Shimin Gu, Dong Yng, Chenglong Liu, Wentong Xue,*

a College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China

b Beijing Key Laboratory of Functional Food from Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China

Keywords:Probiotics Food allergy Intestinal mucosal immune system Gut microbiota

A B S T R A C T With the prevalence of food allergy increasing every year, food allergy has become a common public health problem. More and more studies have shown that probiotics can intervene in food allergy based on the intestinal mucosal immune system. Probiotics and their metabolites can interact with immune cells and gut microbiota to alleviate food allergy. This review outlines the relationship between the intestinal mucosal immune system and food allergy. This review also presents the clinical application and potential immunomodulation mechanisms of probiotics on food allergy. We aim at providing a reference for further studies to explore the key active substances and immunomodulation mechanisms of anti-allergic probiotics.

1. Introduction

Food allergy is def ined as an adverse reaction caused by specif ic immune mechanisms due to exposure to specif ic food ingredients [1].There is a global increase in the prevalence of food allergy [2]. At present, there are many methods to treat food allergy but most of them have shortcomings. For example, it is difficult to implement strict dietary avoidance therapy in practice, and oral tolerance often recurs after stopping the treatment [3]. Therefore, new therapeutic approaches to food allergy need to be proposed [4,5].

Probiotics are living microorganisms that can regulate the host’s immune system and benef it the host when suff iciently administrated [6].The main functions of probiotics are to maintain the balance of gut microbiota and regulate the immune system, which can alleviate inf lammation and alleviate chronic diseases [7-9]. Increasing studies have shown that the number and species of gut microbiota can intervene in food allergy. Therefore, more and more attention has been paid to the effects of probiotics on food allergy [10,11]. Here we will discuss the relationship between the intestinal mucosal immune system and food allergy. We will also review recent research progress in the clinical applications and potential mechanisms of probiotics on food allergy.

2. Epidemiology on food allergy

Food allergy can cause changes in target organs such as the skin, respiratory tract, gastrointestinal tract and cardiovascular system after intaking a certain kind of food. The main symptoms are atopic diseases, asthma, diarrhea and so on [12]. Food allergy can be classified into IgE-mediated, non-IgE-mediated and mixed IgEmediated and non-IgE-mediated. IgE-mediated food allergy is more common in clinical practice [12].

In recent years, the prevalence of food allergy has increased rapidly,and food allergy has become a serious public health problem [2].About 3.5% to 4% of Americans are affected by IgE-mediated food allergy [13]. The prevalence is higher in children compared to adults,with up to 8% of American children suffering from food allergy.Children with atopic diseases are at a higher risk of food allergy [14].About 35% of children with moderate to severe atopic dermatitis suffer from IgE-mediated food allergy [15]. According to the National Institute of Allergy and Infectious Diseases (NIAID), peanuts, nuts,seafood, milk and eggs were the most common food allergens. It also pointed out that the prevalence of peanut allergy in the United States was about 0.6%, and in Denmark, about 2.2% of the population were allergic to milk, of which 54% were IgE-mediated food allergy while 46% were non-IgE-mediated food allergy [16].

The prevalence and severity of food allergy are affected by many factors, such as gender, race, family inheritance and atopic diseases [17-20]. Hong et al. [21] found that the specific loci of peanut allergy were in theHLA-DRandHLA-DQgene regions.A study conducted by the Consortium for Food Allergy Research(CoFAR) found that infants with severe atopic dermatitis had a higher risk of peanut allergy [22]. The occurrence of food allergy is regulated by many factors so there are some differences in the epidemiological data of food allergy.

3. Intestinal mucosal immune system and food allergy

The mucosal system is the frontline defense in the host’s immune system. Most food allergens enter the human body through the mucosal system, among which the intestinal mucosal system is the most closely related to food allergy. The intestinal mucosal system can induce immune tolerance and prevent food allergy with the help of gut associated lymphoid tissue (GALT) and various lymphocytes [23].In addition, the diversity and abundance of gut microbiota can also intervene in the host’s immune system to inhibit food allergy [10,11].

