Helicobacter pylori reshapes stomach cells through an inflammatory relay

Helicobacter pylori reshapes stomach cells not only by damaging the gastric lining and sustaining inflammation. In mice, the bacterium initiated a multistep signaling relay involving epithelial cells, immune cells, and fibroblasts, ultimately pushing the epithelium into a regenerative state whose gene activity resembled that of developing tissue.

H. pylori can persist in the human stomach for years. Infection is associated with chronic gastritis, remodeling of the gastric mucosa, and an increased risk of stomach cancer. Yet many events separate bacterial colonization from long-term changes in tissue architecture. The new study traced much of that chain experimentally.

The key finding is that infection does not simply make the stomach's normal stem cells proliferate more. It changes the regenerative program used by the tissue.

More than an expansion of stem cells

The researchers infected mice with the PMSS1 strain of H. pylori and examined the gastric mucosa after two weeks or two months. By the two-month time point, the model shows inflammation and early pathological changes resembling features associated with premalignant disease. Individual experimental comparisons generally involved three to five mice, while some transcriptomic analyses used fewer samples.

Infected gastric glands became enlarged, and proliferating cells extended well beyond the region where cell division is normally concentrated. One obvious explanation would be an expansion of the conventional Lgr5-associated stem-cell population.

Gene-expression data pointed elsewhere. The Lgr5 stem-cell program was not broadly increased. Instead, the researchers detected a regenerative transcriptional signature together with increased nuclear activity of YAP, a signaling protein that helps coordinate tissue repair.

The authors describe this as a fetal-like regenerative state. That does not mean adult stomach cells literally turn into fetal cells. Rather, they activate a pattern of gene expression similar to programs used by developing or strongly regenerating tissue.

At the same time, H. pylori infection was associated with reduced BMP signaling in the epithelium. BMP normally helps gastric cells differentiate and restrains their responsiveness to inflammatory stimuli. When the researchers genetically removed the BMP receptor Bmpr1a from mouse epithelial cells even without infection, they reproduced gland hyperplasia and many features of the same regenerative program.

But one observation showed that epithelial cells were not acting alone. Removing BMP signaling from isolated gastric organoids did not by itself activate YAP. Something from the surrounding tissue was still required.

A signaling relay across cell types

The next experiments revealed that missing link.

When BMP signaling was active, gastric epithelial cells responded less strongly to bacterial molecules through the inflammatory NF-κB pathway. When BMP signaling was reduced, the epithelium became more inflammatory and produced chemokines that attract immune cells.

Neutrophils and cells of the monocyte-macrophage lineage accumulated in the mucosa. These populations accounted for much of the IL-1β-producing compartment observed in the experiments.

IL-1β, however, did not directly activate YAP when added to epithelial organoids. Its important target was the stromal compartment surrounding the epithelium, particularly fibroblasts.

These fibroblasts express the IL-1 receptor IL1R1. In response to IL-1β they increased activity of COX2 and other components needed to produce prostaglandin E2. Prostaglandin E2 could then act on epithelial cells through the EP4 receptor and stimulate YAP signaling.

The researchers reproduced this sequence in three-dimensional gastric assembloids containing both epithelial and stromal cells. IL-1β increased the number of COX2-positive stromal cells and enhanced nuclear YAP in the epithelium. Blocking the prostaglandin receptor EP4 substantially reduced that YAP response.

The resulting pathway can therefore be summarized as a relay: reduced BMP signaling → epithelial inflammatory signaling → immune-cell recruitment → IL-1β → fibroblast COX2 and prostaglandin E2 → epithelial YAP → regenerative reprogramming.

Removing one link changes the outcome

A particularly informative experiment used mice in which the IL-1 receptor was deleted specifically from stromal cells.

After two months of H. pylori infection, these mice actually carried a higher bacterial burden than infected control animals. The weaker tissue pathology therefore could not be explained by reduced colonization.

Despite the denser infection, the mice developed less gastric gland hyperplasia. They had fewer proliferating epithelial cells, failed to activate epithelial YAP to the same extent, and showed a reduced regenerative gene-expression signature.

This makes stromal IL-1 signaling more than a marker that happens to accompany inflammation. Disrupting that specific step interfered with the tissue-reprogramming pathway itself.

The study does not establish that this pathway directly causes stomach cancer in humans. The causal experiments were performed mainly in mice and mouse-derived organoid or assembloid systems, and several experimental groups were small. The authors also examined previously published human single-cell datasets. Those data support the presence of the relevant cellular machinery: human gastric fibroblasts express IL1R1 and components of the prostaglandin E2 pathway, while IL-1β expression is concentrated mainly in myeloid immune populations. They do not, however, demonstrate the complete causal sequence in patients.

Nor do the findings mean that blocking IL-1, COX2, or prostaglandin signaling is already a strategy for preventing gastric cancer. In fact, disrupting stromal IL-1 signaling increased bacterial colonization in the mice, illustrating that the same inflammatory pathway can contribute both to antimicrobial defense and to pathological tissue remodeling.

The broader message is that chronic infection can alter an organ through more than direct damage to infected cells. It can reconfigure communication among the epithelium, immune system, and surrounding stroma, shifting adult tissue into a persistent repair-like state.