Over the past few years, allergic disorders have become more common around the world, and it is estimated that adults (up to 3%) and children (up to 8%) in industrialised countries are affected by food allergies [1]. The severity of food allergy symptoms, along with the rising prevalence of these pathologies, places great importance on the development of novel therapeutic approaches ^[2][3][4][5][2,3,4,5]. The oral exposure to food allergens can result in three distinct categories of allergic responses: IgE-mediated responses, cell-mediated responses and mixed responses, dependent on both IgE and the immune cells [6]. Some of the most common food items capable of initiating allergic reactions include eggs, fish, soybeans, tree nuts, milk, peanuts, shellfish and wheat ^[7][8][7,8].

Typically, patients develop food allergies in their early childhood and the pathology is resolved by the time they reach adulthood. However, food allergies can persist into adolescence and adulthood. Factors such as the age of diagnosis, timing of resolution, nature of immune responses and associated comorbid allergic diseases determine the severity of this pathology ^[3][9][10][3,9,10].

There are a multitude of diagnostic methods available, with skin prick tests and food-specific IgE serum testing being among the most used. Patient’s medical history and the nature and severity of food allergies should be considered when selecting an appropriate diagnostic technique. Avoiding food allergens through dietary elimination combined with being prepared to quickly address allergic reaction using epinephrine are the prevailing approaches to manage food allergies and prevent anaphylactic reactions. However, these approaches are not ideal, since they do not address the alterations in cellular mechanisms that lead to food allergies. Furthermore, nutritional deficits may ensue from the exclusion of particular foods [11].

IgE-mediated allergic reactions initiate rapidly after the ingestion of allergic foods, with some of the symptoms being shortness of breath, wheezing, coughing, nausea, vomiting and in extreme cases, anaphylactic reactions [12].

Recently, the use of phenolic compounds in the prevention and mitigation of symptoms of these pathologies has been proposed. Both the scientific community and the general population have asserted that the consumption of plant-based foods is good for overall human health, due to their anti-aging, anti-inflammatory and anti-microbial properties ^{[13][14][15][16]}[13,14,15,16]. This has been in part attributed to the high concentration of phenolic compounds present in these foods. In addition, foods rich in phenolic compounds have shown promise in the modulation of food allergies, allowing for the development of new dietary approaches to regulate food allergies.

2. Modulation the Digestion of Food Allergens

The capacity of phenolic compounds to interact with proteins, both at the level of the food matrix and the human body, is one of their most crucial capabilities. This ability is at the origin of the different properties of these compounds, such as properties related to food science and technology (e.g., juices stability, taste properties) as well as being related to human bioactivities (e.g., digestive enzyme modulation) ^[17][51]. As discussed previously, protein stability is one of the defining factors of the immunogenic potential of dietary proteins. Proteins that can resist digestion in the gastrointestinal tract tend to preserve their structure and epitopes, therefore they tend to maintain their ability to initiate allergic reactions after being sampled by the cells of the immune system ^[18][21]. The ability of phenolic compounds to form both soluble and insoluble complexes with different proteins can reduce the allergenicity of dietary allergens, either by changing the structure of their epitope or by diminishing their bioaccessibility ^[19][106]. Dietary proteins, such as those found in seafood, milk and eggs, can form complexes through either irreversible covalent interactions or reversible non-covalent interactions. Both forms of interactions have the ability to modify the secondary and tertiary structures of proteins ^[20][107]. Immunogenicity can be altered by these modifications to protein structure, which may mask structural epitopes or alter their structure. Caffeic and chlorogenic acids, for instance, were reported to form complexes with milk proteins, thereby inhibiting their affinity for food-specific IgE ^[21][22][108,109]. Epigallocatechin gallate (EGGC) was shown to be able to covalently bind to egg allergens ^[23][110], while blueberry phenolic compounds were shown to non-covalently bind to peanut allergens ^[24][111]. In both cases, the secondary structure of these proteins was altered, thus altering their immunogenic potential. These modifications inhibit the binding of food-specific IgE. This could therefore reduce the allergenicity of these antigens and inhibit the degranulation of mast cells and basophils ^[20][107]. Alterations in protein structure may also impact the digestion process. An enhanced digestion of casein and whey proteins was observed as a consequence of the complexation with chlorogenic acid ^[25][112]. Nonetheless, phenolic compounds can also protect dietary protein from digestion, as is the case of wheat proteins treated with flavonoids extracted from onion skin ^[26][113]. This can prove a hindrance in the development of new therapeutic strategies, seeing as undigested proteins tend to keep their immunogenic potential ^[27][30]. Adding to this, an improved digestion of dietary proteins might not be enough to reduce their immunogenic potential, seeing as some large peptides formed during digestion maintain an ability to bind to IgEs ^[28][40]. One example of these are the milk proteins casein and α-lactoalbumin, which are vastly degraded by gastric pepsin in 2 min and yet retain their ability to initiate allergic responses ^[29][32]. Overall, the digestion of dietary proteins is a complex process, and many factors can contribute to the ability of different proteins to initiate allergic responses. Protein stability, preservation of epitopes, the relative abundance in foods and the effects of food matrixes in digestion are all important factors that determine the immunogenic potential of allergens ^[29][30][32,114]. The use of phenolic compounds to modulate the digestion of foods is an exciting new prospect but the full extent of this modulation is still not fully understood ^[31][115]. As seen in this section, different polyphenols interact differently with proteins, either protecting them from digestion or making them more susceptible to degradation ^[32][116]. Adding to this, many studies do not take in the account the effect of food matrixes in this modulation of the digestive process. More studies are then necessary to discern the full extent of the role of phenolic compound binding to dietary proteins in digestion, as well as its effect on the ability of proteins to bind to IgEs and initiate allergic responses.