3.1 Regulation of intestinal mucosal immune system on oral tolerance and food allergy

The gastrointestinal tract is the largest immune organ in human bodies, which is exposed to a large number of microorganisms and food proteins daily. Oral tolerance can be induced due to the presence of various immune cells and tissues in the intestinal mucosal system [24].Intestinal epithelial cells (IECs) are tightly connected to form the intestinal mucosal barrier [25]. In addition, various secretory cells are distributed among IECs, such as goblet cells. They can secrete mucin, which not only protects IECs, but also effectively prevents food antigens from passing through the intestinal mucosa [26-28].Dendritic cells (DCs) and macrophages in lamina propria play an important role in antigen-presenting. Specific antigen-presenting cells interact with antigens to help activate regulatory T (Treg) cells, which can promote immune tolerance and inhibit food allergy [24-29]. A subset of CD103+DCs is vital for immune tolerance. It can not only convert vitamin A into retinoic acid (RA), which helps induce the expression of T cells’ gut-homing moleculesin vitro, but also promote the differentiation of CD4+T cells into Treg cells via RA [30-31]. In addition, there are a large number of lymphoid tissues in GALT, such as the Peyer’s patches (PPs), lymphoid follicles and mesenteric lymph nodes (MLNs), among which MLNs and DCs may be the cores of inducing oral tolerance, while PPs may play an auxiliary role [32].Oral tolerance could still be induced in mice with excised intestinal segments of PPs, suggesting that the uptake of antigen by PPs played a secondary role in the induction of oral tolerance. Oral tolerance could be restored by developing MLNs in mice lacking all lymph nodes and PPs [33].

For IgE-mediated food allergy, oral tolerance and intestinal epithelial barrier are often destroyed. A part of antigens may be taken up by microfold cells in the lamina propria and transported to downstream DCs. These DCs migrate to GALT and deliver antigens to T cells [34]. Some antigens may also cross through IECs by diffusion or transcellular transportation [23]. CX3CR1highcells may also directly take up antigens through IECs and present them to DCs in the lamina propria, thus promoting the differentiation of Th0 cells into Th2 cells [35]. Th2 cells secrete cytokines such as interleukin (IL)-4, IL-5 and IL-13, which promote B lymphocytes to transform into plasma cells and produce antibody IgE. IgE binds to the FcεRI receptor on the basophils and mast cells to sensitize the host [36]. When exposed to the same food antigen again, IgE bound to basophils and mast cells will quickly bind with antigens, resulting in degranulation. Histamine,leukotrienes, IL-4, IL-5 and other substances will be released and act on the skin, gastrointestinal tract and respiratory system, causing local or systemic allergic reactions in a short time [37].

For non-IgE-mediated food allergy, the main symptoms are comprehensive gastrointestinal diseases, such as proctocolitis, allergic eosinophilic gastroenteritis, food protein-induced enterocolitis(FPIES) and so on. Patients often suffer from different degrees of vomiting and diarrhea, which is different from the systemic symptoms caused by IgE-mediated food allergy [38]. T cell responses were in favor of Th2 in patients with non-IgE-mediated milk allergy. The levels of Th2-related cytokines, such as IL-3, IL-5 and IL-13 were significantly increased, but no IgE was detected in patients [39]. In addition,emerging studies speculate that transforming growth factor β (TGF-β)may be a biomarker of FPIES [40]. It was found that the expression of type 1 TGF-β receptor was significantly lower than that of type 2 TGF-β receptor in the duodenum of infants with FPIES. Different receptors had different effects on TGF-β, which could affect the protection of TGF-β on the intestinal epithelial barrier. It was also found that both the expression of tumor necrosis factor α (TNF-α) in the intestinal lamina propria and the permeability of intestine were significantly increased, speculating that food allergens could stimulate the activation of T cells and release TNF-α, which would mediate local intestinal inflammation [41]. In addition, under the stimulation of casein, the expression of TGF in patients with FPIES was insufficient and the expression of casein-specific IgA was inhibited,resulting in the entrance of antigens in the intestinal mucosa [40].At present, there are few studies on the relationship between non-IgE-mediated food allergy and intestinal mucosal system, so further studies are needed urgently.

