Epithelial and subepithelial players in chronic intestinal disease

The intestinal epithelium and the subepithelial layers form the primary barrier in the human gut. It is responsible for the absorption of essential nutrients from the diet and protects against potentially harmful and/or infections substances in the gut lumen. Many chronic intestinal diseases are caused by the toxic effects of such harmful substances on the intestinal epithelium and subepithelial layers, which results in intestinal dysfunction, including intestinal inflammation, fibrosis and cancer. Among them, cigarette smoking is a well-known risk factor for developing (fibrotic) Crohn's disease and colon cancer. However, in what way cigarette smoke directly affects the human intestinal epithelial and subepithelial cells functioning is not really known. This thesis focuses on the effect of cigarette smoke on the human intestinal epithelium and subepithelial cells (myofibroblasts) and analyzed the effect of an antifibrotic drug, pirfenidone, on the fibrogenic potential of intestinal myofibroblasts. This thesis encompasses four parts: 1) the effect of cigarette smoke extract (CSE) on epithelial cell morphogenesis, regeneration, polarity and barrier function; 2) the effect of cigarette smoking/CSE on the expression of immunomodulatory vascular adhesion protein-1 (VAP-1) in inflammatory bowel disease patients and primary human intestinal fibroblasts (p-hIFs); 3) identification and characterization of a subtype of enteroendocrine cells that expresses immunomodulatory VAP-1; and 4) anti-fibrotic function of pirfenidone on p-hIFs and underlying mechanism involved in it. This work displays the value of employing human intestinal organoid and p-hIFs for advancing intestinal chronic disease research and drug development as preclinical tools.