How dietary landscapes impact food allergy

How dietary landscapes impact food allergy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Brief Communication How dietary landscapes impact food allergy Ralph Nanan, Duan Ni, Alistair Senior, Jian Tan, Laurence Macia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4231050/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Diets and environments are critical determinants for food allergy development. Harnessing unprecedented epidemiological and nutritional data, we examined the overall dietary environments for common food allergens and their intrinsic nutrient composition. We found that food and macronutrient supplies minimally impacted food allergy prevalence, but higher protein and glycine in food allergens correlated with less allergies. These findings offer new directions in food allergy research and management. Health sciences/Medical research/Epidemiology Biological sciences/Immunology/Immunological disorders Health sciences/Diseases/Immunological disorders Health sciences/Health care/Nutrition Health sciences/Health care/Public health/Epidemiology Figures Figure 1 Figure 2 Introduction Food allergies is emerging as a significant public health concern 1 , 2 . One of the central ambitions in allergy research is to characterize the risk factors for food allergy. Previous research mostly focused on the macroenvironments (hygiene hypothesis), the individuals’ biological characteristics, and immunological aspects with gut microbiome as an intermediary 1 . Factors that have been neglected, however, include the intrinsic properties of common trigger foods, like their nutrient compositions, and their extrinsic environments, like interactions with other dietary components. Furthermore, early life exposure to allergenic foods is linked to lower risks of food allergies 3 – 5 . Nevertheless, little is known about whether similar protective effects apply to exposures to specific food environments and nutrient environments. Moreover, studies towards what food components trigger allergy have mostly concentrated on allergenic proteins recognized by the immune system 6 . However, accumulating evidence on involvements of other macronutrients, like fats and carbohydrates, in allergenic sensitization 7 – 9 , suggested that a more holistic overview towards food components and their potential interactions is needed. Harnessing comprehensive epidemiological and nutritional data, we systematically analyzed the extrinsic and intrinsic nutritional factors associated with the prevalence of common food allergies. We interrogated how food and nutrient environments correlate with food allergy prevalence and how the nutrient compositions of foods are linked to allergenicity. Survey of a collection of food allergy studies for the 8 most common food allergens found that extrinsic dietary environments, reflected by the food and macronutrient supplies, minimally impacted food allergy prevalence. However, a robust association was observed between the intrinsic protein and glycine content in food allergens and reduced allergy prevalence. We harnessed a dataset investigating allergies for the 8 common food allergens (milk, egg, peanut, tree nut, wheat, soy, fish and shellfish) in Europe from 2001 to 2021 10 (Fig. 1A). This dataset presented a robust epidemiological landscape in a broad spatiotemporal context for these common and well-characterized food allergies. Figure 1B summarized the pooled estimates for all age self-reported food allergy lifetime and point prevalence. Milk and egg exhibited the highest lifetime and point prevalence respectively. Prevalence data were logit transformed and the food and macronutrient data of the same year were collated for analysis. Annual gross domestic product (GDP) was included for adjustments. GDP reflects the socioeconomic status/wealth, potentially influencing allergy prevalences 2 . Early introduction of allergenic foods confers protection against food allergies later in life 3 – 5 . To test whether exposures via dietary environments confers similar effects, food supplies were used as proxies, and modelled against corresponding food allergy prevalence. Linear models were fitted for the food allergy prevalence against the corresponding scaled food supply and GDP data, with consideration of their potential interactions. As shown in Fig. 1C, there was no significant effect of the supplies of the 8 individual allergens on allergy prevalence. Only for tree nut, GDP showed a significant effect. These results suggested that exposures via allergenic food supplies and the socioeconomic environments, were not generally associated with corresponding food allergy prevalence. We previously showed that allergic diseases could be modulated via diets and were associated with the overall nutrient environments, another critical aspect of dietary