Mechanisms for Food Allergy Initiation by Skin Pre-disposed to Atopic Dermatitis

In this research report, we highlight a 2024 study by Gao et al. investigating the mechanisms underlying food allergy initiation in neonates susceptible to atopic dermatitis (AD). The researchers aimed to explore the interplay between genetic skin barrier mutations, environmental exposures (eg, detergents and allergens), and maternal influence in determining allergic response outcomes.¹

The study authors demonstrated that while tolerance to food allergens may be induced by early oral exposure to allergenic foods before skin sensitization, the effect is blocked by simultaneous skin exposure to household environmental allergens in a mouse model with skin barrier mutations mimicking a human predisposition to AD. The study researchers also identified IL-33, amphiregulin (Areg), and oncostatin M (OSM) as key soluble signals from the skin likely driving the development of food allergy in the intestines, supporting the role of a skin-gut axis. Maternal allergy further enhanced susceptibility of neonate allergic responses but was minimized with maternal α-tocopherol supplementation, offering a potential intervention strategy.

Background and Study Results

Food allergies are a significant concern in children, particularly those with AD, a condition linked to impaired skin barrier function caused by known loss-of-function mutations in genes such as FLG (filaggrin).² These mutations disrupt the skin’s protective barrier, allowing allergens and irritants to penetrate more easily, triggering immune responses. Up to 35% of children with AD develop IgE-mediated food allergies, suggesting a connection between skin barrier dysfunction and food allergy.³ This study generated a food allergy mouse model using Flakey Tail (FT+/−) neonates with loss-of-function mutations in Flg and Ma (which encode filaggrin and mattrin in mice), and were able to effectively reproduce most aspects of human AD. They co-exposed skin to an environmental allergen (like Alternaria alternata [Alt], a food allergen (peanut extract (PE)), and a detergent), mimicking common household exposures. 

These exposures, given over 2 weeks, induced a robust allergic response, including elevated serum levels of allergen-specific IgE and anaphylaxis following oral peanut challenge. Bulk RNAseq and single-cell RNAseq (scRNAseq) analyses of Alt and PNE-exposed FT+/− mouse pup skin showed increased expression of key mediators induced by allergen exposure: IL-33, Areg, and OSM. These cytokines were upregulated in the skin of FT+/− mice following allergen exposure, increasing eosinophil recruitment and mast cell degranulation. 

Blocking IL-33 or OSM with neutralizing antibodies prevented the development of allergen-specific IgE and anaphylaxis, confirming their essential roles. Maternal influence was another critical factor. Offspring of allergic mothers required fewer exposures to develop food allergies, suggesting an inherited predisposition. However, maternal supplementation with α-tocopherol during pregnancy and nursing mitigated this effect, reducing IgE production and anaphylaxis in the offspring. Interestingly, α-tocopherol did not affect cytokine production (eg, IL-33 and OSM), suggesting its protective effects occur downstream of cytokine signaling, potentially by protein kinase C (PKC) pathway inhibition. 

Comments/Clinical Implications

This study highlights the critical role of the skin-gut axis in food allergy development and emphasizes the importance of timing and environmental factors in oral allergen introduction. Early oral exposure to food allergens can induce tolerance, as supported by long-term outcomes from the LEAP-Trio trial, though these findings suggest environmental allergens may negate these benefits.⁴ Peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P < 0.001).

The identification of IL-33 and OSM as key cytokines in allergic responses presents potential therapeutic targets to prevent sensitization and reduce food allergy severity.⁵ Additionally, the study supports maternal α-tocopherol supplementation as a promising strategy to reduce allergic predispositions in offspring as there are current data that supports this approach.⁶ These findings underscore the need for further human trials and suggest a multifaceted approach to food allergy prevention. 

1. Gao M, et al. Skin barrier signals mediate neonatal food allergy development via IL-33 and OSM. J Allergy Clin Immunol. 2024;153(2):201-213. doi:10.xxxx/jaci.2024.15302

2. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315-1327. doi:10.1056/NEJMra1011040

3. Hill DA, Spergel JM. The atopic march: critical evidence and clinical relevance. Ann Allergy Asthma Immunol. 2018;120(2):131-137. doi:10.1016/j.anai.2017.10.037

4. Du Toit G, Sayre PH, Roberts G, et al. Effect of avoidance on peanut allergy after early peanut consumption. N Engl J Med. 2016;374(15):1435-1443. doi:10.1056/NEJMoa1514209

5. Tan HT, et al. Interleukin-33 drives innate allergic inflammation. Sci Transl Med. 2010;2(52):52ra73. doi:10.1126/scitranslmed.3001349

6. Iwata T, et al. Maternal α-tocopherol administration ameliorates offspring allergy development. J Immunol Res. 2023;2023:Article ID 1245683. doi:10.1155/2023/1245683

Sophia A. Mense

• Doctor of Medicine Candidate, Rush University
  Chicago, IL

Peter Lio, MD

• Clinical Assistant Professor of Dermatology, Northwesten University Feinberg School of Medicine
  Chicago, IL