The study investigates the role of reduced expression of Paneth cell (PC) α-defensins in the pathogenesis of ileal Crohn's disease (CD). Patients with ileal CD exhibit decreased antibacterial activity in their intestinal mucosal extracts, specifically a reduction in PC α-defensins (HD5 and HD6) compared to controls. This reduction is independent of the degree of inflammation and is not observed in CD limited to the colon, ulcerative colitis, or pouchitis. The functional impact of α-defensin expression levels was assessed using a transgenic mouse model, where changes in HD5 expression levels comparable to those in CD led to significant alterations in the luminal microbiota. The findings suggest that the specific deficiency of PC α-defensins in ileal CD compromises innate immune defenses and may initiate or perpetuate the disease. The study proposes that therapeutic strategies aimed at restoring the host-microbe balance at the intestinal mucosa could be more effective than those that broadly suppress inflammation and adaptive immunity.The study investigates the role of reduced expression of Paneth cell (PC) α-defensins in the pathogenesis of ileal Crohn's disease (CD). Patients with ileal CD exhibit decreased antibacterial activity in their intestinal mucosal extracts, specifically a reduction in PC α-defensins (HD5 and HD6) compared to controls. This reduction is independent of the degree of inflammation and is not observed in CD limited to the colon, ulcerative colitis, or pouchitis. The functional impact of α-defensin expression levels was assessed using a transgenic mouse model, where changes in HD5 expression levels comparable to those in CD led to significant alterations in the luminal microbiota. The findings suggest that the specific deficiency of PC α-defensins in ileal CD compromises innate immune defenses and may initiate or perpetuate the disease. The study proposes that therapeutic strategies aimed at restoring the host-microbe balance at the intestinal mucosa could be more effective than those that broadly suppress inflammation and adaptive immunity.