exposures 11 – 13 . Food allergy prevalence was thus compared against the macronutrient supplies of the corresponding countries and time points. We found no association, except for tree nut and fish exhibiting negative correlations with fat supplies (Fig. 1D). This indicated that the overall nutrient environments, represented by macronutrient supplies, minimally influenced food allergy prevalence. After extrinsic environments, we next attempted to characterize the intrinsic properties of food allergens, examining not only proteins, the main focus previously, but also other nutrient components and their potential interactions. Macronutrient compositions of the 8 common food allergens were calculated (Fig. 2A-B) and compared against the lifetime food allergy prevalence estimates in 2014 14 and 2023 10 . As shown in Fig. 2C-D, protein compositions in foods were negatively correlated with their corresponding food allergy prevalence, while no association was found for other components (Figure S1 A-C). Analysis based on individual studies yielded similar result (Fig. 2E). To account for potential random confounding effects from specific foods or the countries where the studies were carried out, an array of linear mixed-effect models were fitted. Nutrient compositions of the potential allergenic foods were used as predictors. Foods and countries the data was based on were adjusted as random effects. A model considering the effects from protein content with additive random effects from foods and countries was favoured based on Akaike information criterion (Fig. 2F, Table S1 ). It also unveiled a robust negative correlation between protein content and allergy prevalence (Fig. 2G). Significantly, these associations were validated in independent American and Canadian datasets 15 (Figure S1 D-G). We further interrogated whether amino acids might exert similar effects. Indeed, glycine content exhibited consistent negative correlations with allergy prevalence (Fig. 2H-I). Together, our analyses revealed that protein and glycine content, in the 8 common food allergens, negatively correlated with their allergy prevalence. Leveraging epidemiological and nutritional data, we systematically interrogated how extrinsic and intrinsic nutritional factors are linked to food allergy prevalences. While dietary environments lacked evident effects, higher protein and glycine content in food allergens correlated with lower allergy prevalence. It is established that early life exposure to food allergens induces tolerance against allergies 3 – 5 . Our results suggested that exposures reflected by supplies and availabilities of allergenic foods and dietary macronutrients did not confer such protective effect. This warrants further investigations regarding the threshold and timing of exposures for allergy protection. Instead of focusing solely on food allergenic proteins, our analyses delineated the contributions to allergenicity from different nutrient components and their plausible interactions, shifting the paradigm for interrogating the intrinsic determinants of food allergenicity. We found that higher protein content in trigger foods was associated with lower allergy prevalence, while other nutrient components conferred negligible influences. Specifically, glycine content was linked to reduced food allergy prevalence. Our findings were based on the 8 most common food allergens, with well-characterized clinical features and well-documented epidemiological data. Further high quality epidemiological and nutritional data is needed to validate our discoveries beyond aforementioned 8 allergens. Additionally, similar findings were found for both European and North American populations. It remains to be tested if such results would pertain at a broader global scale. It is unclear how protein content modifies food allergenicity (Fig. 2J). High protein content might alter the food digestibility, interfering with allergen exposure to the host and thus tolerance induction. In this context, the amounts of proteins in allergenic foods are likely to also affect antigen uptake and processing, hence influencing allergenic sensitization. Apart from quantity, protein qualitative properties of trigger foods might be equally important. Glycine content in food allergens correlated with decreased allergy prevalence. Its small size might tweak peptide flexibility and further protein biophysical features. This might also interfere with protein digestion, and/or antigen processing and presentation. Additionally, glycine independently exhibits potent immunomodulatory capacities 16 , suppressing acute allergic responses 17 . Whether these properties could extend to high glycine foods remains to be uncovered. Together, our study sheds unprecedented insights towards dietary factors influencing food allergy by comprehensive surveying their epidemiological