the secretion of incretin and glucagon-like peptide-1. Certain specialized structures in the gut microbes, such as flagella, pili, and capsules, are often used as antigens to induce an immune response. For example, stimulation of intestinal epithelial cells with salmonella flagellin triggers upregulation of CCL20 expression and chemotaxis of immature DCs ^[11][22]. Therefore, the intestinal microbiota substantially affects the intestinal mucosal immune system.

3. Influence of Dietary Intakes on Intestinal Microbiota Composition

There is a high-fat diet (HFD) alters the composition of the intestinal microbiota. For example, HFD-fed mice showed increased abundances of Firmicutes, Proteobacteria and Actinobacteria, while decreased abundances of Bacteroidetes phylum, Bifidobacterium, and Akkermansia genera compared to normal mice ^[12][23]. Meanwhile, HFD consumption in humans resulted in increased abundances of Blautia, Alistipes, Bilophila, several genera of the group Gammaproteobacteria, and decreased abundances of Roseburia, Clostridium, and Bacteroidess spp. ^[13][24]. Interestingly, gender also influenced the changes in the microbiota after HFD intake with higher abundances of Campylobacter, Blautia, Flavonifractor and Erysipelatoclostridium, while the abundances of Anaerotruncus, Eisenbergiella, Clostridiales (FamilyXIIIUCG_001) and Lachnospiraceae were higher in males ^[14][25]. Protein is a necessary ingredient in dietary and plays an important role in maintaining host health. It is worth noting that a large number of studies have confirmed that dietary protein intake also regulated the diversity of intestinal microbiota, and there are close relationships between different dietary protein sources and intestinal microbiota profiles. As for plant proteins intake, the abundances of Bifidobacterium and Lactobacillus increased; However, with the intake of animal protein, the abundances of Bifdobacterium, Roseburia, and Eubacterium rectale decreased, and the levels of Bacteroides, Bilophila, and Alistipes markedly increased ^[15][26]. Among them, Roseburia spp. is the most important and abundant bacteria that are involved in butyrate production in the intestine; Bifidobacterium is commonly found in infants’ intestine and increases in these bacteria have been suggested to relieve symptoms of IgE or Th2 allergy ^[16][27]. Similarly, animal protein-based diets have been documented to result in increased relative abundances of Enterococcus, Streptococcus, Turicibater, Escherichia, Peptostreptococcaceae, as well as Ruminococcaceaea in mice; in contrast, plant proteins-based diets enriched Bifidobacteriaceae, Desulfovibrionaceae, and Coriobacteriaceae families in mice. Notably, diets based on both animal and plant proteins showed increased abundances of lactobacilli, Lachnospiraceae, and Erysipelotrichaceae ^[17][28]. Intake of a fiber-rich diet increased the abundances of Bifidobacterium, Prevotellaceae, and Lachnospiraceae in mice, while decreasing the abundances of Porphyromonadaceae and Lactobacilli ^[18][29]. Vitamins also have the potential to modulate the intestinal microbiota. 

4. Relationship between the Intestinal Microbiota and Food Allergy

4.1. Changes in the Intestinal Microbiota in Patients with Food Allergy

Growing evidence suggests that gut dysbiosis, an imbalance in the intestinal microbiota, plays a decisive role in the development of food allergy. Briefly, the intestinal microbiota composition of people with food allergy differs significantly from that of healthy people, and these differences are more evident in infants and children (Table 1).

