Epithelial CXCL1 tracks clinical remission in inflammatory bowel disease in a disease-specific manner.

INTRODUCTION: Stem cell-derived organoids are promising platforms for therapeutic screening in inflammatory bowel disease (IBD), but identifying functional organoid readouts with translational utility is challenging. Colon epithelial organoids from patients with ulcerative colitis (UC) overexpress chemokines CXCL1, CXCL11, CCL2, and CCL28, yet whether these epithelial inflammatory signatures correlate with disease activity and treatment response is unclear. This brief report explores whether organoid-retained chemokines correlate with disease activity and therapeutic outcomes. METHODS: We interrogated three bulk and two single-cell transcriptomic datasets from IBD clinical trials encompassing anti-TNFα and anti-integrin therapies to determine whether epithelial chemokines retained in UC organoids are associated with clinical response and distinguish treatment responders from non-responders to biologic therapy across multiple IBD patient cohorts. RESULTS: In bulk transcriptomic data, CXCL1, CXCL11, and CCL2 were elevated in active UC and normalized only in patients achieving clinical remission, independent of therapy class, with persistent chemokine overexpression in non-responders. Linear regression analysis demonstrated that CXCL1 showed the strongest and most consistent association with Mayo clinical disease activity scores across independent cohorts. Single-cell analysis of epithelial cell types identified CXCL1 as the only chemokine significantly enriched in both enterocytes and LGR5-positive stem cells in UC. CXCL1 expression normalized in remission but remained elevated in non-remission patients, and this pattern was recapitulated in LGR5-high stem cell states. Epithelial CXCL1 expression was not associated with clinical remission in Crohn's disease. CONCLUSIONS: CXCL1 is a remission-associated epithelial chemokine in UC and may represent a candidate biomarker and functional endpoint for epithelial-directed therapeutic screening using patient-derived organoid models.