Eosinophilic gastrointestinal disorders and allergen immunotherapy: Lights and shadows.

Allergic diseases, such as IgE-mediated food allergy, asthma, and allergic rhinitis, are relevant health problems worldwide and show an increasing prevalence. Therapies for food allergies are food avoidance and the prompt administration of intramuscular epinephrine in anaphylaxis occurring after accidental exposure. However, allergen immunotherapy (AIT) is being investigated as a new potential tool for treating severe food allergies. Effective oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) induce desensitization and restore immune tolerance to the causal allergen. While immediate side effects are well known, the long-term effects of food AIT are still underestimated. In this regard, eosinophilic gastrointestinal disorders (EGIDs), mainly eosinophilic esophagitis, have been reported as putative complications of OIT for food allergy and sublingual immunotherapy (SLIT) for allergic asthma and rhinitis. Fortunately, these complications are usually reversible and the patient recovers after AIT discontinuation. This review summarizes current knowledge on the possible causative link between eosinophilic gastrointestinal disorders and AIT, highlighting recent evidence and controversies.

Corrigendum: Advances and potential of omics studies for understanding the development of food allergy.

[This corrects the article DOI: 10.3389/falgy.2023.1149008.].

Advances and potential of omics studies for understanding the development of food allergy.

The prevalence of food allergy continues to rise globally, carrying with it substantial safety, economic, and emotional burdens. Although preventative strategies do exist, the heterogeneity of allergy trajectories and clinical phenotypes has made it difficult to identify patients who would benefit from these strategies. Therefore, further studies investigating the molecular mechanisms that differentiate these trajectories are needed. Large-scale omics studies have identified key insights into the molecular mechanisms for many different diseases, however the application of these technologies to uncover the drivers of food allergy development is in its infancy. Here we review the use of omics approaches in food allergy and highlight key gaps in knowledge for applying these technologies for the characterization of food allergy development.

The First 1000 Days of Life: How Changes in the Microbiota Can Influence Food Allergy Onset in Children.

BACKGROUND: Allergic disease, including food allergies (FA)s, has been identified as a major global disease. The first 1000 days of life can be a "window of opportunity" or a "window of susceptibility", during which several factors can predispose children to FA development. Changes in the composition of the gut microbiota from pregnancy to infancy may play a pivotal role in this regard: some bacterial genera, such as Lactobacillus and Bifidobacterium, seem to be protective against FA development. On the contrary, Clostridium and Staphylococcus appear to be unprotective. METHODS: We conducted research on the most recent literature (2013-2023) using the PubMed and Scopus databases. We included original papers, clinical trials, meta-analyses, and reviews in English. Case reports, series, and letters were excluded. RESULTS: During pregnancy, the maternal diet can play a fundamental role in influencing the gut microbiota composition of newborns. After birth, human milk can promote the development of protective microbial species via human milk oligosaccharides (HMOs), which play a prebiotic role. Moreover, complementary feeding can modify the gut microbiota's composition. CONCLUSIONS: The first two years of life are a critical period, during which several factors can increase the risk of FA development in genetically predisposed children.

Atopic Dermatitis Mediates the Association Between an IL4RA Variant and Food Allergy in School-Aged Children.

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests. OBJECTIVE: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA. METHODS: A total of 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA576 allele. Surveys were administered to determine FA, AD, and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, sex, and household income. Multivariate models were used to determine the association between genotype and FA severity. RESULTS: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03-1.87], P = .03), and AD increased odds of FA 3.67-fold ([2.05- 6.57], P < .01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (odds ratio [95% CI], Q/R = 1.13 [1.02-1.24], R/R = 1.28 [1.04-1.51]; P < .01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26-5.71], P = .01). CONCLUSIONS: In a cohort of children with asthma, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA.

The Road Toward Transformative Treatments for Food Allergy.