and nutritional landscapes, opening novel avenues for allergy research. Our findings prompt future studies to unravel the mechanistic and pathophysiology of food allergies in a broader dietary context, which could guide food allergy managements and/or prevention. Methods Food allergy data and nutritional data were collected as described in Supplementary Information. Analyses were run in RStudio (v4.1.2) with stats and lme4 packages. Detailed methods are available in Supplementary Information. Declarations Data availability All data used in the present study are publicly available as described in Supplementary Information. Acknowledgements This project is supported by the Norman Ernest Bequest Fund. Contributions DN participated to the study design, performed most of the analyses and wrote the manuscript. AS, JT, and LM participated in the analyses and data interpretation. RN supervised the study and wrote the manuscript. All authors read and approved the final manuscript. Ethics declarations LM is a current employee of the Translational Science Hub Global Sanofi Vaccines R&D Brisbane, Australia. Her contribution to this work was when she was an employee of the University of Sydney. The other authors declare no competing interests. References Renz, H. et al. Food allergy. Nat Rev Dis Primers 4 , 17098, doi:10.1038/nrdp.2017.98 (2018). Shin, Y. H. et al. Global, regional, and national burden of allergic disorders and their risk factors in 204 countries and territories, from 1990 to 2019: A systematic analysis for the Global Burden of Disease Study 2019. Allergy 78 , 2232-2254, doi:10.1111/all.15807 (2023). Trogen, B., Jacobs, S. & Nowak-Wegrzyn, A. Early Introduction of Allergenic Foods and the Prevention of Food Allergy. Nutrients 14 , doi:10.3390/nu14132565 (2022). Frazier, A. L., Camargo, C. A., Jr., Malspeis, S., Willett, W. C. & Young, M. C. Prospective study of peripregnancy consumption of peanuts or tree nuts by mothers and the risk of peanut or tree nut allergy in their offspring. JAMA Pediatr 168 , 156-162, doi:10.1001/jamapediatrics.2013.4139 (2014). Bunyavanich, S. et al. Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children. J Allergy Clin Immunol 133 , 1373-1382, doi:10.1016/j.jaci.2013.11.040 (2014). Breiteneder, H. & Mills, E. N. Molecular properties of food allergens. J Allergy Clin Immunol 115 , 14-23; quiz 24, doi:10.1016/j.jaci.2004.10.022 (2005). Bublin, M., Eiwegger, T. & Breiteneder, H. Do lipids influence the allergic sensitization process? J Allergy Clin Immunol 134 , 521-529, doi:10.1016/j.jaci.2014.04.015 (2014). Del Moral, M. G. & Martinez-Naves, E. The Role of Lipids in Development of Allergic Responses. Immune Netw 17 , 133-143, doi:10.4110/in.2017.17.3.133 (2017). Soh, J. Y., Huang, C. H. & Lee, B. W. Carbohydrates as food allergens. Asia Pac Allergy 5 , 17-24, doi:10.5415/apallergy.2015.5.1.17 (2015). Spolidoro, G. C. I. et al. Prevalence estimates of eight big food allergies in Europe: Updated systematic review and meta-analysis. Allergy 78 , 2361-2417, doi:10.1111/all.15801 (2023). Ni, D. et al. Global associations of macronutrient supply and asthma disease burden. Allergy , doi:10.1111/all.16067 (2024). Tan, J. et al. Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways. Cell Rep 15 , 2809-2824, doi:10.1016/j.celrep.2016.05.047 (2016). McKenzie, C., Tan, J., Macia, L. & Mackay, C. R. The nutrition-gut microbiome-physiology axis and allergic diseases. Immunol Rev 278 , 277-295, doi:10.1111/imr.12556 (2017). Nwaru, B. I. et al. Prevalence of common food allergies in Europe: a systematic review and meta-analysis. Allergy 69 , 992-1007, doi:10.1111/all.12423 (2014). Messina, M. & Venter, C. Recent Surveys on Food Allergy Prevalence. Nutrition Today 55 , 22-29, doi:10.1097/nt.0000000000000389 (2020). Aguayo-Ceron, K. A. et al. Glycine: The Smallest Anti-Inflammatory Micronutrient. Int J Mol Sci 24 , doi:10.3390/ijms241411236 (2023). van Bergenhenegouwen, J. et al. Oral exposure to the free amino acid glycine inhibits the acute allergic response in a model of cow's milk allergy in mice. Nutr Res 58 , 95-105, doi:10.1016/j.nutres.2018.07.005 (2018). Additional Declarations Yes there is potential Competing Interest. Laurence Macia is a current employee of the Translational Science Hub Global Sanofi Vaccines R&D Brisbane, Australia. Her contribution to this work was when she was an employee of the University of Sydney. The other authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4231050","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Brief Communication","associatedPublications":[],"authors":[{"id":291289036,"identity":"faea864f-4868-46e5-b07c-21fcb2a44818","order_by":0,"name":"Ralph