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Long-term Proton Pump Inhibitor Administration Caused Physiological and Microbiota Changes in Rats

Yang, Yu-Chen S. H. and Chang, Hsuen-Wen and Lin, I-Hsuan and Chien, Li-Nien and Wu, Min-Ju and Liu, Yun-Ru and Chu, Peiguo G. and Xie, Guoxiang and Dong, Fangcong and Jia, Wei and Chang, Vincent H. S. and Yen, Yun (2020) Long-term Proton Pump Inhibitor Administration Caused Physiological and Microbiota Changes in Rats. Scientific Reports, 10 . Art. No. 866. ISSN 2045-2322. PMCID PMC6972906.

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Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.

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URLURL TypeDescription CentralArticle
Lin, I-Hsuan0000-0002-6207-1299
Jia, Wei0000-0002-3739-8994
Yen, Yun0000-0003-0815-412X
Additional Information:© 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 12 October 2018; Accepted 06 January 2020; Published 21 January 2020. The authors acknowledge the technical support provided by Cancer Translational Core Facility of TMU and Core Laboratory of Human Microbiome of TMU for microbiome sequencing. This work was financially supported in part by a grant from Taipei Medical University, Taiwan (TMU105-AE1-B41), the grants from Ministry of Science and Technology, Taiwan (MOST106-2320-B-038-005) and (MOST-108-2321-B-038-003), the grants from the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, the grants from Health and welfare surcharge of tobacco products grant (MOHW108-TDU-B-212-124014), (MOHW108-TDU-B-212-124026), (MOHW108-TDU-B-212-124020) and a grant from the University System of Taipei Joint Research Program (USTP-NTUT-TMU-105-04). Author Contributions: Study concept and design: V.H.C. and Y.Y. Acquisition of data: Y.C.Y., H.W.C. and M.J.W. Analysis and interpretation of data: I.H.L. and L.N.C. Drafting of the manuscript: Y.C.Y. Critical revision of the manuscript for important: Y.C.Y., I.H.L., V.H.C. and Y.Y. Intellectual content: Y.C.Y., L.N.C., W.J. and Y.Y. Statistical analysi: I.H.L. Obtained funding: Y.C.Y., V.H.C. and Y.Y. Technical or material support: Y.R.L., P.G.C., G.X., F.D. and W.J. Study supervision: Y.Y. All authors read and approved the final manuscript. The authors declare no competing interests.
Funding AgencyGrant Number
Taipei Medical UniversityTMU105-AE1-B41
Ministry of Science and Technology (Taipei)MOST-106-2320-B-038-005
Ministry of Science and Technology (Taipei)MOST-108-2321-B-038-003
Ministry of Education (Taipei)UNSPECIFIED
Ministry of Health and Welfare (Taipei)MOHW108-TDU-B-212-124014
Ministry of Health and Welfare (Taipei)MOHW108-TDU-B-212-124026
Ministry of Health and Welfare (Taipei)MOHW108-TDU-B-212-124020
University System of Taipei Joint Research ProgramUSTP-NTUT-TMU-105-04
PubMed Central ID:PMC6972906
Record Number:CaltechAUTHORS:20200127-154720034
Persistent URL:
Official Citation:Yang, Y.S.H., Chang, H., Lin, I. et al. Long-term Proton Pump Inhibitor Administration Caused Physiological and Microbiota Changes in Rats. Sci Rep 10, 866 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100956
Deposited By: Tony Diaz
Deposited On:28 Jan 2020 18:06
Last Modified:09 Mar 2020 13:19

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