A series of landmark studies have provided conclusive evidence that the early administration of food allergens dramatically prevents the emergence of food allergy. One of the greatest remaining challenges is whether patients with established food allergy can return to health. This challenge is particularly pressing in the case of allergies against peanut, tree nuts, fish, and shellfish which are lifelong in most patients and may elicit severe reactions. The standard of care for food allergy is allergen avoidance and the timely administration of epinephrine upon accidental exposure. Epinephrine, and other therapeutic options like antihistamines provide acute symptom relief but do not target the underlying pathology of the disease. In principle, any transformative treatment for established food allergy would require the restoration of a homeostatic immunological state. This may be attained through either an active, non-harmful immune response (immunological tolerance) or a lack of a harmful immune response (e.g., anergy), such that subsequent exposures to the allergen do not elicit a clinical reaction. Importantly, such a state must persist beyond the course of the treatment and exert its protective effects permanently. In this review, we will discuss the immunological mechanisms that maintain lifelong food allergies and are, consequently, those which must be dismantled or reprogrammed to instate a clinically non-reactive state. Arguably, the restoration of such a state in the context of an established food allergy would require a reprogramming of the immune response against a given food allergen. We will discuss existing and experimental therapeutic strategies to eliminate IgE reactivity and, lastly, will propose outstanding questions to pave the road to the development of novel, transformative therapeutics in food allergy.

Trends in the contributions of atopic family history to pediatric food sensitization and allergy.

Objective: Family history of atopic diseases (FHA) contributes to food allergy (FA). But little is known whether FHA primarily increases IgE-mediated, non-IgE-mediated FA, or both. And the trends in the contributions of FHA to food sensitization (FS) and FA remain unclear. We aim to clarify the associations among FHA, FS and FA and to understand the trends in the contributions of FHA to FS and FA. Methods: We used chi-square test and mediating effect model to analyze the associations among FHA, FS and FA through comparisons between two cross-sectional investigations on FA in children under 2 years old in 2009 and 2019. Results: In 2009 and 2019, the positive FHA proportion tended to be increasing without significance (28.9% to 31.6%, P = 0.39). Subgroup analysis showed the FS rate in FA group decreased significantly (37/39 to 44/62, P = 0.003). In 2009, the FS rate and FA prevalence were higher in FHA (+) group than in FHA (-) group (26% vs. 14.7%, P = 0.008 and 15% vs. 7.7%, P = 0.03), and FS had a complete mediating effect on the association between FHA and FA (Z = 2.54, P = 0.011), but the results lost significance in 2019. Conclusions: The association between FHA and FA was completely mediated by FS, which means FHA mainly increases IgE-mediated FA. And the contributions of FHA to FS and FA tended to be stabilized or even diminished, which means FHA alone could no longer be enough to screen high-risk children.

Clinical Manifestations of Pediatric Food Allergy: a Contemporary Review.

Food allergies (FAs) are an emerging health care issue, and a "second wave of the allergy epidemic" was named. There are extensive data that documented the prevalence rate as high as approximately 10%. FAs are immunological adverse reactions, including IgE-mediated mechanisms, cell-mediated mechanisms, or mixed IgE- and cell-mediated mechanisms. A diagnosis of FA is made by specific symptoms encounter with food, detailed past history, sensitization tests, and oral food challenges (OFCs) if necessary. The component-resolved diagnostics (CRD) test can distinguish true or cross-reaction. "Minimal elimination" from the results of CRD and OFC could avoid unnecessary food restriction. Strict food limitation is harsh and stressful on patients and their families. Children with FAs experience a higher rate of post-traumatic stress symptoms (PTSS) and bullying than others. In the last 20 years, oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) are treatment strategies. OIT and EPIT are the most two encouraging treatments for FA. This review aims to introduce FAs in diverse clinical disorders, new perspectives, and their practical implications in diagnosing and treating FA.

Pro-inflammatory Diet Pictured in Children With Atopic Dermatitis or Food Allergy: Nutritional Data of the LiNA Cohort.

