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The Role of the Microbiota in Food-induced Allergic DisordersBackground: Food-induced allergic disorders (FIAD) have reached pandemic proportions, with an estimated 3-8% of children and adults in Westernized countries living with the daily concern that exposure to certain foods may trigger a life-threatening allergic reaction (1, 2) Currently, there is no cure for food allergies and available medications only treat symptoms after the allergic reaction occurs (3-5). As the public health and economic impact of FIAD continues to grow, there is an urgent need to develop new intervention strategies to prevent and treat these debilitating conditions. While the effector functions mediating food allergies are well described, little is known about the early immunological events that initiate these responses (6-8). Epidemiological studies have demonstrated that cutaneous inflammation associated with atopic dermatitis (AD) is a risk factor for the development of FIAD (9, 10). However, the immunological mechanisms through which antigen sensitization in the skin can predispose to allergic inflammation in the gastrointestinal tract are incompletely understood. Employing a new model of FIAD, my recent studies demonstrated that epicutaneous sensitization to food antigens on an AD-like skin lesion is associated with the infiltration of thymic stromal lymphopoietin (TSLP)-elicited basophils that promote the development of eosinophilic esophagitis (EoE)-like disease and IgE-mediated intestinal food allergy in response to oral antigen exposure (11). Importantly, TSLP-elicited basophil responses were necessary and sufficient for the development of FIAD. Applying a translational approach, we demonstrated that the TSLP-basophil axis is active in patients suffering from EoE, a food-allergy related disease characterized by dense infiltration of eosinophils into inflamed tissue. Further, we found that EoE patients with a polymorphism in the gene encoding for TSLP demonstrated with increased numbers of circulating basophils that positively correlated with the number of eosinophils in the esophageal biopsy. Together, my studies revealed that the TSLP-basophil axis mediates FIAD in a murine model system and is active in patients with EoE. Targeting the TSLP-basophil axis may offer a new therapeutic approach to treat FIAD. Although genetic predisposition is a significant risk factor for developing allergic inflammation, the skyrocketing increase in FIAD over the last three decades suggests that genetic predisposition alone cannot account for the observed phenomenon (12). Recent studies have highlighted that the trillions of bacteria hosting our body are not just hitchhikers, but actively communicate and contribute to the maturation of the host’s immune system (13-15). Alterations in dietary habits, vaccination, antibiotic usage, improved sanitary installations and limited exposure to infections associated with a Western lifestyle may significantly impact the composition of the host’s microbiota (16). There is good evidence from human and animal studies that the risk of allergy relates to a compromised commensal diversity (17, 18). Perturbations in this sophisticated immune-host-microbiota axis may cause dysregulated immune responses fostering the development of food-induced allergic inflammation (19). Understanding the mechanisms by which the microbiota shapes type-2 immune responses may lead to new treatment protocols to limit the development and progression of FIAD. Significance The prevalence of allergic reactions towards foods is continuously rising in developed countries and represents a significant economic burden. Recent work in the field of mucosal immunology demonstrates that alterations in the composition of the microbiota can favor the development of type-2 allergic inflammation. Applying a new-established model of FIAD and state-of-the-art methodologies, the proposed studies will shed light into the relationship and crosstalk between the microbiota and the host’s immune system including its susceptibility to allergic inflammation. Understanding the mechanisms by which microbial communities or microbial-derived metabolites shape type-2 immune responses will help in developing new therapeutic approaches to modulate allergic inflammation.