Crohn's disease: Why the ileum?

Abstract

Crohn's disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.

Keywords: Bile acids; Crohn’s disease; Diet; Genetics; Ileum; Paneth cells; Strictures.

Figure 1

Potential factors involved in ileal Crohn’s disease. While Crohn’s disease (CD) occurs in any part of the gastrointestinal tract, the ileum is frequently involved. Potential factors involved in ileal CD are genetic susceptibility genes and most of these genes are associated with Paneth cell dysfunction. Environmental factors may also be involved such as diet, gut microbiota and smoking. Diet can modulate the composition of bile acids and gut microbiota, which in turn affect the susceptibility of the ileum to inflammation. Created with BioRender.com. CD: Crohn’s disease.

Figure 2

Putative role of gene susceptibility in Paneth cell dysfunction. Paneth cells are secretory epithelial cells located in the intestinal crypts. Paneth cells produce antimicrobial peptides in response to bacterial components and support stem cell function through Wnt signalling. Most of the susceptibility genes associated with ileal Crohn’s disease (CD) involve Paneth cell dysfunction. NOD2 and LRRK2 genes are expressed in Paneth cells and their deficiency in ileal CD modulates the expression of antimicrobial peptides such as alpha-defensins or lysozyme. Similarly, the reduction of the Wnt-signalling pathway transcription factor Tcf-4 is associated with a predisposition for ileal CD and leads to a reduced expression of Paneth cell defensins. The blocking of calcium-activated potassium channel protein (KCNN4) inhibits mouse Paneth cell secretion in response to bacterial stimulation. Created with BioRender.com.