3. Modulation of the Bioavailability of Food Allergens

The formation of complexes between phenolic compounds and dietary proteins can also enhance the bioavailability and preserve the bioactivity of phenolic compounds. The formation of these complexes prevents the metabolization of phenolic compounds in gastrointestinal tract, thereby facilitating their absorption and enabling them to exert their intended bioactivities further ^[33][117]. For example, researcheuthors have reported that protein-rich soybean flour protects anthocyanins from metabolism, thereby increasing their bioavailability ^[34][118]. Covertly, these phenolic compound–protein interactions might alter their hydrophilic characteristics and increase their molecular weight, altering their absorption and potentially reducing their bioavailability ^[35][119]. As such, more studies are needed to fully evaluate the effects of these interactions on the uptake of potentially immunogenic peptides. ResearcAutheors have also reported the ability of these compounds to bind to different families of receptors and transporters, altering their function and ability to translocate different molecules. It is thus possible that phenolic compounds can interact with membrane receptors in the intestinal epithelium, modulating the active transport of peptides and proteins across the intestinal barrier ^[35][119]. For example, the flavonoids quercetin, apigenin and kaempferol bind to OATP1A2 and OATP2B1, transporters which are localised in the apical membrane of the intestinal lumen ^[36][120]. The specific receptors involved in the sampling of dietary antigens by M cells and goblet cells are still not identified. Nonetheless, it is possible that dietary phenolic compounds could alter the sampling process, and thus more studies are required. Finally, phenolic compounds have the ability to modulate the function and expression of tight junctions, as well as other proteins, possibly altering the influx of immunogenic proteins and peptides into the lymphatic tissues located underneath the intestinal lumen ^[37][121]. Plant phenolic compounds can regulate the NF-κB, MAPK, PI3K and PKC signalling pathways, reducing the localized inflammation of gut tissues and preserving the normal function and structure of tight junctions. Overall, phenolic compounds can influence the intestinal barrier through a variety of complex mechanisms, preserving the normal intestinal uptake of potentially allergic peptides and proteins. However, some of these mechanisms and the possible interactions that exist between them are not fully understood. Adding to this, the number of in vivo studies focusing on this topic is limited, so the full implication of the modulatory effect of polyphenols in the bioavailability of allergens is yet to be fully understood.