Nanan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYFAC5gZmKIvxAZAHYfLg1cII18JsQLIWNgmitJi3H2x7XMBwR96c/eyxyp9t1nn8EgmMD962McgbHMCuReZMYrvxDIZnhjt78tJu87alF0vOSGA2nNvGYLgBhxYJhsQ2aR6Gw4wbDuSY3WZsO5y44UYCmzRvGwMjTi38D8Fa7Decf2NW+BOoZf+NBPbfQC32OLVIQGwBGp5jxsALskUigY0ZqCURt5aH7cY8BoeTN9x4YyzNcy49ccaZh82Sc85JJM/E6bDkY495Kg7bbjifY/jxR5l1Yn978sEPb8psbPtwaAECNgYGAyiTEchmEEhsAIcLHsCGxP4DxPy4TR8Fo2AUjIKRCQD+Pl2voEzsdgAAAABJRU5ErkJggg==","orcid":"","institution":"The University of Sydney","correspondingAuthor":true,"prefix":"","firstName":"Ralph","middleName":"","lastName":"Nanan","suffix":""},{"id":291289037,"identity":"2e59d116-e430-4fa7-a856-f94e6a87a63d","order_by":1,"name":"Duan Ni","email":"","orcid":"https://orcid.org/0000-0002-3902-2843","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Duan","middleName":"","lastName":"Ni","suffix":""},{"id":291289038,"identity":"a973f7c2-646d-41aa-b652-598e9f05bf7c","order_by":2,"name":"Alistair Senior","email":"","orcid":"","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Alistair","middleName":"","lastName":"Senior","suffix":""},{"id":291289039,"identity":"be5db6fd-d302-4ebd-9af7-29fd91fd9f8c","order_by":3,"name":"Jian Tan","email":"","orcid":"","institution":"The University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Tan","suffix":""},{"id":291289040,"identity":"f7808ce2-aa47-41fd-9c0a-636bb081b0c6","order_by":4,"name":"Laurence Macia","email":"","orcid":"","institution":"The University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Laurence","middleName":"","lastName":"Macia","suffix":""}],"badges":[],"createdAt":"2024-04-07 11:15:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4231050/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4231050/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55209680,"identity":"bb1ce115-abda-432c-838a-9902c3aa7aa8","added_by":"auto","created_at":"2024-04-24 05:58:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":177159,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-B. \u003c/strong\u003eOverview of allergy studies for the 8 common food allergens (milk, egg, wheat, soy, peanut, tree nut, fish and shellfish, \u003cstrong\u003eA\u003c/strong\u003e) and their pooled results (\u003cstrong\u003eB\u003c/strong\u003e). \u003cstrong\u003eC.\u003c/strong\u003e Effect sizes of the linear modellings for scaled food allergen supplies (kg/capita/year), scaled GDP per capita (U.S. dollars) and the corresponding logit transformed food allergy prevalence. Error bars depict 95% confidence intervals. Red dot denotes statistical significance. \u003cstrong\u003eD.\u003c/strong\u003e Correlation analyses for the logit transformed food allergy prevalence and their corresponding national protein (P, red), carbohydrate (C, cyan) and fat (F, blue) supplies (kg/capita/year) of the same year.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4231050/v1/7405fca836ffd86a4f1e81e2.png"},{"id":55209682,"identity":"a7e6888f-44e2-4c29-97ad-998f077969f6","added_by":"auto","created_at":"2024-04-24 05:58:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":199178,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA-B.\u003c/strong\u003eOverview of the nutrient compositions (g content/100g food, \u003cstrong\u003eA\u003c/strong\u003e) and distributions (\u003cstrong\u003eB\u003c/strong\u003e) of the 8 common food allergens. \u003cstrong\u003eC-D.\u003c/strong\u003eCorrelation analyses for the protein content in food allergens and their corresponding logit transformed allergy prevalence estimates in 2023 (\u003cstrong\u003eC\u003c/strong\u003e) and 2014 (\u003cstrong\u003eD\u003c/strong\u003e). \u003cstrong\u003eE.\u003c/strong\u003e Correlation analysis for the protein content in food allergens and their corresponding logit transformed allergy prevalence reported in 93 studies. \u003cstrong\u003eF.\u003c/strong\u003e Statistical outputs for the null model and the chosen linear mixed-effect model analyzing protein content in food allergens and their corresponding logit transformed allergy prevalence. \u003cstrong\u003eG.\u003c/strong\u003eEstimate plot for the effect of protein content (g/g food) in food allergens and their corresponding logit transformed allergy prevalence based on the chosen linear mixed-effect model. \u003cstrong\u003eH-I.\u003c/strong\u003e Correlation analyses for the glycine content (mg/100g food) in food allergens and their corresponding logit transformed allergy prevalence estimates in 2023 (\u003cstrong\u003eH\u003c/strong\u003e) and 2014 (\u003cstrong\u003eI\u003c/strong\u003e). \u003cstrong\u003eJ.\u003c/strong\u003e Model for the impacts of dietary environments and nutrient compositions on food allergy.