Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease

Abstract: Crohn’s disease is a chronic, inflamma-tory disease of the intestinal mucosa. Although in-testinal bacteria are implicated in disease patho-genesis, the etiology is still unclear. The main lo-cation of disease is the small intestine (ileum) and the colon. Ileal disease has been linked to a muta-tion in the NOD2 gene. Defensins are antimicro-bial peptides and in the ileum, are mainly ex-pressed in Paneth cells, epithelial cells that also express NOD2. In the colon, defensins are ex-pressed by enterocytes or metaplastic Paneth cells. Crohn’s disease patients with ileal involvement, compared with controls or Crohn’s patients with-out ileal involvement, have diminished expression of ileal Paneth cell defensins. This decrease is even more pronounced in Crohn’s patients displaying a NOD2 mutation. In contrast, Crohn’s disease of the colon is characterized by an impaired induction of -defensins in enterocytes. The colonic expres-sion of the constitutive -defensin 1 is also de-creased in the inflamed colonic mucosa, but this decrease is less specific to Crohn’s disease, as it can also be found in ulcerative colitis patients. In con-clusion, the regional localizations of Crohn’s dis-ease, ileal or colonic disease, can be linked to different defensin profiles. Crohn’s disease of the ileum is associated with diminished defensin ex-pression in Paneth cells. Crohn’s disease of the colon is associated with diminished -defensin ex-pression in enterocytes. Thus, it can be speculated that decreased defensin levels lead to a weakened intestinal barrier function to intestinal microbes and might be crucial in the pathophysiology o