Long-term Effect Of Proton Pump Inhibitors On Mice Of Helicobacter Pylori Infection And Its Potential Mechanisms

Background:Helicobacter pylori infection causes gastritis, peptic ulcers and gastric cancer. Proton pump inhibitors are effective inhibitors of gastric acid secretion as well as the regimen for acid-related diseases such as peptic ulcer and upper gastrointestinal bleeding. However, the safety of long-term PPI therapy is being questioned in recent years. There are some studies showed that long-term use of proton pump inhibitors can cause micro-nutrient malabsorption and also lead to increased incidence of intestinal infection. What’s more, the risk of the occurrence of fundic gland polyps and atrophic gastritis tends to be higher in Hp-positive individuals on PPI treatment. Still, these conclusions remain controversial.Aim:To learn the long-term effect of proton pump inhibitors on mice of Hp infection, mainly with respect to the effects on the gastric mucosa and alteration in gastric cancer-related genes.Methods:Sixty C57BL/6 mice were randomly divided into four groups (A, B, C and D), each of which contains 15 mice. Group A was the control group, B and C were Hp group and PPI group respectively. Group D was Hp plus PPI group. Group C and D were fed with special pellets which contain 0.05% of esomeprazole. Five Mice were sacrificed in each group of week 45 and the remaining ten mice were sacrificed in week 57. The wet weight of stomach was measured and intragastric pH was also measured. HE staining and Giemsa staining of gastric mucosa were carried out to detecct gastric pathological changes and to confirm Hp infection. Serum TFF1 level and gastrin level were detected by ELISA. Mouse gastric IL-6, SOX2, CDX2, MUC5AC and TFF1 gene expression were detected by real-time PCR.Results:Intragastric pH in group C and D were significantly higher than that of group A and B. Wet weight of stomach was also heavier in group C and D than in group A and B. No precancerous lesions such as intestinal metaplasia and atrophic gastritis were observed in both week 45 and 57. Gastric mucosa were normal in group A and C, but acute and chronic inflammation can be seen in group B. Group D also showed acute and chronic inflammation, but inflammation level was significantly higher than group B(P=0.000). Serum gastrin level was highest in group D both at week 45 and 57. IL-6 level of gastric mucosa was significantly elevated in group B and D than group A. SOX2 expression in gastric mucosa decreased slightly in group B, while a further decline could be observed in group D. CDX2 level elevated in group B and further elevated in the group D. Serum levels of TFF1 and gastric mucosa expression of TFF1 were not comparable.Conclusions:1. We successfully established a C57BL/6 mouse model of long-term use of PPI plus Hp infection. 2. Infection of Hp up to 14 months in C57BL/6 mouse lead to inflammation of gastricmucosa. No precancerous lesions such as intestinal metaplasia and atrophic gastritis were observed in our study.3. PPI and Hp synergistically increased C57BL/6 mice serum gastrin levels.4. PPI can increase the Hp-induced inflammation, showing a time-dependent manner.5. After Hp infection and application of PPI, expression of gastric mucosa associated tumor suppressor genes were reduced in C57BL/6 mice while cancer-promoting gene expression increased.