Eosinophilic gastrointestinal disorders (EGIDs) encompassing eosinophilic esophagitis (EoE), gastritis, enteritis, and colitis are chronic, immune-mediated conditions characterized by a pathological mucosal eosinophilia throughout the gastrointestinal tract. Driven by mixed or non-IgE-mediated immune responses rather than systemic hypersensitivity, EGIDs are anatomically restricted to defined GI segments and governed by organ-specific epithelial-immune-microbial interactions that systemic models of type 2 disease do not adequately capture. Despite rapid advances in genomic, transcriptomic, proteomic, and epigenomic research, integrative multi-omic frameworks that explain inter- and intra-patient heterogeneity, define molecular endotypes, and identify actionable biomarkers for stratified care remain lacking.

A clinically important and underexplored dimension of EGID biology is its intersection with allergen immunotherapy. Both oral (OIT) and subcutaneous (SLIT) immunotherapy are associated with new-onset or exacerbated EGIDs, most notably EoE, as recognized complications of active tolerance induction. Spontaneous cases arising during allergen exposure highlight a mechanistically distinct pathway in which controlled antigen challenge disrupts GI epithelial-immune homeostasis. The molecular underpinnings of immunotherapy-associated EGIDs including local cytokine dysregulation, mast cell activation, and eosinophil recruitment remain poorly characterized and represent an urgent priority for molecular investigation.

In parallel, biologic therapies are transforming EGID management. Agents targeting IL-4Rα (dupilumab), IL-5/IL-5Rα (mepolizumab, benralizumab), CCR3/IL-13 (cendakimab), and emerging targets such as TSLP, IL-33, and Siglec-8 are in active evaluation for EGIDs. However, clinical responses remain heterogeneous, and the GI-tissue-level molecular determinants of biologic efficacy and resistance are poorly understood. Multi-omic profiling offers a route to predictive response biomarkers and precision therapeutic matching within EGID endotypes.

This Research Topic advances integrative molecular profiling frameworks across the EGID disease spectrum, incorporating immunotherapy as a potential disease trigger and biologics as precision therapeutic tools. It focuses exclusively on EGIDs as a disease group and seeks studies that move beyond single-analyte approaches toward systems-level multi-omic integration. Contributors are invited to submit discovery and translational studies spanning molecular endotyping, biomarker identification, immunotherapy-associated disease mechanisms, and biologic target characterization with an emphasis on cross-disciplinary work linking GI mucosal biology with clinical outcomes in EGID cohorts.

Article Themes include but are not limited to:
• Multi-omic data integration in EGIDs: cross-layer analyses spanning genomic, transcriptomic, proteomic, metabolomic, and epigenomic data
• Molecular biomarker discovery and validation: for EGID diagnosis, disease activity, progression, and therapy response in tissue and non-invasive samples
• Systems biology and machine learning: modeling immune-epithelial-microbial interactions in GI mucosal biology
• Molecular endotypes and signaling networks: driving EGID heterogeneity across esophageal, gastric, small intestinal, and colonic segments
• Food-driven immune sensitization: molecular mechanisms initiating or sustaining eosinophilic GI mucosal inflammation
• Immunotherapy-associated EGIDs: mechanisms of OIT-or SLIT-triggered EoE and other EGIDs; spontaneous cases; epithelial-immune disruption, eosinophil recruitment, and molecular risk stratification
• Biologic agents and therapeutic targets: mechanisms of action of dupilumab, anti-IL-5, cendakimab, and emerging agents in GI tissue; tissue-level biomarkers of response and resistance; omics-guided patient-biologic matching
• Environmental, genetic, and epigenetic modulators: of eosinophilic inflammation across GI tissues and gene-environment interactions in EGID risk
• Translational precision medicine: from molecular endotype discovery to stratified therapy and next-generation diagnostic frameworks

Dr. Antonella Cianferoni is on the Advisory Board of Regeneron / Sanofi. The other Topic Editors report no competing interests related to this Research Topic.

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Molecular Profiling, Immunotherapy Intersections, and Therapeutic Targets in Eosinophilic Gastrointestinal Disorders