P011 Patient-derived organoids as an epithelial model for preclinical IBD research and drug development.

Abstract

Abstract Background The study of the intestinal epithelial barrier is hampered by the lack of a suitable in vitro model system. Patient-derived organoids (PDOs) recapitulate the cellular diversity and patient heterogeneity and provide a relevant platform to study the intestinal epithelium and its response to microbial or inflammatory challenges. Here, we present the characterization of an inflammatory bowel disease (IBD) organoid biobank derived from Crohn’s disease and Ulcerative Colitis patients and its application for IBD drug development efforts. Methods PDOs from different regions of the gastrointestinal tract of 14 IBD patients were established. To recapitulate the full cellular diversity, specialized medium formulations were defined that support the differentiation of distinct epithelial cell lineages as confirmed by transcriptional profiles and histology. To study the inflammation driven loss of barrier integrity observed in the mucosa of IBD patients, we employed organoid derived monolayers and mimicked the inflammatory environment by cytokine challenge (TNF, IFNγ). Results In response to differentiation media, intestinal organoids and monolayers displayed gene expression patterns consistent with maturation of epithelial cell types found in the human gut. The cytokine challenge robustly induces loss of barrier integrity across seven patient-derived monolayers. The barrier breakdown was ameliorated in all models by treatment with the IBD therapy Tofacitinib. Conclusion Intestinal PDOs were generated from IBD patients and were capable to differentiate into mature epithelial cell types. PDO-derived monolayers built trans-epithelial electrical resistance (TEER) and are a relevant model to study epithelial barrier function and inflammation mediated barrier breakdown. Proof-of-concept studies with Tofacitinib demonstrated the suitability of the assay for IBD drug development efforts.