4. Modulation of the Human Immune System

Phenolic compounds are capable of directly modulating the immune system. Several studies have demonstrated that these compounds possess the ability to regulate the immune response to food allergens through the inhibition of different enzymes involved in allergic reactions. For example, resveratrol has been shown to inhibit the cyclooxygenase family of enzymes in mice, thereby preventing the synthesis of prostaglandins. Prostaglandins are essential mediators of inflammation; therefore, inhibiting their synthesis could potentially mitigate localised inflammation in intestinal tissues ^[38][122]. Other phenolic compounds, like curcumin, inhibit IKK and MAPK in mice, downregulating the NF-κB signalling pathway and the MAPK signalling pathway, respectively ^[39][123]. As discussed previously, these signalling pathways are crucial for the degranulation of basophils and mast cells ^[40][50], and as such, their downregulation might prove useful for reducing the symptoms of food allergies. Phenolic compounds can also inhibit the expression of specific enzymes that are implicated in the IgE-mediated allergic response to food allergens. The administration of epigallocatechin (EGCG) to human epithelial cells results in the inhibition of iNOS expression in macrophages, thereby leading to a decrease in the synthesis of critical inflammatory mediators ^[19][106]. Also susceptible to dietary phenolic compounds are the differentiation process and quantity of immune system cells. Male C3h/HeN mice that were treated with phenolic compounds extracted from fruit palm trees exhibited an increase in the number of Th1 cells in the intestinal lumen. Conversely, mice that were treated with the phenolic compounds baicalin and apigenin displayed a diminished count of Th2 cells. An increased count of Th2 cells is indicative of the deterioration of the oral tolerance to dietary antigens ^[41][42][124,125]. Phenolic compounds can also regulate the production of cytokines, either promoting a pro-inflammatory state through the production of IL-1β, IL-2, Il-6, IL-8 and TNF-α, or an anti-inflammatory state via the production of IL-10, IL-4 and TGF-β. Alterations to this equilibrium will have an impact on immune responses. It has been demonstrated that a number of phenolic compounds inhibit the expression of pro-inflammatory cytokines in various cell types, including activated human mast cell lines and lipopolysaccharide-activated mouse primary macrophages ^[43][44][126,127]. The major biological event associated with IgE-mediated food allergies is the degranulation of basophil and mast cells ^[40][45][50,128]. After the loss of oral tolerance, exposure to dietary allergens results in the production of food-specific IgE antibodies by immune system cells. Phenolic compounds have been used in the modulation of the degranulation of mast cells and basophils, even though the mechanism through which these modulations occur are still not completely understood. Nonetheless, some phenolic compounds reduce the secretion of pro-inflammatory mediators such as histamines and β-hexosaminidase. The degranulation of these cells is a hallmark of allergic reactions to orally ingested allergens and, as such, a decrease in the secretion of these pro-inflammatory molecules could reduce the symptoms associated with food allergies ^[46][47][129,130].

