Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in immature murine small intestine

Abstract

Summary Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer causing subsequent inflammation and tissue necrosis. Normally the Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and pro-inflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found they were significantly decreased compared to age matched controls. We were able to model this loss in the intestine of P14-16 day old mice by treating them with the zinc chelator dithizone. Intestines from dithizone treated animals retained approximately half the number of Paneth cells as controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology consistent with other currently used animal models, but is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment.