The gastric bacterium Helicobacter pylori chronically colonizes approximately half of the world’s population and triggers a cascade of inflammatory responses that can ultimately lead to gastric intestinal metaplasia (GIM) and gastric cancer (GC). While the early stages of this pathological cascade are reversible with H. pylori eradication via antibiotic treatment, GIM often represents a point of no return, placing patients at high risk for cancer. GIM is defined as the replacement of the gastric mucosa with an epithelium of intestinal identity, characterized by the appearance of goblet cells in the stomach. While the architectural features of this lesion are well characterized, the underlying molecular mechanisms remain largely unclear.

Using CRISPR/Cas9 technology, we generated TP53 loss-of-function mutations in gastric organoids and functionally characterized them through RNA-seq, microscopy and infection experiments. Moreover, we validated our findings in TP53-mutant mice and patient-derived samples.

TP53 mutant gastric organoids showed clear signs of reprogramming toward intestinal cells, including the activation of key intestinal markers such as the mucin MUC2 and CDX2, a hallmark of GIM. Interestingly, TP53 mutation in gastric organoids increased the production of antimicrobial peptides, including DMBT1. This antimicrobial protein, which was only expressed in metaplastic cells, showed potent activity against H. pylori.

Our results suggest that TP53 loss-of-function mutations drive GIM in the stomach and may contribute to its irreversible progression to gastric cancer. Furthermore, the identification of DMBT1 as a mutant p53-dependent antimicrobial factor provides new insights into the mechanisms underlying H. pylori clearance in the precancerous stage of GIM.