3.2 Regulation of gut microbiota on food allergy

There may be a potential relationship between the disorder of gut microbiota and food allergy [42]. The diversity and abundance of gut microbiota and its metabolites play an important role in immunomodulation [10,11]. There are significant differences in the gut microbiota between allergic people and healthy people [43].The abundance of Clostridia and Firmicutes was related to infants with milk allergy [44]. Mice susceptible to food allergy (Il4raF709)also showed distinct microbial characteristics. The abundance of Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Porphyromonadaceae were significantly different from the control group [45]. Further studies transferred the gut microbiota from infants with milk-allergy and healthy infants to susceptible Il4raF709mice respectively. It was found that mice receiving gut microbiota from healthy infants developed immune tolerance, which was hypothesized to be associated with Clostridiales [46]. In addition, the diversity of gut microbiota can also affect food allergy. Germ-free mice and mice with low diversity of gut microbiota spontaneously produced high levels of IgE in their early lives, but their allergic responses would improve if the intestine was colonized with various microorganisms later [47]. These results indicate that maintaining the balance of gut microbiota plays an important role in preventing food allergy.

There are two ways for gut microbiota to intervene in food allergy.On the one hand, the gut microbiota can directly affect IECs. Some studies have found that the gut microbiota can interact with DCs and macrophages to induce them producing IL-22 and strengthen the tight junction between IECs. At the same time, the metabolites produced by the gut microbiota, such as short-chain fatty acids (SCFAs), can also provide energy for the repair and proliferation of IECs [48,49].On the other hand, the gut microbiota can regulate the differentiation of T cells to maintain the balance of Th1/Th2 and Treg/Th17,thus regulating the host’s immune system [50]. Both newborn infants and young germ-free mice show Th2 immune bias, which indicates that appropriate colonization of the gut microbiota is the key to inducing immune tolerance [50,51]. Some strains ofClostridiumfrom human microbiota could enhance the expression of Treg cells and alleviate the symptoms of colitis and allergic diarrhea in mice [52].Atarashi et al. [53] also found that Gram-positive bacteria and spore-forming microorganisms played an important role in inducing colonic Treg cells in mice, andClostridiumwas the most prominent characteristic bacterium inherent in gastrointestinal tract in mice.Then the studyconfirmedthatClostridiumcould significantly increase Treg cells in the colonic lamina propria.

4. Overview of probiotics

Probiotics are living microorganisms that can regulate the host’s immune system and benefit the host, when sufficiently administrated [6].The intake of probiotics may theoretically be the most direct way to improve the gut microbiota in hosts [43]. At present, emerging studies have demonstrated that probiotics such asBifidobacteriumandLactobacillusplay an important role in relieving the symptoms of food allergy. Probiotics can maintain the balance of gut microbiota by colonizing in the human intestine and producing metabolites such as SCFAs to maintain the stability of intestinal environment, thereby preventing food allergy [25,54].

Table 1 Summary of clinical application of probiotics in the prevention and treatment of food allergy.

As shown in Table 1,LactobacillusandBifidobacteriumare the most commonly used for preventing food allergy in clinical practice. Different treatment time of probiotics for pregnant women and newborns has different intervention effects. The intervention of probiotics during pregnancy could effectively reduce the risk of eczema in infants. Prenatal probiotics administration may change the composition of vaginal and gut microbiota of pregnant women, and then affect the colonization of the neonatal gut microbiota [57,64]. In addition, continued administration of probiotics during breastfeeding may play a better role based on the prenatal intervention [57,65].

There is still a controversy about whether probiotics can be used to treat and prevent food allergy because the differences in probiotic strains and the duration of administration will affect the clinical application [66]. To this end, the World Allergy Organization (WAO)proposed guidelines on probiotics for the prevention of allergic diseases based on the principle of GRADE in 2015: although the supplementation of probiotics had not been shown to reduce the risk of allergic reactions in children based on the current evidence, probiotics were still recommended to be used in pregnant women whose fetuses with a high risk of allergy. Probiotics were recommended to be used in mothers whose infants were prone to allergy and mothers were also suggested to take breastfeeding. Probiotics were recommended to be used in infants who were prone to allergy [67]. The guidelines emphasized that all recommendations were conditional, and due to the great differences between current studies on probiotics, it was difficult to translate these recommendations into practice advice on specific strains, optimal dose, duration of administration [67].

