Causal immune-inflammation mapping of the GERD-Barrett-adenocarcinoma cascade identifies FGF19-HLA-DR⁺ T-cell axis driving esophagogastric junction metaplasia.

Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined. Summary-level genome-wide association study (GWAS) data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran's Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in esophagogastric junction (EGJ) organoids and mouse models. MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4 + T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR + T-cell axis, experimental studies demonstrated that FGF19 promotes EGJ glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8 + T cells, validated in EGJ organoids and mouse models. This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a candidate cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8 + T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.