Sustained <i>Helicobacter pylori</i> infection accelerates gastric dysplasia in a mouse model
Valerie P. O’Brien, Amanda Koehne, Julien Dubrulle, Armando E. Rodriguez, Christina K. Leverich, V Kong, Jean S. Campbell, Robert H. Pierce, James R. Goldenring, Eunyoung Choi, Nina R. Salama
Abstract
More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori ( Hp ). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/− Hp infection. Hp +/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp + and Hp − cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.