Eosinophil-epithelial interactions mediate protective intestinal remodeling during food allergy

Food allergies are associated with progressive gastrointestinal symptoms driven by exacerbated mucosal type-2 immunity. Here, we investigated whether cellular interactions between the gut epithelium and innate immune cells regulate the severity of allergic symptoms in mice. Using the BALB/c OVA-alum food allergy model, we observed that repeated oral allergen challenges remodel the gut epithelium, expanding tuft cells, while shifting the intestinal stem cell niche toward a fetal-like repair state. Using uLIPSTIC, we systematically characterized in vivo immune-epithelial interactions and found that eosinophils and mast cells directly interact with intestinal epithelial cells (iECs) in an allergen challenge-dependent manner. Epithelial subset-specific uLIPSTIC provided further resolution and revealed that eosinophils and mast cells contact enteroendocrine cells and Paneth cells in a regionally compartmentalized manner. Allergic challenge was associated with rapid eosinophil migration towards the crypts and modulation of iEC differentiation. Depletion of eosinophils using two independent approaches reversed key markers of food allergy-associated epithelial remodeling, while exacerbating allergic diarrhea and mortality from anaphylactic shock. These findings establish eosinophils as orchestrators of protective epithelial remodeling in food allergies.