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

• Published in: Scientific reports Vol. 10; no. 1; p. 866
• Main Authors: Yang, Yu-Chen S. H., Chang, Hsuen-Wen, Lin, I-Hsuan, Chien, Li-Nien, Wu, Min-Ju, Liu, Yun-Ru, Chu, Peiguo G., Xie, Guoxiang, Dong, Fangcong, Jia, Wei, Chang, Vincent H. S., Yen, Yun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-01-2020; Nature Publishing Group
• Subjects: 13/51; 45/23; 631/326/2565; 692/308/1426; Abuse; Administration, Oral; alpha-Tocopherol - blood; Animal models; Animals; Bile; Bile Duct Neoplasms - genetics; Bile ducts; Bile Ducts - drug effects; Bile Ducts - pathology; Cell Transformation, Neoplastic - drug effects; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholestasis - chemically induced; Cholestasis - pathology; Epithelium; Fecal microflora; Feces - microbiology; Gastrointestinal Microbiome - drug effects; Gastrointestinal Microbiome - physiology; Gene Expression Regulation - drug effects; High fat diet; Humanities and Social Sciences; Humans; Hyperplasia; Intestinal microflora; Metabolites; Microbiota; multidisciplinary; Omeprazole; Omeprazole - administration & dosage; Omeprazole - adverse effects; Omeprazole - pharmacology; Proton pump inhibitors; Proton Pump Inhibitors - administration & dosage; Proton Pump Inhibitors - adverse effects; Proton Pump Inhibitors - pharmacology; Rats, Wistar; Retinoid X Receptor alpha - genetics; Retinoid X Receptor alpha - metabolism; RNA, Ribosomal, 16S; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Stricture; Tyrosine - blood
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-57612-8

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.