Inflammasome Signaling Powers Intestinal Stem Cell Defense Against Salmonella

Researchers from the Hebrew University of Jerusalem and the Weizmann Institute of Science have identified a previously unrecognized defense mechanism in the intestine, showing that intestinal stem cells can actively respond to Salmonella infection and help protect the gut from bacterial invasion.

Intestinal stem cells are responsible for continuously renewing the intestinal lining and maintaining barrier integrity. Until now, these cells were largely considered passive participants during infection, relying on surrounding immune and epithelial cells for protection.

The new study, led by Sacha Lebon, was published in Nature Immunology. The researchers demonstrate that intestinal stem cells can directly sense intracellular Salmonella enterica bacteria and activate an inflammasome-dependent response. Following infection, the stem cells rapidly differentiate into antimicrobial Paneth cells, which secrete molecules that help limit bacterial persistence in the intestinal crypt.

"Our findings show that intestinal stem cells are not only responsible for tissue regeneration, but also participate directly in the early defense against bacterial infection," said co-senior author Matan Hofree.

Using single-cell RNA sequencing, lineage tracing, organoid models, and genetic perturbation approaches, the team mapped the early epithelial response to Salmonella infection at high resolution. The study identified a rapid remodeling process in the intestinal epithelium driven by stem-cell differentiation toward antimicrobial cell types.

The researchers further showed that this response depends on inflammasome signaling mediated by the adaptor protein ASC (encoded by Pycard). When this pathway was disrupted, the protective differentiation response was impaired, leading to increased bacterial persistence and dissemination.

"Our results suggest that stem cell differentiation is part of an intrinsic protective program that helps preserve intestinal function during infection," said co-senior author Moshe Biton.

The study also demonstrated that a similar response occurs in human intestinal organoids, suggesting that the mechanism is conserved in humans. In addition, the researchers found that the Salmonella-associated stem cell signature is enriched in intestinal stem cells from patients with Crohn's disease, pointing to a possible connection between epithelial defense pathways and inflammatory bowel disease.