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

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.