Assessing and Comparing Potential Allergenicity of Two Partially Hydrolyzed Whey-Based Formulas for Infants: A Population-Based Study in China.

SCOPE: In cases where breast milk is unavailable or inadequate, hydrolyzed infant formula is recommended as the primary alternative. The aim of this study is to assess and compare the allergenicity of two partially hydrolyzed whey-based formulas (PHF-Ws) using serum samples from patients with cow's milk allergy (CMA). METHODS AND RESULTS: LC-MS/MS technology is used to investigate the peptide distribution in both samples. The immunoreactivity of two PHF-Ws in 27 serum samples from 50 Chinese infants (02 years) with CMA is analyzed. The results demonstrate that even with a similar a degree of hydrolysis (DH), primary protein sources, peptides with molecular weights <5 kDa, and differences in the number of residual allergenic epitopes in the hydrolyzed peptide segments can lead to varying immune responses. CONCLUSION: The two PHF-Ws have notably high intolerance rates, exceeding 10% among infants with CMA. Therefore, suggesting that PHF-Ws may not be suitable for infants and children with CMA in China.

Epidemiology of Paediatric Italian Food Allergy: Results of the EPIFA study.

Background: Updated epidemiologic data are important for defining effective public health strategies for pediatric food allergy (FA). Objective: The Epidemiology of Paediatric Italian Food Allergy (EPIFA) study was designed to investigate the epidemiology of pediatric FA in one of the most heavily populated Italian regions. Methods: A retrospective cohort study was performed in collaboration with family pediatricians aimed at investigating the epidemiology of Italian pediatric FA during 2009 to 2021. Family pediatricians in the Campania region were invited to use the Google Forms platform for online compilation of data forms. Data forms were reviewed by experienced pediatric allergists at the coordinating center. Results: A total population of 105,151 subjects (aged 0-14 years) was screened during the study period. Data from 752 FA patients were evaluated. A progressive increase in FA incidence and prevalence was observed from 2009 to 2021, with a relative increase up to 34% and 113.6%, respectively, at the end of study period. The relative increase in FA prevalence was higher in the 0-3-year-old age group in the same study period (+120.8%). The most frequent allergens were cow's milk, hen's egg, and nuts. Conclusion: The results of the EPIFA study showed an increase in pediatric FA incidence and prevalence from 2009 to 2021 in Italy. These results underline the necessity of new effective strategies for preventing and managing these conditions.

Allergenicity Modulation of Casein with the Modifications of Linearization, Cross-Linking, and Glycation via the Regulation of Th1/Th2 Homeostasis.

Casein (CN) is the primary allergenic protein in cow's milk, contributing to the worldwide escalating prevalence of food allergies. However, there remains limited knowledge regarding the effect of structural modifications on CN allergenicity. Herein, we prepared three modified CNs (mCN), including sodium dodecyl sulfate and dithiothreitol-induced linear CN (LCN), transglutaminase-cross-linked CN (TCN), and glucose-glycated CN (GCN). The electrophoresis results indicated widespread protein aggregation among mCN, causing variations in their molecular weights. The unique internal and external structural characteristics of mCN were substantiated by disparities in surface microstructure, alterations in the secondary structure, variations in free amino acid contents, and modifications in functional molecular groups. Despite the lower digestibility of TCN and GCN compared to LCN, they significantly suppressed IL-8 production in Caco-2 cells without significantly promoting their proliferation. Moreover, GCN showed the weakest capacity to induce LAD2 cell degranulation. Despite the therapeutic effect of TCN, GCN-treated mice displayed the most prominent attenuation of allergic reactions and a remarkably restored Th1/Th2 imbalance, while LCN administration resulted in severe allergic phenotypes and endotypes in both cellular and murine models. This study highlighted the detrimental effect of linear modifications and underscored the significance of glycation in relation to CN allergenicity.

Consumption of cow's milk formula in the nursery and the development of milk allergy.

