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Updated: Jun 14, 2025
Author Spotlight: Investigating the Pathophysiology of Eosinophilic Esophagitis
Published on: May 10, 2024
Increased expression of proton pump and allergic inflammation genes predicts PPI failure in pediatric eosinophilic
Paroma Bose1, Wenwu Zhang2, Pegah Mehrpouya-Bahrami2,3
1Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, IN, USA.
Insights
Proton pump inhibitor (PPI) treatment for eosinophilic esophagitis (EoE) shows variable success. Higher baseline gene expression of mast cell, cytokine, and proton pump genes in children predicts non-responsiveness to PPIs.
Area of Science:
- Gastroenterology
- Immunology
- Genetics
Background:
- Proton pump inhibitors (PPIs) are a standard treatment for eosinophilic esophagitis (EoE).
- However, PPI response rates in pediatric EoE studies vary significantly (23-63%).
- Predicting PPI responsiveness is crucial for effective EoE management.
Purpose of the Study:
- To investigate whether specific gene expression in esophageal mucosa can predict PPI responsiveness in pediatric EoE.
- To identify potential biomarkers for PPI treatment outcomes in EoE.
Main Methods:
- Prospective study of children with newly diagnosed EoE treated with PPIs for 8 weeks.
- Esophageal biopsies analyzed for gene expression using Nanostring nCounter and immunohistochemistry.
- Patients classified as PPI-Responsive (PPI-R) or PPI-Nonresponsive (PPI-NR) based on follow-up biopsy eosinophil counts.
Main Results:
- 32% of children with EoE achieved PPI-R.
- Higher baseline expression of ATP12A, ATP4A, tryptase-beta 2 (TPSB2), CLC, and IL13 genes was observed in PPI-NR EoE compared to PPI-R EoE and controls.
- ATP12A staining was elevated in both PPI-R and PPI-NR EoE compared to controls.
- PPI-NR EoE showed significantly higher baseline gene expression related to mast cells, cytokines, proton pumps, and eosinophils.
Conclusions:
- Elevated baseline expression of mast cell, cytokine, and proton pump genes may predict PPI non-responsiveness in EoE.
- A potential mechanism involves mast cell activation, IL-13 release, and upregulation of proton pump genes (ATP12A, ATP4A), leading to eosinophil recruitment.
- Histologic PPI failure might occur when these inflammatory components are highly expressed and cannot be pharmacologically overcome.
Abstract:
Proton pump inhibitors (PPIs) are one of the standards of care of eosinophilic esophagitis (EoE) treatment, though PPI response rates are variable ranging from 23 to 63% in pediatric studies. We sought to determine if expression of select genes in esophageal mucosa can predict PPI responsiveness in EoE. Children with a new diagnosis of EoE (15 or more eosinophils/hpf on esophageal biopsy) were prospectively treated with 8 weeks of PPI therapy before follow-up esophagogastroduodenoscopy (EGD). Children with <15 eosinophils/hpf on follow-up were classified as having PPI-Responsive EoE (PPI-R) and ≥ 15 eosinophils/hpf as PPI-Nonresponsive EoE (PPI-NR). Using the Nanostring nCounter Analysis System, mRNA expression of a custom panel of genes was measured in esophageal biopsies. Immunohistochemical staining of biopsies was performed. Among children with EoE, 32% (8/25) had PPI-R EoE. ATP12A, ATP4A, tryptase-beta 2 (TPSB2), CLC and IL13 had higher expression in PPI-NR EoE compared to PPI-R EoE or controls. Immunohistochemical staining of ATP12A was higher among PPI-R EoE and PPI-NR EoE, compared to non-EoE controls. In this study, PPI-NR EoE had significantly higher baseline gene expression of mast cell, cytokine, proton pump, and eosinophil genes compared to PPI-R EoE. PPIs may be involved in an inflammatory cascade of mast cell activation that stimulates IL-13 release, which upregulates ATP12A and ATP4A that leads to eosinophil recruitment. Histologic PPI failure may occur when increased gene expression of these components is high and cannot be overcome pharmacologically, especially in the case of proton pump genes.
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