Gastric Alterations in Response to Helicobacter pylori Infection

Abstract

Colonization of the human stomach by Helicobacter pylori is the primary risk factor for development of gastric cancer. H. pylori infection stimulates a gastric mucosal inflammatory response and can trigger a cascade of premalignant alterations that potentially lead to gastric adenocarcinoma. The molecular alterations accompanying H. pylori-induced premalignant pathology are incompletely understood. My thesis work has utilized the Mongolian gerbil model of H. pylori-induced gastric carcinogenesis to investigate mechanisms by which H. pylori colonization of the stomach can result in gastric cancer. Conventional histologic staining of gastric tissues revealed that animals infected with a wild-type H. pylori strain had varying levels of gastric pathology, ranging from mild inflammation to adenocarcinoma. Atrophic gastritis, a premalignant condition characterized by the loss of parietal cells and chief cells in a region of the stomach known as the corpus, was detected in many of the H. pylori-infected animals. Transcriptional profiling of gastric tissues revealed an increased abundance of transcripts for proinflammatory cytokines and chemokines; increased abundance of markers for neutrophils, B cells, and Th1/Th17 cells; and loss of markers for specialized corpus cells in animals with atrophic gastritis compared to other groups of animals. Analyses of gastric tissues using imaging mass spectrometry and liquid chromatography tandem mass spectrometry revealed striking differences in the protein and lipid content of the gastric corpus compared to the antrum, with almost 500 proteins preferentially localized to the corpus in uninfected stomachs. Many of the corpus-specific proteins and lipids were reduced in abundance in stomachs from animals with atrophic gastritis compared to stomachs from other groups of animals; these included dozens of proteins with metabolic functions. Other corpus-specific proteins were diffusely delocalized throughout the stomach in animals with atrophic gastritis; these included many proteins with roles in protein processing. Atrophic gastritis, gastric cancer, and corresponding alterations in gastric lipids and proteins were not detected in animals infected with a ∆cagT mutant strain, which lacks Cag type IV secretion system activity. These results provide novel insights into H. pylori-induced gastric molecular alterations that are associated with gastric carcinogenesis.