BACKGROUND: The effect of the amount of transient cow's milk formula (CMF) consumed during the first days of life on IgE-cow's milk allergy (IgE-CMA) is unknown. METHODS: A cohort of 58 patients with IgE-CMA was identified from a large scale population-based study of 13,019 infants followed from birth. A group of 116 infants matched for sex and breastfeeding only duration (beyond the nursery period), and another random group of 259 healthy infants were used as controls. Parents were interviewed and the infants' medical records were searched to assess CMF consumption in the nursery. RESULTS: While 96% of the mothers of the 174 infants (58 with Cow's milk allergy and 116 controls) reported on exclusive breastfeeding during the stay in the nursery, CMF consumption was documented in 96 (55%) of the infants. Of those, most (57; 59%) received one to three feedings, 20 (21%) received four to nine feedings, and 19 (20%) received ≥10 feedings. Fewer formula feeds (1-3) were significantly more common in the allergic group than ≥4 feeds (p = 0.0003) and no feeds at all (p = 0.02) compared to controls (n = 116). Of those exclusively breastfed in the nursery, 13/23 allergic infants (57%) introduced CMF at age 105-194 days (the period with highest-risk for IgE-CMA) compared to 33/98 (34%) from the random control group (n = 259) (p = 0.04). CONCLUSIONS: Most infants end up receiving few CMF feeds in the nursery. Transient CMF in the nursery is associated with increased risk of IgE-CMA.

Longitudinal Growth Trajectories in Children with Cow's Milk Allergy: Effects of Elimination Diet and Post-Termination Period.

INTRODUCTION: The primary dietary approach for managing cow's milk allergy (CMA) is the elimination diet. We aimed to compare the growth patterns of children with CMA during and after the elimination diet with healthy peers and identify influencing factors. METHODS: We compared 74 CMA children with age-matched healthy peers. Anthropometric data were collected during the third month of cow's milk elimination (CME) diet (T1), 3 months after diet cessation (T2), and after ≥3 months of normal diet (T3). Control group measurements coincided. Nutrient intake was assessed by a 3-day record, and patient laboratory results were noted at T3. RESULTS: CMA children had consistently lower weight-for-age (WFA) and height-for-age (HFA) z-scores than controls. WtHt z-score of patients was lower than those of the healthy group at T2. HC z-scores of patients were lower than those of the healthy group at T0, T2, and T3. At T3, the HFA z-score of the CME group demonstrated a negative correlation with the duration of the elimination diet (p = 0.045). Inadequate intake of energy, vitamins A, E, B1, B6, C, folic acid, magnesium, and iron was significantly higher in CMA children (p < 0.05). T3 WFA z-score correlated positively with fiber, vitamin B1, magnesium, and iron intake (p < 0.05). T3 WtHt showed a positive moderate correlation with energy, protein, vitamin E, vitamin B1, vitamin B2, vitamin B6, calcium, magnesium, phosphor, iron intake (p < 0.05). CONCLUSIONS: Post-elimination diet, children with CMA need sustained monitoring and potentially micronutrient supplementation to match healthy peers' growth.

Degree of hydrolysis is a poor predictor of the sensitizing capacity of whey- and casein-based hydrolysates in a Brown Norway rat model of cow's milk allergy.

The use of infant formulas (IFs) based on hydrolyzed cow's milk proteins to prevent cow's milk allergy (CMA) is highly debated. The risk of sensitization to milk proteins induced by IFs may be affected by the degree of hydrolysis (DH) as well as other physicochemical properties of the cow's milk-based protein hydrolysates within the IFs. The immunogenicity (specific IgG1 induction) and sensitizing capacity (specific IgE induction) of 30 whey- or casein-based hydrolysates with different physicochemical characteristics were compared using an intraperitoneal model of CMA in Brown Norway rats. In general, the whey-based hydrolysates demonstrated higher immunogenicity than casein-based hydrolysates, inducing higher levels of hydrolysate-specific and intact-specific IgG1. The immunogenicity of the hydrolysates was influenced by DH, peptide size distribution profile, peptide aggregation, nano-sized particle formation, and surface hydrophobicity. Yet, only the surface hydrophobicity was found to affect the sensitizing capacity of hydrolysates, as high hydrophobicity was associated with higher levels of specific IgE. The whey- and casein-based hydrolysates exhibited distinct immunological properties with highly diverse molecular composition and physicochemical properties which are not accounted for by measuring DH, which was a poor predictor of sensitizing capacity. Thus, future studies should consider and account for physicochemical characteristics when assessing the sensitizing capacity of cow's milk-based protein hydrolysates.

