Non-TGFβ profibrotic signaling in ulcerative colitis after in vivo experimental intestinal injury in humans.

Abstract

Although impaired regeneration is important in many gastrointestinal diseases including ulcerative colitis (UC), the dynamics of mucosal regeneration in humans are poorly investigated. We have developed a model to study these processes in vivo in humans. Epithelial restitution (ER) and extracellular matrix (ECM) regulation after an experimental injury of the sigmoid colonic mucosa was assessed by repeated high resolution endoscopic imaging, histologic assessment, RNA sequencing, deconvolution analysis, and 16S rDNA sequencing of the injury niche microbiome of 19 UC patients in remission and 20 control subjects. Human ER had a 48-hour lag before induction of regenerative epithelial cells (WAE and TA cells) along with increase of fibroblast derived stem cell growth factor Gremlin 1 mRNA (GREM1). However, in UC deconvolution data showed aby rapid induction of inflammatory fibroblasts, and upregulation of major structural ECM collagen mRNAs and along with tissue inhibitor of metalloproteinase 1 (TIMP1) suggesting increased profibrotic ECM deposition. No change was seen in transforming growth factor β (TGFβ) mRNA whereas and the profibrotic cytokines interleukin 13 (IL13) and IL11 were upregulated in UC suggesting that human post injury responses could be TGFβ-independent. In conclusion, we found distinct regulatory layers of regeneration in the normal human colon and a potential targetable profibrotic dysregulation in UC that could lead to long-term end organ failure - i.e., intestinal damage.