While the incidence of gastric cancer in the United States is relatively low due to the diagnosis and treatment of the major risk factor Helicobacter pylori (H. pylori), 5-year patient survival is only approximately 29%. Even after H. pylori infection has been eradicated there is still a risk of developing gastric cancer. Gastric cancer is the final clinical outcome that is often initiated by a sustained inflammatory response and altered epithelial cell differentiation and metaplasia in response to H. pylori infection. Identifying the early epithelial responses to H. pylori infection is important in advancing our understanding of the events that shape a conducive environment for the progression of gastric cancer. Thus, we developed a human gastric tissue-derived organoid-based approach to identify the initiating molecular events that trigger gastric cancer development in response to bacterial infection.