To Diet or Not to Diet This Is the Question in Food-Protein-Induced Allergic Proctocolitis (FPIAP)-A Comprehensive Review of Current Recommendations.

Food-protein-induced allergic proctocolitis (FPIAP) is an increasingly reported transient and benign form of colitis that occurs commonly in the first weeks of life in healthy breastfed or formula-fed infants. Distal colon mucosal inflammation is caused by a non-IgE immune reaction to food allergens, more commonly to cow's milk protein. Rectal bleeding possibly associated with mucus and loose stools is the clinical hallmark of FPIAP. To date, no specific biomarker is available, and investigations are reserved for severe cases. Disappearance of blood in the stool may occur within days or weeks from starting the maternal or infant elimination diet, and tolerance to the food allergen is typically acquired before one year of life in most patients. In some infants, no relapse of bleeding occurs when the presumed offending food is reassumed after a few weeks of the elimination diet. Many guidelines and expert consensus on cow's milk allergy have recently been published. However, the role of diet is still debated, and recommendations on the appropriateness and duration of allergen elimination in FPIAP are heterogeneous. This review summarizes and compares the different proposed nutritional management of infants suffering from FPIAP, highlighting the pros and cons according to the most recent literature data.

The future of cow's milk allergy - milk ladders in IgE-mediated food allergy.

Cow's milk allergy (CMA) is one of the most common and complex presentations of allergy in early childhood. CMA can present as IgE and non-IgE mediated forms of food allergy. Non-IgE mediated CMA includes food protein-induced enterocolitis syndrome (FPIES), eosinophilic gastrointestinal disorders (EGIDs), and food protein-induced proctocolitis (FPIAP). There are recent guidelines addressing CMA diagnosis, management, and treatment. Each of these guidelines have their own strengths and limitations. To best manage CMA, individualized avoidance advice should be given. Cow's milk (CM) can be replaced in the diet by using hypoallergenic formulas or plant-based milk, depending on factors such as the child's age and their current food intake. Oral and epicutaneous immunotherapy is used to increase tolerance in children with CMA but is not without risk, and the long-term outcome of sustained unresponsiveness is still unclear. The allergenicity of CM proteins are affected differently by different forms of heating, leading to the use of baked milk or milk ladders in the management of CMA, most likely the most promising option for future management and treatment of CMA. Future management of children with CMA will also include discussion around the immunomodulatory potential of the child's dietary intake.

Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Mobile App/Web Platform for Monitoring Food Oral Immunotherapy in Children: Longitudinal Clinical Validation Study.

BACKGROUND: Milk and egg allergies significantly impact the quality of life, particularly in children. In this regard, food oral immunotherapy (OIT) has emerged as an effective treatment option; however, the occurrence of frequent adverse reactions poses a challenge, necessitating close monitoring during treatment. OBJECTIVE: This study aims to evaluate the ability of a new mobile/web app called OITcontrol to monitor milk and egg OIT. METHODS: Patients undergoing milk or egg OIT were recruited and divided into 2 groups: the active group used the OITcontrol app in conjunction with standard written monitoring methods, whereas the control group relied solely on written diaries. Investigators documented hospital doses, hospital reactions, and administered treatments on the website. Patients recorded their daily allergen home-dose intake, home reactions, and administered treatments using the app. The following variables were compared between both groups: number and severity of hospital and reported home reactions, patient's adhesion to the OITcontrol app or written diary or both in terms of daily home-dose intake and home reactions recording, and treatment and dose adjustment compliance at home in case of reaction. RESULTS: Sixteen patients were assigned to be monitored using the OITcontrol app along with additional written methods (active group), while 14 patients relied solely on a written paper diary (control group). A similar distribution was observed in terms of sex, age, basal characteristics, allergen treated in OIT, premedication, and sensitization profile. Active patients reported a comparable number of hospital and home reactions compared with the control group. In terms of recording system usage, 13/16 (81%) active patients used the OITcontrol app, while 10/14 (71%) control patients relied on the written diary. Among active patients, 6/16 (38%) used both methods, and 1 active patient used only written methods. However, control patients recorded home reactions more frequently than active patients (P=.009). Among active patients, the app was the preferred method for recording reactions (59/86, 69%), compared with the written diary (15/86, 17%) or both methods (12/86, 14%; P<.001). Treatment compliance in home-recorded reactions was similar between both groups (P=.15). However, treatment indications after an adverse reaction were more frequently followed (P=.04) in reactions recorded solely in the app (36/59, 61%) than in the written diary (29/71, 41%) or both systems (4/12, 33%). Moreover, compliance with dose adjustments after a moderate-severe reaction in home-recorded reactions was higher in the active group than in the control group (P<.001). Home reactions recorded only in the app (16/19, 84%) were more likely to follow dose adjustments (P<.001) than those recorded in the written diary (3/20, 15%) or using both methods (2/3, 67%). CONCLUSIONS: The OITcontrol app appears to be a valuable tool for monitoring OIT treatment in children with food allergies. It proves to be a suitable method for recording daily home dose intakes and reactions, and it seems to enhance adherence to treatment indications following an adverse reaction as well as compliance with dose adjustments in home reactions. However, additional studies are necessary to comprehensively grasp the benefits and limitations of using the OITcontrol app in the management of OIT.

