Abstract
Bile reflux and bacterial dysbiosis are recognized risk factors for gastric carcinogenesis; however, whether bile acids and bacterial-derived metabolites enhance gastric epithelial plasticity and drive inflammatory and metaplastic remodeling remains poorly understood. Here, using human gastric organoids and complementary mouse models, we investigated how chenodeoxycholic acid (CDCA) and the bacterial metabolite β-ADP-heptose influence gastric epitheliallineage identity during early gastric carcinogenesis. Transcriptomic analysis revealed that combined exposure to CDCA and β-ADP-heptose induced extensive epithelial remodeling, characterized by activation of inflammatory and stem-cell pluripotency-associated pathways. Mechanistically, combined CDCA and β-ADP-heptose treatment activated NF-κB signaling, resulting in robust induction of leukemia inhibitory factor (LIF). Elevated LIF expression was accompanied by loss of gastric lineage identity, including reduced expression of TFF2, GKN1, and GKN2, and acquisition of intestinal metaplasia-associated features marked by increased REG4 and CDX1 expression. Pharmacological inhibition of NF-κB or genetic depletion of LIF substantially attenuated these pathological changes, restoring gastric lineage markers and suppressing intestinal-like differentiation. Collectively, our findings show that exposure to CDCA and β-ADP-heptose activates NF-κB-LIF signaling and promotes gastric epithelial lineage remodeling characterized by loss of gastric lineage-associated features and acquisition of intestinal-like features.