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4231050/v1/d9a174b20b0791991be02381.png"},{"id":58787534,"identity":"a6fb02be-6150-4cce-a354-77f21dbf4e66","added_by":"auto","created_at":"2024-06-21 06:28:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":600452,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4231050/v1/438fb1db-3806-4095-bc85-94a7995ce963.pdf"},{"id":55209683,"identity":"1f22c8b4-5c22-4714-af1c-14df5a2a46d8","added_by":"auto","created_at":"2024-04-24 05:58:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":292444,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Supplementaryinformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4231050/v1/0c25103ac48a9cddf6ce3494.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nLaurence Macia is a current employee of the Translational Science Hub Global Sanofi Vaccines R\u0026D Brisbane, Australia. Her contribution to this work was when she was an employee of the University of Sydney. The other authors declare no competing interests.","formattedTitle":"How dietary landscapes impact food allergy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFood allergies is emerging as a significant public health concern\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. One of the central ambitions in allergy research is to characterize the risk factors for food allergy. Previous research mostly focused on the macroenvironments (hygiene hypothesis), the individuals\u0026rsquo; biological characteristics, and immunological aspects with gut microbiome as an intermediary\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Factors that have been neglected, however, include the intrinsic properties of common trigger foods, like their nutrient compositions, and their extrinsic environments, like interactions with other dietary components.\u003c/p\u003e \u003cp\u003eFurthermore, early life exposure to allergenic foods is linked to lower risks of food allergies\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Nevertheless, little is known about whether similar protective effects apply to exposures to specific food environments and nutrient environments. Moreover, studies towards what food components trigger allergy have mostly concentrated on allergenic proteins recognized by the immune system\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, accumulating evidence on involvements of other macronutrients, like fats and carbohydrates, in allergenic sensitization\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, suggested that a more holistic overview towards food components and their potential interactions is needed.\u003c/p\u003e \u003cp\u003eHarnessing comprehensive epidemiological and nutritional data, we systematically analyzed the extrinsic and intrinsic nutritional factors associated with the prevalence of common food allergies. We interrogated how food and nutrient environments correlate with food allergy prevalence and how the nutrient compositions of foods are linked to allergenicity. Survey of a collection of food allergy studies for the 8 most common food allergens found that extrinsic dietary environments, reflected by the food and macronutrient supplies, minimally impacted food allergy prevalence. However, a robust association was observed between the intrinsic protein and glycine content in food allergens and reduced allergy prevalence.\u003c/p\u003e \u003cp\u003eWe harnessed a dataset investigating allergies for the 8 common food allergens (milk, egg, peanut, tree nut, wheat, soy, fish and shellfish) in Europe from 2001 to 2021\u003csup\u003e10\u003c/sup\u003e (Fig.\u0026nbsp;1A). This dataset presented a robust epidemiological landscape in a broad spatiotemporal context for these common and well-characterized food allergies. Figure\u0026nbsp;1B summarized the pooled estimates for all age self-reported food allergy lifetime and point prevalence. Milk and egg exhibited the highest lifetime and point prevalence respectively.\u003c/p\u003e \u003cp\u003ePrevalence data were logit transformed and the food and macronutrient data of the same year were collated for analysis. Annual gross domestic product (GDP) was included for adjustments. GDP reflects the socioeconomic status/wealth, potentially influencing allergy prevalences\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEarly introduction of allergenic foods confers protection against food allergies later in life\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. To test whether exposures via dietary environments confers similar effects, food supplies were used as proxies, and modelled against corresponding food allergy prevalence. Linear models were fitted for the food allergy prevalence against the corresponding scaled food supply and GDP data, with consideration of their potential interactions. As shown in Fig.\u0026nbsp;1C, there was no significant effect of the supplies of the 8 individual allergens on allergy prevalence. Only for tree nut, GDP showed a significant effect. These results suggested that exposures via allergenic food supplies and the socioeconomic environments, were not generally associated with corresponding food allergy prevalence.