Helicobacter pylori Exploit Short-Chain Fatty Acids-Induced CAPZA1 Overexpression to Emerge CD44v9-Positive Stemness.

BACKGROUND AND AIMS: Although Helicobacter pylori infects a large proportion of the global population, only a small subset of the infected individuals develop gastric cancer. The molecular mechanisms underlying the selective progression of gastric carcinogenesis are not fully understood. This study aimed to elucidate these mechanisms by focusing on CD44v9-positive cell generation in H pylori-infected gastric mucosa. METHODS: Using H pylori infection models in human gastric adenocarcinoma cells, mice, and mouse-derived gastric organoids, we examined the effects of short-chain fatty acids (SCFAs) on the induction of CD44v9-positive cells using western blotting and immunofluorescence. SCFA concentrations and microbiota compositions were analyzed in gastric juice samples from H pylori-infected patients to evaluate their association with gastric cancer risk. RESULTS: Propionate and butyrate induced capping actin protein of muscle Z-line α subunit 1 (CAPZA1) overexpression via histone deacetylase inhibition. In SCFA-induced CAPZA1-overexpressing cells, the H pylori-derived oncoprotein CagA accumulated due to impaired autophagic degradation, leading to enhanced CD44v9 expression. In the gastric antrum, CD44v9-positive cells undergo CagA-mediated stem cell transformation, whereas a distinct signaling mechanism operates in the gastric corpus. In patients with early gastric cancer, intragastric concentrations of propionate and butyrate are elevated, and the microbiota is enriched with SCFA-producing bacteria. CONCLUSION: SCFA-induced CAPZA1-overexpressing cells serve as a scaffold niche that supports CagA activity and promotes CD44v9-positive cancer stem-like cells. This study sheds new light on the early molecular events driving H pylori-associated gastric carcinogenesis and may inform future strategies for early detection and intervention.