5. Modulation of the Human Oral Microbiota

As mentioned previously, the populations of commensal bacteria that reside in the oral cavity also greatly modulate oral tolerance to food allergens. The contributions of the oral microbiome to food allergies are often overlooked. Recent studies have highlighted the relation between several pathologies, either systemic or in the oral cavity, and dysbiosis of the oral microbiome. Changes in the oral microbiome can also alter the function of the host’s immune system ^[48][131]. The immunomodulatory role of the oral microbiome has been studied with animal models. The colonization of gastrointestinal tract of mice with Klebsiella bacteria isolated from the oral cavity of Crohn’s disease patients resulted in an inflammatory Th1 response, thus indicating the potential role of the oral microbiota as promoters of inflammation ^[49][132]. In another study, ligature-induced periodontitis resulted in the infiltration of B, Th17 and γδ Τ cells in the lamina propria of the intestines of mice, thus indicating that the oral microbiome and its composition could influence the populations of intestinal immune cells ^[50][133]. Human trial studies have also highlighted the importance of the oral microbiome in the maintenance of normal oral tolerance to food allergens ^[51][52][134,135]. In one of these studies, the microbiome of the oral cavity of patients with peanut allergies had a difference in composition and a lower phylogenetic diversity when compared with the oral microbiome of healthy individuals. Lower levels of Bacteroidales, Bacillales, Lactobacillales and Streptophyta were observed, while increased levels of Neisseriales were also reported. Along with these differences, the levels of oral SCFAs in individuals with peanut allergies were significantly lower than in healthy individuals. Finally, IL-4 secretion was increased in peanut-allergic subjects ^[53][136]. Studies like these point to a possible correlation between food allergies and dysbiosis in the oral microbiota. The oral microbiome is the first one to be in contact with food and, therefore, the microorganisms rely on the compounds present in the ingested food. Diets high in dietary sugars reduce the populations of early colonizers like Mitis streptococci, allowing for the proliferation of potentially pathogenic microorganisms ^[54][137]. Their benefits rely on their increased capacity to adhere to teeth, their ability to grow more quickly and the synthesis of different compounds that inhibit the growth of cariogenic bacteria ^[54][137]. However, when this interspecies competition is disrupted, pathogenic processes take place. For example, the types of consumed foods can affect the pH level in the mouth, which in turn can influence the growth and survival of different oral bacteria. An excess of fermentable carbohydrates might upset the equilibrium between commensals and pathogens because the fermentation of carbohydrates can lead to an increase in the acidity of the mouth, promoting the growth of acidogenic bacteria, such as Streptococcus mutans. In contrast, a diet rich in fibre, whole grains, fruits and vegetables can promote a more alkaline pH in the mouth, which can support the growth of beneficial bacteria, such as Lactobacillus and Bifidobacterium ^[55][138]. While a large amount of research has been devoted to the effect of sugars in the oral microbiome, namely on pathogens, studies have only recently been focused on phenolic compound effects. Despite mounting evidence for phenolic compounds’ antimicrobial activity against some periodontal pathogens ^[55][138], other mechanisms through which they can modulate microbial populations, such as their anti-adherent ability and anti-inflammatory properties, need to be assessed to fully understand the interplay between phenolic compounds and the oral microbiome ^[56][139]. One of the most studied foods rich in phenolic compounds is green tea. It has been reported that tea consumption can consistently change oral bacteria in humans related to carcinogenesis ^[57][140]. A clinical trial investigated the effects of green tea phenolic compounds on the oral microbiome and immune-related parameters in patients with dental caries. The results showed that green tea phenolic compounds can modulate the oral microbiome by reducing the abundance of pathogenic bacteria and promoting the growth of beneficial bacteria. In addition, green tea phenolic compounds were found to reduce inflammation and improve immune function in patients with dental caries. Other phenolic compounds, such as the ones present in grape and red wine, exhibit a strong inhibition of the adherence of pathogenic microbiota to oral cells, thus preventing oral dysbiosis ^[58][59][141,142]. This protective effect could be useful in the management of not only periodontal diseases, but also food allergies. In addition, oral microorganisms can metabolize those compounds ^[60][90]. Although these mechanisms are not as well explored as the metabolization of phenolic compounds by the gut microbiome, the metabolization of phenolic compounds starts in the oral cavity. ResearcAutheors have described a moderate metabolization of glycosylated phenolic compounds by the glycosidases produced by the oral microbiome ^[61][143]. This will naturally affect their bioactivity and bioavailability, meaning that the immunomodulatory properties of phenolic compounds could also be altered. Despite all of this, the role of the oral microbiome in the maintenance of oral tolerance and the progression of food allergies is still not as well understood as the role of the intestinal microbiome. Due to this, further research is needed to fully understand the mechanism through which this modulation occurs. Overall, the role of phenolic compounds in the human oral microbiome is complex and multifaceted, and more research is needed to fully understand their mechanisms of action. However, while the available evidence suggests that consuming foods and beverages rich in phenolic compounds can promote a healthy oral microbiome and reduce the risk of oral health problems, there is limited research on the specific effects of phenolic compounds on the oral microbiome in the context of food allergies.

