Persistent infection with Helicobacter pylori causes chronic gastritis, an essential precursor to gastric cancer. Genetic polymorphisms in the IL18 gene correlate with an increased risk of atrophic gastritis and gastric cancer, yet the regulation and processing of this cytokine in H. pylori inflammation remain poorly understood. It has been reported that sensing of microbial components by NOD-like receptor (NLR) family members (e. g. NLRP1, 3, 6, NLRC4) mediate the processing and secretion of active IL-18 in myeloid cells via inflammasome activation. We have identified non-hematopoietic cells as being the major source of IL-18 in response to H. pylori infection in the gastric mucosa and showed that this was independent of classical inflammasome activation. Furthermore, loss of IL-18 in these cells resulted in gastric hyperplasia and increased acid mucin production. Given that NOD1 recognition of cell wall peptidoglycan plays a key role in gastric epithelial cell (GEC) responses to H. pylori infection, we investigated the involvement of this NLR in H. pylori-induced IL-18 responses. Here, we demonstrate that H. pylori bacterial strains or outer membrane vesicles, able to deliver peptidoglycan to cytosolic NOD1, induce the secretion of mature IL-18 in mouse and human GECs. We showed that H. pylori-induced IL-18 secretion is driven by NOD1 which interacts directly with caspase-1 via its caspase-activation recruitment domain, resulting in processing of pro-IL-18. Collectively, this is the first study to our knowledge that: 1) reveals an unanticipated function of NOD1 in a new type of inflammasome required for post-translational regulation of IL-18 responses in epithelial cells; and 2) demonstrates an important role for IL-18 in the maintenance of gastric mucosal homeostasis. These findings provide a rationale for targeting the NOD1/IL-18 signalling pathway to prevent gastric carcinogenesis due to H. pylori infection.