Early or late antibiotic intervention prevents Helicobacter pylori-induced gastric cancer in a mouse model

Abstract

H. pylori infection causes gastritis, peptic ulcers and gastric cancer. Eradicating H. pylori prevents ulcers, but to what extent this prevents cancer remains unknown, especially if given after intestinal metaplasia has developed. H. pylori infected wild-type (WT) mice do not develop cancer, but mice lacking the tumor suppressor p27 do so, thus providing an experimental model of H. pylori-induced cancer. We infected p27-deficient mice with H. pylori strain SS1 at 6-8 weeks of age. Persistently H. pylori-infected WT C57BL/6 mice served as controls. Mice in the eradication arms received antimicrobial therapy (omeprazole, metronidazole and clarithromycin) either "early" (at 15 weeks post infection, WPI) or "late" at 45 WPI. At 70 WPI, mice were euthanized for H. pylori determination, histopathology and cytokine/chemokine expression. Persistently infected mice developed premalignant lesions including high-grade dysplasia, whereas those given antibiotics did not. Histologic activity scores in the eradication groups were similar to each other, and were significantly decreased compared with controls for inflammation, epithelial defects, hyperplasia, metaplasia, atrophy and dysplasia. IP-10 and MIG levels in groups that received antibiotics were significantly lower than controls. There were no significant differences in expression of IFN-γ, TNF-α, IL-1β, RANTES, MCP-1, MIP-1α or MIP-1β among the three groups. Thus, H. pylori eradication given either early or late after infection significantly attenuated gastric inflammation, gastric atrophy, hyperplasia, and dysplasia in the p27-deficient mice model of H. pylori-induced gastric cancer, irrespective of the timing of antibiotic administration. This was associated with reduced expression of IP-10 and MIG.

Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer

“…In addition, H. pylori infection of transgenic mice overexpressing gastrin could induce gastric adenocarcinoma [ 25 ], while gastric carcinogenesis was inhibited when H. pylori eradication therapy was introduced [ 26 ]. H. pylori eradication in mice deficient in p27 similarly reversed premalignant lesions [ 27 ].…”

A novel chimeric flagellum fused with the multi-epitope vaccine CTB-UE prevents Helicobacter pylori-induced gastric cancer in a BALB/c mouse model

“…Real-time qPCR to detect the number of H. pylori in the gastric mucosa A real-time quantitative PCR (qPCR) assay was used to measure the ureC copy number to detect H. pylori given that there is only one copy of the ureC gene exists per bacterium, as previously described (He et al 2002;Shukla et al 2011;Zhang et al 2014). Briefly, 30 mg of gastric tissue for each group was resuspended in 1 ml of PBS and homogenized at full speed for 30 s with a blade-blender homogenizer.…”

Mouse models for gastric cancer: Matching models to biological questions

“…Although antibiotic treatment clearly shows effectiveness in controlling Helicobacter infection in mice, the response in a specific preclinical model is likely to be affected by compounding mutations and genetic polymorphisms carried by the host. H. pylori infection of p27‐deficient mice, for instance, revealed that a combination treatment regime of Omeprazole, Metronidazole, and Clarithromycin controlled infection equally well irrespective of whether the treatment occurred 15 or 45 weeks post‐infection, with both groups scoring similarly for inflammation, epithelial defects, metaplasia, and atrophy . By contrast, H. pylori eradication in INS‐GAS mice was more effective when therapeutic intervention was administered at an early point of infection …”