The Natural History and Risk Factors for the Development of Food Allergies in Children and Adults.

PURPOSE OF REVIEW: This narrative review explores food allergy prevalence and natural history stratified by life stages, especially in context of evolving knowledge over the last few decades. RECENT FINDINGS: The prevalence of food allergy remains highest in early childhood with common food triggers being cow's milk, soy, hen's egg, wheat, peanut, tree nuts, sesame, fish, and shellfish. This correlates with certain risk factors especially pertinent in the postnatal period which appear to predispose an individual to developing a food allergy. Some allergies (such as milk and egg) were previously thought to be easily outgrown in early life; however, recent studies suggest increasing rates of persistence of these allergies into young adulthood; the reason behind this is unknown. Despite this, there is also evidence demonstrating that food allergies can be outgrown in adolescents and adults. An understanding of the paradigm shifts in the natural history of food allergy allows clinicians to provide updated, age-appropriate, and tailored advice for patients on the management and prognosis of food allergy.

Research progress on the mechanism of probiotics regulating cow milk allergy in early childhood and its application in hypoallergenic infant formula.

Some infants and young children suffer from cow's milk allergy (CMA), and have always mainly used hypoallergenic infant formula as a substitute for breast milk, but some of these formulas can still cause allergic reactions. In recent years, it has been found that probiotic nutritional interventions can regulate CMA in children. Scientific and reasonable application of probiotics to hypoallergenic infant formula is the key research direction in the future. This paper discusses the mechanism and clinical symptoms of CMA in children. This review critically ex- amines the issue of how probiotics use intestinal flora as the main vector to combine with the immune system to exert physiological functions to intervene CMA in children, with a particular focus on four mechanisms: promoting the early establishment of intestinal microecological balance, regulating the body's immunity and alleviating allergic response, enhancing the intestinal mucosal barrier function, and destroying allergen epitopes. Additionally, it overviews the development process of hypoallergenic infant formula and the research progress of probiotics in hypoallergenic infant formula. The article also offers suggestions and outlines potential future research directions and ideas in this field.

Micronutrients in infants suffering from cow's milk allergy fed with dietary formulas and breast milk.

INTRODUCTION: Cow's milk allergy (CMA) is the most common food allergy in infants. As this food allergy indicates a wide range of clinical syndromes due to immunological reactions to cow's milk proteins, we aimed to evaluate the status of micronutrients in infants suffering from cow's milk allergy. METHODS: In this historical cohort study, infants with CMA were divided into two equal groups: breastfeeding and diet formula feeding. Data were gathered by a form, including the micronutrients such as iron, selenium, calcium, phosphorus, zinc, and vitamin D. Groups were compared and data were analyzed by the IBM SPSS version 21. RESULTS: This study involved 60 six-month-old infants, and the findings revealed no significant difference between the two groups concerning magnesium, phosphorus, zinc, and vitamin D. However, infants in the formula-feeding group exhibited significantly elevated mean serum levels of iron and selenium, whereas breastfed infants displayed higher levels of calcium. CONCLUSION: The findings of this research revealed a significant difference in calcium, selenium, and iron levels between formula-fed and breastfed infants, even though all variables were within the normal range for both groups. In light of these results, conducting further studies with a larger sample size and extended follow-up periods becomes imperative.

