A Scalable Microarrayed Organoid Platform for Precision Modeling of Intestinal Epithelial Damage and Recovery

ABSTRACT: Chronic inflammatory bowel diseases (IBD), including Crohn's disease, are characterized by relapsing-remitting intestinal inflammation associated with a dysfunctional intestinal epithelial barrier. Existing preclinical in vitro models of IBD have limitations in accurately reproducing the dynamic processes of epithelial barrier dysfunction and repair, which hinders the translation of research findings into new therapeutic approaches. Here, we established a scalable, microarrayed 3D human intestinal organoid platform that enables high-throughput, single-organoid resolution modeling of inflammation-induced epithelial damage and subsequent regenerative responses, recapitulating both morphological and transcriptional signatures of biopsy-derived mucosal tissues from Crohn’s disease patients. Employing time-resolved morphological imaging, transcriptomics, and a novel quantitative epithelial recovery metric, introduced as the 'Intestinal Organoid Recovery Score (IORS),' we distinguished responder organoids to preventive and therapeutic bioactives, notably dexamethasone (DEX), nicotinamide (NAM), and β-hydroxybutyrate (BHB). These interventions effectively mitigated inflammation-induced barrier disruption and promoted regenerative epithelial barrier programs to restore barrier function. Transcriptomic analysis further revealed differential modulation of pathways associated with epithelial integrity and inflammatory responses in DEX and NAM interventions, highlighting distinct regenerative mechanisms of action that may be utilized for future combinatorial therapies. Collectively, this robust, single-organoid resolution approach offers an unprecedented opportunity for precision medicine-driven screening and therapeutic development in the context of chronic gastrointestinal diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294920 | GEO | 2026/08/10

REPOSITORIES: GEO