Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2017; 23(9): 1586-1593
Published online Mar 7, 2017. doi: 10.3748/wjg.v23.i9.1586
Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu
Shiori Mori, Yui Kadochi, Yi Luo, Rina Fujiwara-Tani, Yukiko Nishiguchi, Shingo Kishi, Kiyomu Fujii, Hitoshi Ohmori, Hiroki Kuniyasu, Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara 634-8521, Japan
Author contributions: Kuniyasu H designed research; Mori S, Kadochi Y, Luo Y, Fujiwara-Tani R and Nishiguchi Y performed research; Kishi S contributed analytic tools; Fijii K and Ohmori H analyzed data; Mori S wrote the paper.
Supported by MEXT KAKENHI, No. 14478268 and No. 16675788.
Institutional review board statement: The study was approved by the Institutional Review Board of the Nara Medical University (No. 937).
Conflict-of-interest statement: The authors disclose no potential conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Hiroki Kuniyasu, MD, PhD, Professor, Chairman, Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
Telephone: +81-744-223051 Fax: +81-744-257308
Received: September 26, 2016
Peer-review started: September 27, 2016
First decision: October 28, 2016
Revised: November 13, 2016
Accepted: January 2, 2017
Article in press: January 3, 2017
Published online: March 7, 2017

To elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined.


Collagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry.


CT26 cells expressed a Na+-H+ exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor β and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease.


From these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis.

Keywords: Proton pump inhibitor, Collagenous colitis, pH, Fibrosis, Oxidative stress

Core tip: The main contribution of our paper is the finding of the basic mechanism of proton pump inhibitor evoking collagenous colitis with direct effects to colon epithelial cells. The collagenous colitis is a major cause of non-hemorrhagic watery diarrhea; however, the mechanism of the disease has not been fully elucidated. Our research findings show that proton pump inhibitor causes oxidative stress and collagen synthesis in colon epithelial cells, which might provide an impact to understanding pathogenesis of collagenous colitis and the side effect of proton pump inhibitor.