5. Potential mechanisms of probiotics on food allergy

The regulation of probiotics on food allergy is mainly based on the intestinal mucosal immune system. Probiotics and their metabolites can control the balance between immune tolerance and food allergy,as well as anti-inflammatory and pro-inflammatory reactions through the interaction with innate and adaptive immune cells and the gut microbiota [68].

5.1 Regulation of probiotics on DCs

There are a large number of DCs in the intestinal lamina propria,which are mainly divided into two types: CD103+CX3CR1-DCs and CD103-CX3CR1+DCs. CD103+CX3CR1-DCs are always considered to mediate immune tolerance [29]. CD103 molecules can bind to E-cadherin proteins of IECs and mediate lymphocyte homing. They can also produce RA. Foxp3+Treg cells can be produced mediated by TGF-β and RA, which plays an important role in immunomodulation [31,69].

Probiotics can alleviate food allergy by regulating CD103+DCs [25]. It was found that oral administration of a mixture of probiotics (L. gasseriLK001,L. salivariusLK002,L. johnsoniiLK003,L. paracaseiLK004,L. reuteriLK005,B.animalisLK011)could induce the accumulation of CD103+DCs in PPs and MLNs and promote the secretion of TGF-β, thereby inducing the differentiation of T cells into Treg cells [11].B. infantis14.518 could stimulate the maturation of DCs and the accumulation of CD103+DCs, thus alleviating the allergic reactions in the tropomyosin (TM)-sensitized mice [70]. Further studies showed that probiotics were associated with retinaldehyde dehydrogenase (RALDH)-positive DCs. The number of CD103+RALDH+DCs and the Foxp3+lymphocytes in the intestinal lamina propria increased in mice treated withB. infantis.It was speculated that RALDH+DCs in the intestinal lamina propria were important for probiotics to regulate mucosal immunity [71].These results suggest that probiotics may alleviate food allergy by stimulating the accumulation of CD103+DCs, thus inducing Foxp3+Treg cells mediated by TGF-β.

Probiotics can also regulate DCs from the aspects of oxidative stress. The imbalance between the reactive oxygen species (ROS) and antioxidants in the host will lead to the increase of pro-inflammatory factors and produce inflammation [72,73]. Based on the population studies, it was found that the activity of glutathione peroxidase(GPx) in children with shrimp or crab allergy was significantly lower than that in healthy children. There was a significant negative correlation between the activity of GPx and specific IgE [73]. DCs were affected by the redox state of glutathione, thus regulating the balance between Th1 and Th2 [74,75]. At the same time, ROS could also mediate the maturation and functions of DCs. DCs treated with ROS could stimulate the proliferation of T cells more than normal DCs [76,77]. Probiotics contain various antioxidant enzymes, such as GPx, thioredoxin reductase and superoxide dismutase (SOD),which can scavenge ROS [78,79].B. infantis(BB) could reduce the oxidative stress of DCs in ovalbumin (OVA)-sensitized mice. SOD in BB could also down-regulate STAT6-TIM4 signal transduction of DCs and inhibit food allergy [80]. However, the oxidation resistance of probiotics is still unclear in terms of affecting immune cells and alleviating food allergy.

The components of probiotic cell walls, such as surface polysaccharides, may be the key effectors to regulate DCs.Exopolysaccharides (EPS) ofBacillus subtiliscould treat intestinal inflammation in mice mediated by toll-like receptors (TLR) 4. No protective effect was observed when using an EPS-deficient mutant ofB. subtilis, indicating that EPS might be the protective factor [81].Polysaccharide A of probiotics could interact with TLR on the plasma DCs to specifically stimulate CD4+T cells to secrete IL-10 [82]. The polysaccharides of probiotics could also promote DCs to induce Treg cells [44].

