RNAseq analyses of Esophageal biopsies from proton pump inhibitor (PPI)-responsive and PPI-unresponsive Pediatric patients with Eosinophilic Esophagitis.

Clinical trials have identified two distinct eosinophilic esophagitis (EoE) treatment phenotypes, proton pump inhibitor (PPI)-responsive (PPI-R) and PPI-unresponsive (PPI-UR). Herein, we performed clinical, endoscopic, and histologic evaluation of esophageal biopsies from pediatric PPI-R and PPI-UR EoE individuals prior to PPI therapy (diagnosis) and following PPI trial. RNAseq analyses of esophageal biopsy samples revealed common immune and inflammatory transcriptional signatures in both PPI-R EoE and PPI-UR EoE at diagnosis and distinct signatures enriched for processes related to neuropeptide signaling and cell cycle and division. PPI therapy induced histologic, endoscopic, and transcriptional remission in PPI-R EoE, but not in PPI-UR EoE. Persistent disease in PPI-UR EoE was associated with the presence of Th2 inflammatory and dedifferentiated esophageal epithelial transcriptomic signatures, while PPI-R EoE revealed genes enriched in cellular responses to LPS, host defense to viruses and type-I interferon signaling. In silico analyses identified common and unique EoE disease gene drivers in PPI-R and PPI-UR EoE. These studies indicate that the two EoE phenotypes have unique transcriptomic elements that underlie the molecular nature of PPI-R and PPI-UR EoE disease.