Beyond eosinophils: A proteomic dissection of remodeling and inflammation in suspected eosinophilic esophagitis

OBJECTIVES: Eosinophilic esophagitis (EoE) is characterized by eosinophilic inflammation and epithelial remodeling. However, current biomarkers focus predominantly on eosinophilia, overlooking basal cell hyperplasia (BCH), a histologic feature that may persist despite treatment. We aimed to differentiate EoE from non-EoE based on inflammatory biomarker profiles, identify biomarkers associated with BCH, and explore their relation toPPI response and food impaction using high-throughput proteomics. METHODS: We conducted a prospective case-control study of patients aged 6-65 undergoing upper endoscopy for suspected EoE. Histology classified patients as EoE (>15 eos/hpf), non-EoE, and assessed for the presence of BCH. Serum was analyzed using the Olink® Explore 384 Inflammation Panel. We compared biomarker expression between EoE versus non-EoE, and BCH versus non-BCH, with adjustment for age, sex, and atopic disease. Exploratory analyses investigated biomarkers related to PPI response and food impaction. RESULTS: Among 86 patients, 26 (30.2%) had EoE and 32 (37.2%) had BCH. CCL26, a marker of eosinophilic inflammation, was the most significantly upregulated biomarker in EoE, was also elevated in BCH, and remained nominally significant even after adjusting for maximum eosinophil count. ITGA11 and TNFRSF11A were nominally associated with BCH independent of eosinophil count. COL9A1 was nominally associated with PPI response and downregulated in non-EoE patients. Oncostatin M (OSM) and TGF-α were nominally associated with food impaction. CONCLUSIONS: High-throughput proteomic profiling revealed distinct biomarker signatures in EoE. CCL26 was the most significantly upregulated marker, associated with both eosinophilic inflammation and epithelial remodeling. COL9A1 may be associated with GERD-related inflammation and PPI responsiveness. These findings support a dual-pathway model of EoE and suggest potential for biomarker-guided diagnosis and treatment.