Impaired mucosal integrity in proximal esophagus is involved in development of proton pump inhibitor-refractory nonerosive reflux disease

Kazuaki Norita, Kiyotaka Asanuma, Tomoyuki Koike, Tomoki Okata, Taku Fujiya, Yasuaki Abe, Kenichiro Nakagawa, Waku Hatta, Kaname Uno, Tomohiro Nakamura, Naoki Nakaya, Naoki Asano, Akira Imatani, Tooru Shimosegawa, Atsushi Masamune

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Objective: Weakly acidic reflux reaching to the proximal esophagus is closely related to the perception of gastroesophageal reflux in patients with nonerosive reflux disease despite treatment with a proton pump inhibitor (PPI). However, little is known about the involvement of the patients' mucosal integrity of the proximal esophagus. Methods: We recruited 15 symptomatic nonerosive gastroesophageal reflux disease (GERD) patients with a positive symptom index despite PPI treatment and 11 healthy asymptomatic volunteers as controls. The biopsy specimens obtained from the proximal and distal esophagus were applied to a mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) against a pH 4 weak acid. The esophageal biopsy samples were subjected to quantitative real-time PCR and immunohistochemical analysis. Results: In the proximal esophagus, the weak acid exposure reduced the TEER in the PPI-refractory patients compared to that in the controls. The frequency of the reflux extending to the proximal esophagus had a significant correlation with the reduction in the proximal esophageal TEER in the patients. The reduced TEER in the proximal esophagus was accompanied by an increase in IL-8 and IL-1β mRNA and a decrease in occludin mRNA levels. The proximal esophageal mucosa in the patients presented infiltration of CD3-positive lymphocytes and an increased expression of solute carrier organic anion transporter family member 2A1 (SLCO2A1), a passage gate of reflux symptom-evoking molecules. Conclusions: The reflux perception is related to an impairment of the proximal esophageal mucosal integrity in patients with nonerosive reflux disease despite PPI.

Original languageEnglish
JournalDigestion
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • Acid hypersensitivity
  • Nonerosive reflux disease
  • Proton pump inhibitor refractory
  • Proximal esophagus
  • Transepithelial electrical resistance

ASJC Scopus subject areas

  • Gastroenterology

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