ABSTRACT Upper Eosinophilic Gastrointestinal Diseases (EGIDs) include Eosinophilic Esophagitis (EoE) and Eosinophilic Gastroenteritis (EGE, which encompasses Eosinophilic Gastritis, EoG, and Eosinophilic Duodenitis, EoD). EGE is one of the more rare EGID subtypes which results in significant morbidity in all genders and ages. Patients with EGE suffer from significant GI symptoms, often mislabeled as irritable bowel syndrome, abdominal pain, and diarrhea. Due to issues in ascertainment of adequate biopsy tissues and eosinophil enumeration in biopsies, these diseases often go under-recognized, resulting in significant healthcare and patient cost. While the etiology of EGE is unknown, we and others have observed that 60-80% of EGE cases coexist with EoE and the remaining 20-40% are isolated EGE cases. Similar to EoE, EGE likely has different immune underpinnings potentially reflected by whether the disease manifests as a more diffuse eosinophilic disease (EGE+EoE) or whether it is isolated eosinophilic disease (EGE). We propose to investigate immunologic signatures in EGE cases with and without concurrent EoE and determine if these signatures predict elevated gastrointestinal eosinophil counts in high-risk relatives without a diagnosis of EGE. Certain tissue-based RNA signatures (especially those related to eosinophil inflammation) may accurately identify and predict EGE, and thus provide a solution to the under-recognition from poor biopsy protocols and lack of eosinophil enumeration. We have recently published that EoE increases one’s risk for EGE in self and families. Identification of relatives of EoE probands with Th2 (or other) mediated inflammation may reflect increased eosinophilia, identifying missed disease or those who would benefit from further work up with eosinophil enumeration. This proposal seeks to further understanding of the immunopathology of EGE through study of those with and without involvement of EoE and associated conditions. This project will aid in the identification of biomarkers for earlier diagnosis and management of EGE leading to fewer endoscopies and biopsies along with more personalized disease management.