NOD2 is highly expressed in ileal Paneth cells where it regulates the ileal microbiota through secretion of antimicrobial molecules and controls pro-inflammatory immune responses to intestinal microbiota through upregulation of anti-inflammatory mediators and downregulation of pro-inflammatory cytokines.127,128 Mutations in NOD2 are the most strongly associated genetic risk factors for ileal CD,129–131 suggesting that dysregulation of the SI microbiota contributes to CD disease pathogenesis. Here, NOD2 is linked to Cowden disease.