Background: Lifestyle and environmental factors are known to contribute to allergic disease development, especially very early in life. However, the link between diet composition and allergic outcomes remains unclear. Methods: In the present population-based cohort study we evaluated the dietary intake of 10-year-old children and analyses were performed with particular focus on atopic dermatitis or food allergy, allergic diseases known to be affected by dietary allergens. Dietary intake was assessed via semi-quantitative food frequency questionnaires. Based on these data, individual nutrient intake as well as children's Dietary Inflammatory Index (C-DII™) scores were calculated. Information about atopic manifestations during the first 10 years of life and confounding factors were obtained from standardized questionnaires during pregnancy and annually thereafter. Results: Analyses from confounder-adjusted logistic regression models (n = 211) revealed that having atopic outcomes was associated with having a pro-inflammatory pattern at the age of 10 years: OR = 2.22 (95% CI: 1.14-4.31) for children with atopic dermatitis and OR = 3.82 (95% CI: 1.47-9.93) for children with food allergy in the first 10 years of life. Conclusion: A pro-inflammatory dietary pattern might worsen the atopic outcome and reduce the buffering capacity of the individual against harmful environmental exposures or triggers. For pediatricians it is recommended to test for the individual tolerance of allergenic foods and to increase the nutrient density of tolerable food items to avoid undesirable effects of eating a pro-inflammatory diet.

The Environmental Microbiome, Allergic Disease, and Asthma.

The environmental microbiome represents the entirety of the microbes and their metabolites that we encounter in our environments. A growing body of evidence supports the role of the environmental microbiome in risk for and severity of allergic diseases and asthma. The environmental microbiome represents a ubiquitous, lifelong exposure to non-self antigens. During the critical window between birth and 1 year of life, interactions between our early immune system and the environmental microbiome have 2 consequences: our individual microbiome is populated by environmental microbes, and our immune system is trained regarding which antigens to tolerate. During this time, a diversity of exposures appears largely protective, dramatically decreasing the risk of developing allergic diseases and asthma. As we grow older, our interactions with the environmental microbiome change. While it continues to exert influence over the composition of the human microbiome, the environmental microbiome becomes increasingly a source for antigenic stimulation and infection. The same microbial exposure protective against disease development may exacerbate disease severity. Although much has been learned about the importance of the environmental microbiome in allergic disease, much more remains to be understood about these complicated interactions between our environment, our microbiome, our immune system, and disease.

The Infant Microbiome and Its Impact on Development of Food Allergy.

The prevalence of food allergy (FA) has been increasing over the past few decades; recent statistics suggest that FA has an impact on up to 10% of the population and 8% of children. Although the pathogenesis of FA is unclear, studies suggest gut microbiome plays a role in the development of FA. The gut microbiome is influenced by infant feeding method, infant diet, and maternal diet during lactation. Breastfeeding, Mediterranean diet, and probiotics are associated with commensal gut microbiota that protect against FA. This area of research is essential to discovering potential preventive methods or therapeutic targets against FA.

Pathogenesis of Children's Allergic Diseases: Refocusing the Role of the Gut Microbiota.

Allergic diseases comprise a genetically heterogeneous cluster of immunologically mediated diseases, including asthma, food allergy (FA), allergic rhinitis (AR) and eczema, that have become major worldwide health problems. Over the past few decades, the spread of allergic diseases has displayed an increasing trend, and it has been reported that 22% of 1.39 billion people in 30 countries have a type of allergic disease. Undoubtedly, allergic diseases, which can be chronic, with significant morbidity, mortality and dynamic progression, impose major economic burdens on society and families; thus, exploring the cause of allergic diseases and reducing their prevalence is a top priority. Recently, it has been reported that the gastrointestinal (GI) microbiota can provide vital signals for the development, function, and regulation of the immune system, and the above-mentioned contributions make the GI microbiota a key player in allergic diseases. Notably, the GI microbiota is highly influenced by the mode of delivery, infant diet, environment, antibiotic use and so on. Specifically, changes in the environment can result in the dysbiosis of the GI microbiota. The proper function of the GI microbiota depends on a stable cellular composition which in the case of the human microbiota consists mainly of bacteria. Large shifts in the ratio between these phyla or the expansion of new bacterial groups lead to a disease-promoting imbalance, which is often referred to as dysbiosis. And the dysbiosis can lead to alterations of the composition of the microbiota and subsequent changes in metabolism. Further, the GI microbiota can affect the physiological characteristics of the human host and modulate the immune response of the host. The objectives of this review are to evaluate the development of the GI microbiota, the main drivers of the colonization of the GI tract, and the potential role of the GI microbiota in allergic diseases and provide a theoretical basis as well as molecular strategies for clinical practice.