Long-term High-dose Proton Pump Inhibitor Administration to Helicobacter pylori-infected Mongolian gerbils Enhances Neuroendocrine tumor Development in the Glandular Stomach

Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often withlong-term application. However, there has been some concern about the long-term safety and the possibilityof cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzedthe influence of PPI use on tumor development histologically, immunohistochemically, and serologically in theglandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGswere divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups weregiven 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach sampleswere evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin andgastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI,Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPIadministration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, butnot influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions,PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfectedglandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development andserum gastrin in the MG model.