Allergens Involved	Study Population	Age	Changes of Gut Microbiota in Food Allergy	Reference
Milk, eggs, wheat, nut, peanuts, fish, shrimp, soybeans	166 infants	0 to 1 year	↑	Enterobacteriaceae/Bacteroidaceae ratio	↓	Ruminococcaceae	[19]	[36]
Milk, eggs, wheat, nut, peanuts, fish, shrimp, soybeans	49 healthy infants 38 infants with food allergy	1 week to 12 months of age	↑	Bifidobacterium	spp. —	Lactobacillus	spp. and	Clostridium perfringens	[20]	[37]
Milk, eggs, wheat, nut, peanuts, fish, shrimp, soybean	34 infants with food allergy 45 healthy controls	2 to 11 years	↑	Firmicutes and Fusobacteria	↓	Bacteroidetes, Proteobacteria and Actinobacteria	↑	Clostridium sensustricto	and	Anaerobacter	↓	Bacteroides	and	Clostridium XVIII	[21]	[38]
Egg white, cow’s milk, wheat, peanut, soybean, gluten	23 children with food allergy 22 healthy children	6 to 24 months	↑	Sphingomonas, Sutterella, Bifidobacterium	,	Collinsella	,	Clostridium sensustricto	,	Clostridium IV	,	Enterococcus, Lactobacillus	,	Roseburia	,	Faecalibacterium, Ruminococcus	,	Subdoligranulum,	and	Akkermansia	, ↓	Bacteroides	,	Parabacteroides	,	Prevotella	,	Alistipes	,	Streptococcus,	and	Veillonella	[22]	[39]
Egg, soybean, sesame, milk, shrimp, crab, peanut, wheat	4 children with food allergy 4 healthy children	18 months to 6 years	↓	Dorea	and	Akkermansia	↑	Lachnospira	,	Veillonella, and Sutterella	[23]	[40]
Egg	141 children with egg allergy	3 to 16 months	Lachnospiraceae	,	Streptococcaceae	, and	Leuconostocaceae	families were differentially abundant in children with egg allergy	[24]	[42]
Cow milk	226 children with milk allergy	3 to 16 months	Clostridia	and	Firmicutes	could be studied as probiotic candidates for milk allergy therapy	[25]	[43]
Peanuts, tree nuts, shellfish	1879 participants was 81.5%, ranging from 2.5% for peanuts to 40.5% for seasonal.	mean age, 45.5 years; 46.9% male	higher	Bacteroidales	and reduced	Clostridiales	taxa in nut and seasonal allergies	[26]	[44]
Egg, crab, shrimp	256 children with food allergy	4 to 12 years	Bifidobacterium lactis	can effectively alleviate allergic reactions on food-specific IgE of food in children	[27]	[45]

In summary, these findings suggest that the intestinal microbiota is critical for modulating food allergy and suggest that regulating the microbiota community composition may be therapeutically relevant for food allergy. So far, research on the characteristics of the intestinal microbiota in patients with food allergy is still in its infancy, and no specific bacterial taxa has been identified that may be associated with the occurrence of food allergy. Additionally, the main limitation of all these studies is that the number of patients with sensitization or food allergy is small, such that statistical analyses of the effects of potential confounding variables, such as delivery modes, breastfeeding, diet, antibiotic intake, and pets, have not been possible. In addition, several studies have focused on sensitization to food rather than evaluating people with a history of allergic reactions to food or a confirmatory food challenge coupled with skin and/or serum IgE food-specific testing. 

4.2. Relationship between Intestinal Microbial Metabolites and Food Allergy

The intestinal microbiota is involved in developing and regulating host physiology and immunity by directly participating in the decomposition of dietary components to synthesize and re-synthesize metabolites. Dietary fiber, composed of indigestible carbohydrates extracted from plant polysaccharides and oligosaccharides, is the main source of nutrients for intestinal bacteria, and their fermentation leads to the production of SCFAs (mainly acetic, butyric, and propionic acid). SCFAs are key intermediaries regulating mucosal and systemic immune homeostasis. Intestinal IgA, regulated by the intestinal microbiota, also plays an important role in maintaining intestinal homeostasis and normal function. The SCFAs metabolite, acetate, has been proved to promote intestinal IgA responses mediated by the “metabolite-sensing” receptor, GPR43 ^[28][47]. Treatment of mice with the SCFA, propionate, resulted in bone marrow hematopoietic alterations characterized by enhanced generation of macrophages and DC precursors via GPR41, which inhibits Th2 effector cells, thus alleviating allergic inflammation ^[29][48]. Moreover, GPR109a is required for butyrate-mediated Treg cells induction and IL-18 in the formation of immune tolerance to food allergens ^[30][49].

Emerging evidence has shown that microbiota-derived tryptophan and bile-acid metabolites also play vital roles in food allergy. Tryptophan is an essential amino acid that is degraded to serotonin, kynurenine, or indole in the gut. Supplementation of D-tryptophan produced by Bifidobacterium and Lactobacillus has been shown to inhibit allergic inflammation in the lungs by increasing intestinal microbial diversity and promoting Treg cell production ^[31][55]. 

4.3. Potential Mechanisms of Intestinal Microbiota in Regulating Food Allergy

Although the occurrence of food allergy is related to the composition of the intestinal microbiota, the exact mechanism is not clear. In this section, we Tdescribe in detail the possible mechanisms by which the intestinal microbiota modulates food allergy are described in detail (Figure 2): (1) regulation of allergen uptake and (2) regulation of signaling molecules involved in immune responses.