The Potential Link Between Eosinophilic Esophagitis and Food Allergy: Inflammatory Pathogenesis and Management

Maria Parmigiani,1,2,* Irene Maria Rita Giuliani,3,* Elena Grueso-Navarro,4– 6 Alfredo J Lucendo4– 61Department of Gastroenterology and Endoscopy, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy; 2Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; 3Post-Acute Care Unit, Giuseppe Serini Long-Term Care Facility, Sabbioneta, Italy; 4Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain; 5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; 6Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Toledo, Spain*These authors contributed equally to this workCorrespondence: Alfredo J Lucendo, Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos, s/n, Tomelloso, Ciudad Real, 13700, Spain, Tel +34 926 525 137, Fax +34 926 525 870, Email ajlucendo@hotmail.comAbstract: Eosinophilic esophagitis (EoE) has transitioned from an isolated gastrointestinal disorder to a recognized type 2 immune-mediated allergic disease, most likely representing a late manifestation of the atopic march. This comprehensive review examines the complex inflammatory pathogenesis linking EoE and food allergy, and critically discusses the mechanisms of disease induction, dietary treatments, and emerging clinical challenges. While genome-wide association studies identify shared susceptibility loci with classic atopy, EoE exhibits distinct tissue-specific pathways, particularly dominated by the local interleukin (IL)-13 axis and highly esophagus-selective proteases like Calpain-14. This unique immunological interplay is clinically epitomized by food oral immunotherapy (OIT)-induced EoE. During OIT, systemic immune reprogramming successfully drives immune tolerance—marked by a robust increase in plasma food-specific IgG4—but fails at the local level, due to the persistence of pathogenic Th2 cells and aberrant mucosal IgG4 immune complex deposition within the esophageal lamina propria. Regarding therapeutic management, conventional skin and serum allergy testing remain highly inaccurate in identifying dietary triggers, rendering test-guided diets ineffective. Conversely, empiric elimination diets achieve robust histological remission, ranging from standardized six-food restrictions to pragmatic single-food approaches targeting cow’s milk. Furthermore, novel insights into industrial milk processing (such as UHT sterilization and homogenization) and specific beta-casein genetic variants (A1 vs A2) highlight how altered protein structures generate neoantigens that accelerate esophageal immunogenicity. In conclusion, decoding the divergent immunological mechanisms operating in the refractory esophagus is essential to move beyond trial-and-error dietary interventions towards non-invasive monitoring tools, precision medicine, and optimized biological therapies in EoE management.Keywords: eosinophilic esophagitis, immunotherapy, oral, diet, food hypersensitivity, immunoglobulin G4, Calpain14, food handling