Current insights into cow's milk allergy in children: Microbiome, metabolome, and immune response-A systematic review.

The increasing prevalence of IgE-mediated cow's milk allergy (CMA) in childhood is a worldwide health concern. There is a growing awareness that the gut microbiome (GM) might play an important role in CMA development. Therefore, treatment with probiotics and prebiotics has gained popularity. This systematic review provides an overview of the alterations of the GM, metabolome, and immune response in CMA children and animal models, including post-treatment modifications. MEDLINE, PubMed, Scopus, and Web of Science were searched for studies on GM in CMA-diagnosed children, published before 1 March 2023. A total of 21 articles (13 on children and 8 on animal models) were included. The studies suggest that the GM, characterized by an enrichment of the Clostridia class and reductions in the Lactobacillales order and Bifidobacterium genus, is associated with CMA in early life. Additionally, reduced levels of short-chain fatty acids (SCFAs) and altered amino acid metabolism were reported in CMA children. Commonly used probiotic strains belong to the Bifidobacterium and Lactobacillus genera. However, only Bifidobacterium levels were consistently upregulated after the intervention, while alterations of other bacteria taxa remain inconclusive. These interventions appear to contribute to the restoration of SCFAs and amino acid metabolism balance. Mouse models indicate that these interventions tend to restore the Th 2/Th 1 balance, increase the Treg response, and/or silence the overall pro- and anti-inflammatory cytokine response. Overall, this systematic review highlights the need for multi-omics-related research in CMA children to gain a mechanistic understanding of this disease and to develop effective treatments and preventive strategies.

Cow's Milk Allergy May Induce Lipid Metabolism Disorder in BALB/c Mice via Exosomes.

Allergic diseases and lipid-metabolism-disorder-derived diseases are both significant public health issues. Recent studies have shown that exosomes are associated with the course of allergic diseases and are involved in lipid metabolism. In this study, exosomes derived from cow's milk allergic (CMA) mice medially loaded lesser proteins favoring cholesterol metabolism. The levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) in the serum were increased in the CMA mice, and hepatic lipid deposition was observed in the liver, but these phenomena were improved by inhibiting the exosome release. Specifically, the higher expression of the sterol regulatory element binding factor 2 (SREBP2) protein and HMGCR gene in the liver of CMA mice indicated an increase in cholesterol synthesis. NPC1L1 was also highly expressed in the small intestine of CMA mice, and fecal TC level was decreased, suggesting that the reabsorption of cholesterol was elevated. The biosynthesis of cholesterol, the reverse cholesterol transport (RCT) process, and the synthesis of bile acid in the liver were improved by inhibiting exosome release, as well as the reabsorption of cholesterol in the small intestine. This study has for the first time demonstrated the lipid metabolism disorder caused by CMA, especially the important role of exosomes in food allergies and lipid metabolism.

Effect of lactic acid bacteria fermentation on cow milk allergenicity and antigenicity: A review.

Cow milk is a major allergenic food. The potential prevention and treatment effects of lactic acid bacteria (LAB)-fermented dairy products on allergic symptoms have garnered considerable attention. Cow milk allergy (CMA) is mainly attributed to extracellular and/or cell envelope proteolytic enzymes with hydrolysis specificity. Numerous studies have demonstrated that LAB prevents the risk of allergies by modulating the development and regulation of the host immune system. Specifically, LAB and its effectors can enhance intestinal barrier function and affect immune cells by interfering with humoral and cellular immunity. Fermentation hydrolysis of allergenic epitopes is considered the main mechanism of reducing CMA. This article reviews the linear epitopes of allergens in cow milk and the effect of LAB on these allergens and provides insight into the means of predicting allergenic epitopes by conventional laboratory analysis methods combined with molecular simulation. Although LAB can reduce CMA in several ways, the mechanism of action remains partially clarified. Therefore, this review additionally attempts to summarize the main mechanism of LAB fermentation to provide guidance for establishing an effective preventive and treatment method for CMA and serve as a reference for the screening, research, and application of LAB-based intervention.