6. Modulation of the Human Intestinal Microbiome

The human gut microbiome, is crucial in the normal function of many organs and biological processes. First, the human gut microbiome has a crucial role in the digestion of food ^[62][144], increasing nutrient harvest ^[63][64][145,146] and altering appetite signalling ^[65][66][147,148]. It also provides hosts with specific and unique enzymes and biochemical pathways. Many of the metabolic processes of the human microbiome are beneficial to the host, as they are involved in either the degradation of xenobiotics or nutrient acquisition ^[64][146]. The human gut microbiome acts as a physical barrier, protecting hosts against the excessive proliferation of potentially harmful pathogens through a combination of the secretion of antibacterial substances and competitive exclusion ^[67][68][69][59,149,150]. The maintenance of the normal intestinal microbiome is crucial for the maintenance of oral tolerance, as dysbiosis in the gut could lead to an abnormal function of the host’s immune system ^[70][71][151,152]. Research conducted using germ-free animals indicates that the microorganisms present in the gastrointestinal tract modulate the function of the immune system, being involved primarily in promoting the normal development of immune functions and the maturation of immune cells ^[71][152]. Germ-free animal models possessed abnormal levels of several immune cell types, had poor development of their GALT and thymus, smaller Peyer’s patches, mesenteric lymph nodes and differences in cytokine levels ^{[70][72][73][74][75]}[151,153,154,155,156]. On the other hand, germ-free mice inoculated at birth with normal mouse intestinal microbiota no longer possessed an undeveloped immune system, thus reinforcing the importance of the interactions established between these microbial populations and their hosts ^[76][157]. Other studies have also called attention to the pivotal role of the gastrointestinal tract microbial population in the progression of many diseases, such as liver pathologies, metabolic disorders, infections, respiratory diseases and autoimmune diseases ^{[77][78][79][80][81][82]}[64,158,159,160,161,162]. Experiments using germ-free animals have also confirmed the key role of intestinal microbiota in the regulation of oral tolerance. The exposure of germ-free animals to food allergens resulted in a loss of oral tolerance and subsequent exposures resulted in allergic reactions. However, the restoration of different microbial populations lead to a normal function of the immune system, with the establishment of Treg cell populations ^[83][84][163,164]. Cohort studies of patients with cow’s milk allergies have also revealed that a considerable intestinal microbial dysbiosis is common in these patients ^[85][165]. The gut microbiome and the oral microbiome, are not independent, as changes in one could alter the microbial ecosystem and bacterial metabolism in the other. Microorganisms primarily found in the oral cavity have been detected in the gastrointestinal tract of Crohn’s disease patients, colorectal cancer patients and HIV patients ^[49][69][86][132,150,166], while microbiota usually found in the oral cavity, like Streptococcus, Pervotella, Rothia, Neisseria and Gemella were detected in the stools of patients suffering from chronic intestinal inflammation ^[49][132]. Parallelly, inflammatory bowel disease (IBD) patients appeared to have a higher risk of developing pathologies in the oral cavity ^[87][88][167,168]. The composition and function of the gut microbiome can be modulated by phenolic compounds. Overall, research conducted in vitro and in vivo has demonstrated that phenolic compounds reduce the abundance of potentially harmful bacteria, such as C. perfringens and C. histolyticum, while increasing the quantity of advantageous Clostridium, Bifidobacterium and Lactobacilli. By resetting the dysbiosis that is characteristic of food allergy with phenolic compounds, abnormal immunogenic responses to dietary allergens can be regulated ^[89][169]. For example, researcheuthors have described that red wine phenolic compounds can act as prebiotics, promoting the maintenance of the normal gut microbiome by increasing the populations of the beneficial bacteria of the genus Bifidobacteria, Bacteroides and Provotella ^[90][170] and by decreasing the populations of bacteria typical of intestinal dysbiosis, Escherichia coli and Enterobacter cloacae ^[91][171]. In another study, proanthocyanin-rich extract from grape seeds also had the ability to positively modulate the composition of the human gut microbiome ^[92][172]. The modulation of the gut microbiome, using phenolic compounds could also result in changes in SCFA production. As explored in previous chapters, SCFAs are produced during microbial metabolism and have a plethora of immunomodulatory properties. Seeing as the production of these metabolites is dependent on the composition of the gut microbiome, the prebiotic effect of phenolic compounds could alter SCFAs production. Indeed, many researcheuthors have described increases in SCFA production in mice treated with different phenolic compounds extracts and isolated phenolic compounds ^{[93][94][95][96][97]}[173,174,175,176,177]. The gut microbiome plays a role in the metabolization of orally ingested dietary phenolic compounds. These bacteria produce a vast array of enzymes with the ability to degrade phenolic compounds into new metabolites, with a different bioavailability and bioactivity ^[98][99][178,179]. This can in turn alter not only their ability to modulate the gut microbiome, and the metabolites it produces, but also their ability to bind to proteins in the small intestine and their ability to modulate the immune system cells. As such, the gut microbiome can significantly influence other biological systems ^[100][180].