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ABSTRACT Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis. IMPORTANCEMouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.