Helicobacter pylori infection causes gastric mucosal reprogramming into a fetal-like antimicrobial state

ABSTRACT: During gastrointestinal homeostasis, Wnt/R-spondin and BMP signaling regulate the proliferation and differentiation of Lgr5+ cells. Injuries trigger transient epithelial reprogramming into a highly proliferative fetal-like regenerative state, which is Lgr5 signaling-independent and is instead fueled by alternative pathways such as Hippo/YAP signaling. Mechanisms that drive tissue reprogramming are not well understood. In the stomach, infection with the gastric pathogen Helicobacter pylori triggers gland hyperplasia and causes premalignant development. While infection is associated with alterations of homeostatic signals such as enhanced R-spondin signaling and reduced BMP signaling, the development of gastric pathology has also been linked to YAP activation. The exact interplay between these signaling molecules and their contribution to H. pylori-driven pathology remains unclear. Here, we demonstrate that H. pylori-driven gland hyperplasia is fueled by fetal-like regenerative reprogramming, which is mechanistically linked to reduced BMP signaling. The loss of epithelial BMP signaling is sufficient to induce the fetal-like state in vivo but not in organoids, indicating the involvement of cell-extrinsic mechanisms. We discover that epithelial cells that lack BMP signaling are primed to respond to microbes by producing proinflammatory chemokines, which drive tissue infiltration by macrophages and neutrophils. These immune cells in turn trigger stromal remodeling and production of pro-regenerative factors such as prostaglandin E via IL-1β signaling, thus promoting epithelial fetal-like regenerative state. Depletion of the IL-1 receptor in the stroma is sufficient to prevent H. pylori-driven tissue reprogramming and pathology. Our data provide mechanistic insights into fetal-like mucosal reprogramming and demonstrate how this epithelial-immune-stromal cascade is highjacked in the context of H. pylori-driven gastric pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE319373 | GEO | 2026/08/06

REPOSITORIES: GEO