BackgroundMetabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified.MethodsXanthurenic acid (XA) was measured in gastric cancer cells treated withH. pyloriorH. pylorivirulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlyingH. pylorimediated kynurenine pathway in intestinal metaplasia in vivo and in vitro.ResultsHerein, we, for the first time, demonstrated thatH. pyloricontributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway.H. pyloripromoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically,H. pyloriactivated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect ofH. pylorion CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated withH. pyloriafter IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2.ConclusionThese finding suggestedH. pyloricontributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused byH. pyloriinfection.Video AbstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12964-023-01162-9.