\u003c/p\u003e \u003cp\u003eWe previously showed that allergic diseases could be modulated via diets and were associated with the overall nutrient environments, another critical aspect of dietary exposures\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Food allergy prevalence was thus compared against the macronutrient supplies of the corresponding countries and time points. We found no association, except for tree nut and fish exhibiting negative correlations with fat supplies (Fig.\u0026nbsp;1D). This indicated that the overall nutrient environments, represented by macronutrient supplies, minimally influenced food allergy prevalence.\u003c/p\u003e \u003cp\u003eAfter extrinsic environments, we next attempted to characterize the intrinsic properties of food allergens, examining not only proteins, the main focus previously, but also other nutrient components and their potential interactions.\u003c/p\u003e \u003cp\u003eMacronutrient compositions of the 8 common food allergens were calculated (Fig.\u0026nbsp;2A-B) and compared against the lifetime food allergy prevalence estimates in 2014\u003csup\u003e14\u003c/sup\u003e and 2023\u003csup\u003e10\u003c/sup\u003e. As shown in Fig.\u0026nbsp;2C-D, protein compositions in foods were negatively correlated with their corresponding food allergy prevalence, while no association was found for other components (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA-C). Analysis based on individual studies yielded similar result (Fig.\u0026nbsp;2E). To account for potential random confounding effects from specific foods or the countries where the studies were carried out, an array of linear mixed-effect models were fitted. Nutrient compositions of the potential allergenic foods were used as predictors. Foods and countries the data was based on were adjusted as random effects. A model considering the effects from protein content with additive random effects from foods and countries was favoured based on Akaike information criterion (Fig.\u0026nbsp;2F, Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). It also unveiled a robust negative correlation between protein content and allergy prevalence (Fig.\u0026nbsp;2G). Significantly, these associations were validated in independent American and Canadian datasets\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eD-G).\u003c/p\u003e \u003cp\u003eWe further interrogated whether amino acids might exert similar effects. Indeed, glycine content exhibited consistent negative correlations with allergy prevalence (Fig.\u0026nbsp;2H-I).\u003c/p\u003e \u003cp\u003eTogether, our analyses revealed that protein and glycine content, in the 8 common food allergens, negatively correlated with their allergy prevalence.\u003c/p\u003e \u003cp\u003eLeveraging epidemiological and nutritional data, we systematically interrogated how extrinsic and intrinsic nutritional factors are linked to food allergy prevalences. While dietary environments lacked evident effects, higher protein and glycine content in food allergens correlated with lower allergy prevalence.\u003c/p\u003e \u003cp\u003eIt is established that early life exposure to food allergens induces tolerance against allergies\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Our results suggested that exposures reflected by supplies and availabilities of allergenic foods and dietary macronutrients did not confer such protective effect. This warrants further investigations regarding the threshold and timing of exposures for allergy protection.\u003c/p\u003e \u003cp\u003eInstead of focusing solely on food allergenic proteins, our analyses delineated the contributions to allergenicity from different nutrient components and their plausible interactions, shifting the paradigm for interrogating the intrinsic determinants of food allergenicity. We found that higher protein content in trigger foods was associated with lower allergy prevalence, while other nutrient components conferred negligible influences. Specifically, glycine content was linked to reduced food allergy prevalence. Our findings were based on the 8 most common food allergens, with well-characterized clinical features and well-documented epidemiological data. Further high quality epidemiological and nutritional data is needed to validate our discoveries beyond aforementioned 8 allergens. Additionally, similar findings were found for both European and North American populations. It remains to be tested if such results would pertain at a broader global scale.\u003c/p\u003e \u003cp\u003eIt is unclear how protein content modifies food allergenicity (Fig.\u0026nbsp;2J). High protein content might alter the food digestibility, interfering with allergen exposure to the host and thus tolerance induction. In this context, the amounts of proteins in allergenic foods are likely to also affect antigen uptake and processing, hence influencing allergenic sensitization.