5.2 Regulation of probiotics on IECs

IECs are important components of intestinal barrier. Probiotics can repair and strengthen IECs, thus preventing food allergens from crossing the intestinal barrier [25].

Probiotics can enhance the function of IECs by increasing the expression of tight junction proteins of IECs. IECs rely on transmembrane proteins and cytoplasmic proteins to form tight junctions. Tight junctions are mainly formed by Claudin and Occludin, while cytoplasmic tight junction proteins such as zonula occludens-1 (ZO-1) and ZO-2 can enhance tight junctions between IECs [83,84].Streptococcus thermophilus,ATCC 19258 andL. acidophilus,ATCC 4356 could significantly alleviate the phosphorylation of Occludin and ZO-1 caused by enteroinvasiveEscherichia coli(EIEC). And if the intervention of probiotics was carried out before the infection of EIEC, the phosphorylation of tight junction proteins would be completely avoided [85]. WhenE. coliNissle 1917 (ECN) was transplanted into germ-free mice,ECN could up-regulate the expression of ZO-1. When ECN was given to mice with colitis, the expression of ZO-1 was also significantly observed [84]. The secretions ofB. infantis,ATCC 15697 andL. acidophilus,ATCC 53103 could also protect IECs [86]. Further studies found that S-layer proteins (Slp) on the surface of some strains ofLactobacillusexhibited bioactivity that could strengthen the interaction with IECs [87]. Slp ofL. acidophilusNCFM could up-regulate the expression of Claudin-1, and inhibit the decrease in transepithelial electrical resistance and the increase in intestinal permeability [88].

Probiotics can also regulate inflammatory signals of IECs.Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) are two important inflammatory pathways.Studies have found that probiotics can inhibit the activation of NF-κB.L. plantarumAR113 could inhibit IL-1β, IL-6 and TNF-α and up-regulate the expression of anti-inflammatory-related cytokines, such as IL-10 in mice with colitis. The expression of NF-κB/TLR4/myeloid differentiation factor 88 was also reduced [89].The extracellular vesicles ofP. freudenreichiiCIRM-BIA 129 contained SlpB, which could mediate inflammatory responses by regulating the activity of transcription factors in NF-κB. It was speculated that Slp might be the key to regulating the activation of NF-κB [90]. Extracellular vesicles are released actively by cells, which carry important signal molecules and transmit bacterial components to immune cells [90,91]. At present,many studies have found that the extracellular vesicles of probiotics are important for inhibiting apoptosis of hepatic cancer cells and regulating immune responses of IECs [92-94]. In addition to NF-κB,probiotics can also regulate MAPK. The lactic acid bacteria could inhibit the phosphorylation of p38 MAPK and p65 NF-κB to mediate inflammatory responses [95].L. acidophilusL-92 could activate Th1 and Treg cells by participating in MAPK and NOD-like receptor pathways [96].

In addition, the adhesins of probiotics can enhance their colonization on IECs, which helps prevent antigens from crossing the intestinal barrier [25]. Some probiotics such asL. acidophilusM92 had Slp, which could not only maintain the shape of bacterium,but also had adhesive properties. The adhesins to porcine IECs were significantly reduced if Slp of the strain was removed by lithium chloride [97,98]. IECs have adhesin receptors which have been proved to be related toD-mannose. Different adhesins will recognize different receptors on IECs [99].

5.3 Regulation of probiotics on gut microbiota

More and more studies have shown that the gut microbiota plays an important role in the susceptibility to food allergy [43].As mentioned in section 3.2, there are significant differences in the species and abundance of the gut microbiota between allergic and healthy people. Many clinical studies and animal models have demonstrated that probiotics can balance the gut microbiota. It was found that6-month-old infantsgivenL. rhamnosus, ATCC 53103 daily had high abundance of beneficial species, such as Lactobacillaceae and Bifidobacteriaceae. These species might affect the gastrointestinal tract through secondary metabolites [100].In another study, 20 healthy infants and 19 infants with milk allergy were treated with hydrolyzed formulas containingL. rhamnosus. It was found thatOscillospirawas the only different microorganism in abundance [101].B. infantis14.518 could inhibit allergic reactions of TM-sensitized mice. And it was also found that the up-regulation ofDoreaand down-regulation ofRalstoniawere significantly correlated with Th2/Treg ratio in mice [70].In addition,B.longumsubsp.1.2202, ATCC 15697 andBacillus coagulans09.712 could also regulate the gut microbiota in TMsensitized mice. It was found that Firmicutes levels were negatively correlated with the production of Treg-related cytokine IL-10, whileBacteroideslevels were positively correlated with IL-10, indicating that both of them could affect Treg cells and immune tolerance [102].