Integrated gut metabolome and microbiome fingerprinting reveals that dysbiosis precedes allergic inflammation in IgE-mediated pediatric cow's milk allergy.

BACKGROUND: IgE-mediated cow's milk allergy (IgE-CMA) is one of the first allergies to arise in early childhood and may result from exposure to various milk allergens, of which ß-lactoglobulin (BLG) and casein are the most important. Understanding the underlying mechanisms behind IgE-CMA is imperative for the discovery of novel biomarkers and the design of innovative treatment and prevention strategies. METHODS: We report a longitudinal in vivo murine model, in which two mice strains (BALB/c and C57Bl/6) were sensitized to BLG using either cholera toxin or an oil emulsion (n = 6 per group). After sensitization, mice were challenged orally, their clinical signs monitored, antibody (IgE and IgG1) and cytokine levels (IL-4 and IFN-γ) measured, and fecal samples subjected to metabolomics. The results of the murine models were further extrapolated to fecal microbiome-metabolome data from our population of IgE-CMA (n = 22) and healthy (n = 23) children (Trial: NCT04249973), on which polar metabolomics, lipidomics and 16S rRNA metasequencing were performed. In vitro gastrointestinal digestions and multi-omics corroborated the microbial origin of proposed metabolic changes. RESULTS: During mice sensitization, we observed multiple microbially derived metabolic alterations, most importantly bile acid, energy and tryptophan metabolites, that preceded allergic inflammation. We confirmed microbial dysbiosis, and its associated effect on metabolic alterations in our patient cohort, through in vitro digestions and multi-omics, which was accompanied by metabolic signatures of low-grade inflammation. CONCLUSION: Our results indicate that gut dysbiosis precedes allergic inflammation and nurtures a chronic low-grade inflammation in children on elimination diets, opening important new opportunities for future prevention and treatment strategies.

Higher Potential Sensitization of Cow αS1-Casein over Goat αS1-Casein in a Mouse Model due to Enhanced Dendritic Cell Uptake and Activation.

Cow's milk allergy is a common food allergy, with the milk protein αS1-casein being a major allergen. This study aimed to investigate differences in sensitization between cow and goat αS1-CN. Cow and goat αS1-CN were labeled with fluorescent dyes and given to mice sensitized with cholera toxin adjuvant. Both proteins reached immune organs, suggesting no major difference in digestion. However, compared with goat αS1-CN, cow αS1-CN is more readily taken up by dendritic cells, inducing dendritic cell maturation. Furthermore, cow αS1-CN can more effectively induce the generation of Th2 cells, leading to a higher production of specific IgE. In a Caco-2/RBL-2H3 cell model, cow αS1-CN caused more mast cell degranulation and loss of epithelial barrier integrity than goat αS1-CN. In summary, this study found differences in immune responses between cow and goat milk αS1-CN. Cow αS1-CN elicited stronger dendritic cell and Th2 responses, leading to increased mast cell degranulation.

Epigenomic and epigenetic investigations of food allergy.

As a potential link between genetic predisposition, environmental exposures, and food allergy outcomes, epigenetics has been a molecular variable of interest in ongoing efforts to understand food allergy mechanisms and outcomes. Here we review population-based investigations of epigenetic loci associated with food allergy, focusing on established clinical food allergy. We first provide an overview of epigenetic mechanisms that have been studied in cohorts with food allergy, predominantly DNA methylation but also microRNA. We then discuss investigations that have implemented epigenome-wide approaches aimed at genome-wide profiling and discovery. Such epigenome-wide studies have collectively identified differentially methylated and differentially regulated loci associated with T cell development, antigen presentation, reaction severity, and causal mediation in food allergy. We then discuss candidate-gene investigations that have honed in on Th1, Th2, T regulatory, and innate genes of a priori interest in food allergy. These studies have highlighted methylation changes in specific candidate genes as associated with T regulatory cell activity as well as differential methylation of Type 1 and Type 2 cytokine genes associated with various food allergies. Intriguingly, epigenetic loci associated with food allergy have also been explored as potential biomarkers for the clinical management of food allergy. We conclude by highlighting several priority directions for advancing population-based epigenomic and epigenetic understandings of food allergy.