Reduced Paneth cell α-defensins in ileal Crohn's disease

TLDR

Crohn’s disease is thought to arise from bacterial triggers that provoke mucosal inflammation in genetically susceptible hosts, and Paneth cells secrete the key antimicrobial peptides HD5 and HD6. The study aimed to determine whether reduced Paneth cell α‑defensin expression weakens mucosal defenses and predisposes to ileal Crohn’s disease. Using a transgenic mouse with altered HD5 levels, the authors showed that changes in α‑defensin expression markedly altered the luminal microbiota. Ileal Crohn’s patients exhibited lower antibacterial activity and specific α‑defensin deficiency, independent of inflammation, suggesting that this loss compromises innate immunity and may drive disease initiation or persistence.

Abstract

The pathogenesis of Crohn′s disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human α-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC α-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC α-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of α-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of α-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.