Some studies have further explored the key active substances of probiotics in regulating gut microbiota. It was found thatD-tryptophan isolated from the supernatant of probiotics could increase the diversity of the gut microbiota and reduce allergic airway diseases [103]. These results indicate that probiotics can alleviate food allergy by regulating the gut microbiota, but the immunomodulation signals and the overall immune pathway after changing the gut microbiota by probiotics still need further studies.

5.4 Regulation of probiotics metabolites

Probiotics can ferment dietary fiber to produce SCFAs, among which acetate, butyrate and propionate are vital in maintaining metabolic physiology and regulating the immune system of hosts [29].The specific effect of SCFAs is largely mediated by the selective activation of G protein-coupled receptors (GPCRs) or free fatty acid receptors, such as GPR41, GPR43 and GPR109A [104-107]. Lactic acid bacteria could produce SCFAs through the phosphoketolase pathway [108].Bifidobacteriumproduced acetate and formate under carbohydrate-limiting conditions, while acetate and lactate were produced when carbohydrates were in excess [109].L. rhamnosuscould produce large amounts of propionate in the MRS media, instead of butyrate or acetate [110].

Probiotics can regulate inflammation and immune responses by increasing the concentration of SCFAs. SCFAs could not only activate GPR41 and GPR43 on IECs to stimulate the secretion of chemokines and cytokines, but also regulate the precursor cells of bone marrowderived DCs depending on GPR41 to inhibit Th2 responses [111].Propionate relied on GPR41 rather than GPR43 to alleviate allergic inflammation. Propionate could change the hematopoiesis of bone marrow in mice and increase the production of the macrophages’precursors and DCs’ precursors [112]. Butyrate could provide energy for colonic epithelium, and GPR109A receptor could recognize butyrate [105,113]. SCFAs, especially butyrate, could induce the expression of RALDH1 and increase the number of Treg cells to regulate the immune system [114]. Butyrate could promote the production of Foxp3+Treg cells outside the thymus in mice. It was speculated that butyrate was related to increased acetylation of histone H3 at the Foxp3 promoter. Butyrate could significantly accelerate the differentiation of T cells into Treg cells in the colon and improve colitis [115]. These studies have shown that the metabolites of probiotics can mediate the immune system and alleviate food allergy.

Fig. 1 Potential mechanisms of probiotics in alleviating food allergy.

5.5 Regulation of probiotics on other immune cells

Probiotics can also regulate other immune cells such as Treg cells and mast cells [116,117]. The establishment of oral tolerance involves a variety of Treg cells. Foxp3+Treg cells in the intestinal mucosa can secrete IL-10 and TGF-β, which play an important role in oral tolerance [116]. Probiotics can inhibit the differentiation of T cells into Th17 cells and enhance the expression of Treg cells,which can maintain the balance between Treg cells and Th17 cells and alleviate inflammatory responses caused by Th17 cells [68,118].Clostridium butyricumCGMCC0313-1 could increase secretory IgA and CD4+CD25+Foxp3+Treg cells and reverse the imbalance of Th1/Th2 and Th17/Treg [119].L. reutericould increase the expression of IL-10, TGF-β and Foxp3+Treg cells and reduce the production of IgE in OVA-sensitized mice. The allergic diarrhea in mice was also alleviated [120]. Some studies further found thatB. coagulans09.712 could inhibit mammalian target of rapamycin(mTOR) signaling, thereby inhibiting the phosphorylation of downstream factors and inducing the production of CD4+Foxp3+Treg cells and IL-10 in allergic mice [121]. In addition, as described in sections 5.1 and 5.3, probiotics can also stimulate the formation of Foxp3+Treg cells by promoting the accumulation of CD103+DCs and the production of SCFAs. Therefore, probiotics can induce Foxp3+Treg cells in multiple ways to prevent food allergy.

