From intestinal stem cells to inflammatory bowel diseases

Abstract

The pathogenesis of both entities of inflammatory bowel disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC), is still complex and under investigation. The importance of the microbial flora in developing IBD is beyond debate. In the last few years, the focus has changed from adaptive towards innate immunity. Crohn's ileitis is associated with a deficiency of the antimicrobial shield, as shown by a reduced expression and secretion of the Paneth cell defensin HD5 and HD6, which is related to a Paneth cell differentiation defect mediated by a diminished expression of the Wnt transcription factor TCF4. In UC, the protective mucus layer, acting as a physical and chemical barrier between the gut epithelium and the luminal microbes, is thinner and in part denuded as compared to controls. This could be caused by a missing induction of the goblet cell differentiation factors Hath1 and KLF4 leading to immature goblet cells. This defective Paneth and goblet cell differentiation in Crohn's ileitis and UC may enable the luminal microbes to invade the mucosa and trigger the inflammation. The exact molecular mechanisms behind ileal CD and also UC must be further clarified, but these observations could give rise to new therapeutic strategies based on a stimulation of the protective innate immune system.

Keywords: Cell differentiation; Goblet cells; Hath1; Inflammatory bowel disease; KLF4; Paneth cells; TCF4.

Figure 1

Proposed model for the pathogenesis of ileal Crohn’s disease and ulcerative colitis. A: In the healthy ileal and colonic mucosa, luminal microbes are sufficiently controlled by an adequate secretion of antimicrobials peptides and a sufficient mucus layer; B: In ileal Crohn’s disease, defective Paneth cell differentiation mediated by a reduction of the Wnt transcription factor TCF4 leads to a decreased Paneth cell defensin secretion, especially in case of NOD2 mutations. This allows the luminal microbes to attach and invade in the mucosa causing inflammation; C: In ulcerative colitis, a defective goblet cell differentiation based on a missing induction of the transcription factors Hath1 and KLF4 results in mucus deficiency enabling the luminal microbes to invade the mucosa and trigger inflammation.