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

35 Pages Posted: 27 Sep 2018

See all articles by Yu-Chen S. H. Yang

Yu-Chen S. H. Yang

Taipei Medical University

Hsuen-Wen Chang

Taipei Medical University

I-Hsuan Lin

Taipei Medical University

Li-Nien Chien

Taipei Medical University

Min-Ju Wu

Taipei Medical University

Yun-Ru Liu

Taipei Medical University

Peiguo G. Chu

City of Hope National Medical Center

Guoxiang Xie

University of Hawaii

Fangcong Dong

University of Hawaii

Wei Jia

University of Hawaii

Vincent H. S. Chang

Taipei Medical University, College of Medical Science and Technology, PhD Program for Translational Medicine

Yun Yen

Taipei Medical University, College of Medical Science and Technology, PhD Program for Cancer Biology and Drug Discovery; California Institute of Technology - Division of Chemistry and Chemical Engineering

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Abstract

Background: 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.

Methods: Twenty-one Wistar rats were given omeprazole orally for 30 days. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S rRNA gene profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts.

Findings: After long-term PPI exposure, the fecal microbial and metabolites profile was altered and showed similarity to those observed in high-fat diet studies. 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.

Interpretation: We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes, metabolic change and biliary epithelial hyperplasia are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet.

Funding Statement: This work was financially supported in part by a grant from Taipei Medical University, Taiwan (TMU105-AE1-B41), a grant from Ministry of Science and Technology, Taiwan (MOST106-2320-B-038-005) and 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.

Declaration of Interests: The authors declare that they have no competing interests.

Ethics Approval Statement: All animals were maintained and handled in an accredited facility in accordance with IACUC (Institutional Animal Care and Use Committee) guidelines and institutional ethics review board approval.

Keywords: proton pump inhibitors, omeprazole, microbiota, metabolomics, bile duct, high-fat diet

Suggested Citation

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, Long-Term Proton Pump Inhibitor Administration Caused Physiological and Microbiota Changes in Rats (November 9, 2018). Available at SSRN: https://ssrn.com/abstract=3247873

Yu-Chen S. H. Yang

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

Hsuen-Wen Chang

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

I-Hsuan Lin

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

Li-Nien Chien

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

Min-Ju Wu

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

Yun-Ru Liu

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

Peiguo G. Chu

City of Hope National Medical Center

CA
United States

Guoxiang Xie

University of Hawaii

Honolulu, HI 96822
United States

Fangcong Dong

University of Hawaii

Honolulu, HI 96822
United States

Wei Jia

University of Hawaii

Honolulu, HI 96822
United States

Vincent H. S. Chang (Contact Author)

Taipei Medical University, College of Medical Science and Technology, PhD Program for Translational Medicine ( email )

Taiwan

Yun Yen

Taipei Medical University, College of Medical Science and Technology, PhD Program for Cancer Biology and Drug Discovery ( email )

Taiwan

California Institute of Technology - Division of Chemistry and Chemical Engineering ( email )

1200 East California Boulevard
Pasadena, CA 91125
United States

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