Mast cells are the main effector cells in the pathogenesis of food allergy, which can cause systemic allergic reactions [122]. There may be some potential relationships between the activation of mast cells and T cells [29]. Studies have found that Treg cells can directly inhibit the activation of mast cells to alleviate food allergy [123].L. plantarumisolated from kimchi could reduce the infiltration and activation of mast cells in OVA-sensitized mice, and significantly inhibit the expression of Th2-related gene GATA3 and Th2-related cytokines,such as IL-4, IL-5 and IL-13 in the small intestine as well [124].However, some studies found that some probiotics, such asB.longumKACC 91563, could alleviate the symptoms of food allergy only by reducing the number of mast cells in small intestinal lymph nodes without intervening in T cells, speculating that it was caused by extracellular vesicles of probiotics [117]. The anti-allergic inotodiol extracted from Chaga mushroom had a similar effect on food allergy.It could selectively inhibit the function of mast cells, with no obvious effect on other immune responses [125]. At present, the studies of probiotics on food allergy mainly focus on lymphocytes and antigenpresenting cells, with less attention on mast cells, while mast cells play an important role in inflammatory responses. Therefore, further exploration of the regulation of mast cells by probiotics can be considered in the future.

As shown in Fig. 1, probiotics can regulate food allergy in various pathways based on the intestinal mucosal immune system. The main mechanisms are as follows: (I) Probiotics regulate DCs. Vitamin A can be converted into RA under CD103+DCs. Th0 can differentiate into Foxp3+Treg cells mediated by RA and TGF-β, which inhibit the production of Th17 cells and prevent inflammation. EPS of probiotics may be the key to regulating DCs; (II) Probiotics regulate IECs mainly in three ways. The tight junction of Occludin and Claudin is enhanced to maintain the integrity of IECs; NF-κB and MAPK inflammatory pathways of IECs are inhibited to reduce inflammatory reactions; antigens are prevented from crossing the IECs due to the colonization of probiotics, and Slp of some probiotics may be the key to the adhesiveness to the receptors of IECs; (III) Probiotics regulate the abundance and diversity of gut microbiota to prevent food allergy; (IV) Probiotics ferment dietary fiber and increase the concentration of SCFAs. Propionate can bind to GPR41. Butyrate can bind to GPR109A, which can provide energy for IECs and induce the expression of Foxp3+Treg cells by signal transduction; (V) Probiotics regulate other immune cells. Probiotics promote the production of Foxp3+Treg cells by inhibiting mTOR signaling and inducing apoptosis of mast cells to prevent degranulation.

6. Conclusions

The interaction with MLNs, PPs, DCs, T cell subsets and gut microbiota in the intestinal mucosal immune system can maintain the balance between Th1 and Th2 and induce oral tolerance [24].Probiotics can regulate the immune systems by interacting with lymphocytes, gut microbiota and metabolites based on the intestinal mucosal immune system. Although many animal experiments show that probiotics play an important role in alleviating food allergy,their effects on the clinical application are still controversial. Since the occurrence of food allergy is affected by many factors, such as the cleanliness of the living environment, family genetics, dietary structure, there are great differences among various patients, which causes great difficulties in the clinical application of probiotics and poses new challenges to the effective screening of probiotics[19,126,127]. In addition, the duration of the probiotic administration will also affect the treatment of food allergy. Therefore, further studies on the clinical application of probiotics are still required [66].This review outlines the potential mechanisms of probiotics in food allergy based on the intestinal mucosal immune system, in order to provide a reference for screening probiotics for clinical treatment in the near future.

Declaration of competing interest

The authors report no conflict of interest.

Acknowledgment

This review is supported by the National Key Research and Development Program of China (2019YFC1605000) and the National Natural Science Foundation (31872904).