Contribution of Stroma to Inflammatory Bowel Disease Progression Revealed in Patient-Derived Human Colon Chips

Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function, enhanced inflammation, and increased cancer risk, with symptoms sometimes being exacerbated in women during pregnancy. To investigate the IBD phenotype and disease progression in human intestine, we leveraged organ-on-a-chip (Organ Chip) technology to engineer human Colon Chips lined by homotypic or heterotypic recombinants of intestinal epithelium interfaced with stromal fibroblasts isolated from Healthy or IBD patient-derived colon resections. Chips created with both epithelial and stromal cells from the same ulcerative colitis or Crohn's disease patient showed increased IBD-associated gene pathway activation, elevated pro-inflammatory cytokines, reduced mucus layer thickness, increased intestinal barrier permeability, compared to homotypic Healthy Colon Chips. When heterotypic tissue recombinants were created, the IBD stromal fibroblasts induced the IBD phenotype in healthy epithelium, and healthy colonic fibroblasts partially reduced inflammation in the IBD epithelium. Using this system, we discovered that peristalsis-like mechanical deformations directly impact colon tissue physiology by increasing mucin gene expression, mucus thickness, and barrier permeability in both Healthy and IBD Chips, and that they only stimulate a fibrotic response in IBD Chips. We also found that both inflammation and fibrosis were accentuated in IBD Chips created with cells from a female patient that were exposed to pregnancy-associated hormones. Interestingly, exposure to a carcinogen (N-ethyl-N-nitrosourea) for 3 weeks in vitro induced histological changes and gene duplication in the IBD Chips, but not in the Healthy Chips. These data suggest that the stroma plays a key role in driving inflammation and disease progression in IBD patients and that human Organ Chip technology may represent a new preclinical tool to gain insight into these mechanisms as well as to identify novel diagnostic biomarkers and therapeutics.