\u003c/p\u003e \u003cp\u003eApart from quantity, protein qualitative properties of trigger foods might be equally important. Glycine content in food allergens correlated with decreased allergy prevalence. Its small size might tweak peptide flexibility and further protein biophysical features. This might also interfere with protein digestion, and/or antigen processing and presentation. Additionally, glycine independently exhibits potent immunomodulatory capacities\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, suppressing acute allergic responses\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Whether these properties could extend to high glycine foods remains to be uncovered.\u003c/p\u003e \u003cp\u003eTogether, our study sheds unprecedented insights towards dietary factors influencing food allergy by comprehensive surveying their epidemiological and nutritional landscapes, opening novel avenues for allergy research. Our findings prompt future studies to unravel the mechanistic and pathophysiology of food allergies in a broader dietary context, which could guide food allergy managements and/or prevention.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eFood allergy data and nutritional data were collected as described in Supplementary Information. Analyses were run in RStudio (v4.1.2) with \u003cem\u003estats\u003c/em\u003e and \u003cem\u003elme4\u003c/em\u003e packages. Detailed methods are available in Supplementary Information.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data used in the present study are publicly available as described in Supplementary Information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project is supported by the Norman Ernest Bequest Fund.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDN participated to the study design, performed most of the analyses and wrote the manuscript. AS, JT, and LM participated in the analyses and data interpretation. RN supervised the study and wrote the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLM is a current employee of the Translational Science Hub Global Sanofi Vaccines R\u0026amp;D Brisbane, Australia. Her contribution to this work was when she was an employee of the University of Sydney. The other authors declare no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRenz, H.\u003cem\u003e et al.\u003c/em\u003e Food allergy. \u003cem\u003eNat Rev Dis Primers\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 17098, doi:10.1038/nrdp.2017.98 (2018).\u003c/li\u003e\n\u003cli\u003eShin, Y. 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A.\u003cem\u003e et al.\u003c/em\u003e Glycine: The Smallest Anti-Inflammatory Micronutrient. \u003cem\u003eInt J Mol Sci\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, doi:10.3390/ijms241411236 (2023).\u003c/li\u003e\n\u003cli\u003evan Bergenhenegouwen, J.\u003cem\u003e et al.\u003c/em\u003e Oral exposure to the free amino acid glycine inhibits the acute allergic response in a model of cow\u0026apos;s milk allergy in mice. \u003cem\u003eNutr Res\u003c/em\u003e \u003cstrong\u003e58\u003c/strong\u003e, 95-105, doi:10.1016/j.nutres.2018.07.005 (2018).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4231050/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4231050/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDiets and environments are critical determinants for food allergy development. Harnessing unprecedented epidemiological and nutritional data, we examined the overall dietary environments for common food allergens and their intrinsic nutrient composition. We found that food and macronutrient supplies minimally impacted food allergy prevalence, but higher protein and glycine in food allergens correlated with less allergies. These findings offer new directions in food allergy research and management.\u003c/p\u003e","manuscriptTitle":"How dietary landscapes impact food allergy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-24 05:58:06","doi":"10.21203/rs.3.rs-4231050/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41e4f23a-7a10-41b0-b483-972402c20901","owner":[],"postedDate":"April 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30680577,"name":"Health sciences/Medical research/Epidemiology"},{"id":30680578,"name":"Biological sciences/Immunology/Immunological disorders"},{"id":30680579,"name":"Health sciences/Diseases/Immunological disorders"},{"id":30680580,"name":"Health sciences/Health care/Nutrition"},{"id":30680581,"name":"Health sciences/Health care/Public health/Epidemiology"}],"tags":[],"updatedAt":"2024-06-21T06:20:26+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-24 05:58:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4231050","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4231050","identity":"rs-4231050","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}