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.
Highlights
Long-term pump inhibitors (PPIs) use have been associated with adverse consequences, including chronic kidney injury, acute kidney injury, acute interstitial nephritis, hypomagnesemia, Clostridium difficile infection, community-acquired pneumonia, bone fracture and increased risks of gastric and periampullary cancers development and death[5,6,7,8]
We investigated the effects of long-term omeprazole exposure on fecal microbiome and pathophysiology of Wistar rats and discussed the possibility of promoting physiological change
Since the emergence of PPI in the 1970’s, it has been widely used for the treatment of a variety of gastric acid-related diseases
Summary
Long-term PPI use have been associated with adverse consequences, including chronic kidney injury, acute kidney injury, acute interstitial nephritis, hypomagnesemia, Clostridium difficile infection, community-acquired pneumonia, bone fracture and increased risks of gastric and periampullary cancers development and death[5,6,7,8]. Many of these are retrospective and longitudinal observational studies, bias may be introduced and results can be influenced by confounding variables. We investigated the effects of long-term omeprazole exposure on fecal microbiome and pathophysiology of Wistar rats and discussed the possibility of promoting physiological change
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