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

Abstract

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. Proton Pump Inhibitors (PPIs) are one of the most prescribed drugs in many countries. It inhibits the H + /K + ATPase enzyme system in the stomach to suppress acid production, resulting in higher gastric pH. Long-term PPI use is an effective treatment for gastroesophageal disorders and Helicobacter pylori infection, and are taken without prescription to relieve heartburn 1. Despite their increased usage and popularity, over-the-counter (OTC) PPIs such as omeprazole, lansoprazole and pantoprazole are prone to overuse and misuse. There are growing concerns in the medical community about the inappropriate and overuse of PPIs 2-4 .

Association Between Proton Pump Inhibitor Use and Biliary Tract Cancer Risk: A Swedish Population‐Based Cohort Study

“…Chronic, recurrent inflammation of the biliary epithelium, bile stasis and infection are recognizable risk factors for the development of biliary tract cancers (40,41). Many experimental and clinical studies noted higher risk of enteric infections (9,10,13,42), and precancerous changes in the bile duct similar to those observed in high fat diet with PPI use (43). Whether PPI use affects biliary motility is still debated, but chronic hypochlorhydria in PPI use allows harmful bacterial overgrowth and subsequent retrograde biliary tract infection (44)(45)(46).…”

TESC Promotes TGF-α/EGFR-FOXM1-Mediated Tumor Progression in Cholangiocarcinoma

“…To investigate the role of TESC in cholangiocarcinoma tumorigenesis, a rat model of caerulein-induced bile-duct lesions was employed [22]. Immunohistochemical analysis revealed that the TESC expression was higher in the caerulein treatment group compared with the non-treatment group (Figure S4).…”

Clinical significance and intestinal microbiota composition in immunocompromised children with norovirus gastroenteritis

“…In the weighted UniFrac PCoA analysis, a difference in Saccharimonadaceae was found in omeprazole-treated rats compared to untreated rats, implying a role of anti-acid mucosal immunity 26 . One microbiota profile study showed that Oribacterium was one of the major genera in early, invasive colorectal cancer 27 .…”