Investigating the Interaction of Inflammation-Associated Fibroblasts (IAFs) with Colon Epithelial Cells in Inflammatory Bowel Disease (IBD)

Abstract Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease that affects the epithelial lining of the gastrointestinal tract. Recent single cell RNA-sequencing (scRNA-seq) studies suggested that inflammation-associated fibroblasts (IAFs) play important roles in the disease pathogenesis and drug resistance. To elucidate IAF’s role in IBD, we isolated fibroblasts from patients with IBD and profiled their responses to a panel of pro-inflammatory cytokines. We found a cocktail of the cytokines can induce IAF marker genes in the patient-derived fibroblasts. These cytokine-stimulated fibroblasts recapitulate many characteristics of IAFs, including increased ECM and chemokine secretion. Furthermore, when co-cultured with colon organoids, the cytokine-stimulated fibroblasts secrete prostaglandin E2 (PGE2) to induce organoid swelling through EP4-cAMP-PKA-CFTR signaling, which mimics diarrhea and crypt distortion of IBD. Furthermore, rapid swelling increases the chance of mitosis error and activates p53 pathway, which increases the risk of tumorigenesis. Thus, we are reporting novel mechanisms of fibroblasts that regulates the pathogenesis of IBD. This study was funded by Takeda Development Center Americas, Inc.