Gastric stem cells promote inflammation and gland remodeling in response to Helicobacter pylori via Rspo3‐Lgr4 axis

Helicobacter pylori is a pathogen that colonizes the stomach and causes chronic gastritis. Helicobacter pylori can colonize deep inside gastric glands, triggering increased R‐spondin 3 (Rspo3) signaling. This causes an expansion of the “gland base module,” which consists of self‐renewing stem cells and antimicrobial secretory cells and results in gland hyperplasia. The contribution of Rspo3 receptors Lgr4 and Lgr5 is not well explored. Here, we identified that Lgr4 regulates Lgr5 expression and is required for H. pylori ‐induced hyperplasia and inflammation, while Lgr5 alone is not. Using conditional knockout mice, we reveal that R‐spondin signaling via Lgr4 drives proliferation of stem cells and also induces NF‐κB activity in the proliferative stem cells. Upon exposure to H. pylori , the Lgr4‐driven NF‐κB activation is responsible for the expansion of the gland base module and simultaneously enables chemokine expression in stem cells, resulting in gland hyperplasia and neutrophil recruitment. This demonstrates a connection between R‐spondin‐Lgr and NF‐κB signaling that links epithelial stem cell behavior and inflammatory responses to gland‐invading H. pylori . Synopsis The R‐spondin 3–Lgr4 receptor pathway controls gastric gland‐invading pathogen by triggering epithelial expansion and release of pro‐inflammatory mediators. Conditional depletion of Lgr4 in the mouse stomach exhausts Lgr5 expression in the gland base and impairs gland response to Helicobacter pylori . Conditional depletion of Lgr5 alone does not affect epithelial homeostasis and responses to H. pylori . Rspo3 triggers epithelial self‐renewal and hyperplasia via Lgr4, increasing NF‐kappaB signaling‐dependent release of pro‐inflammatory cytokines in stem cells. Graphical Abstract The R‐spondin 3–Lgr4 receptor pathway controls gastric gland‐invading pathogen by triggering epithelial expansion and release of pro‐inflammatory mediators.