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

Abstract

SUMMARYNecrotizing 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, 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 proinflammatory 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 that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with 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 that is consistent with other currently used animal models, but this technique 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.

A novel bioactive peptide from yoghurts modulates expression of the gel-forming MUC2 mucin as well as population of goblet cells and Paneth cells along the small intestine

“…In humans, the α-defensins found in PCs are α-defensin-5 and -6 (HD-5 and HD-6) [35]. PCs play an essential role in controlling intestinal barrier penetration by pathogenic or commensal bacteria, in regulating the intestinal microbiota and in maintaining homeostasis of the small intestinal stem cell niche [36][37][38][39]. It should be noted that antibacterial factors secreted by PCs are retained by the mucus barrier, which allows it to regulate bacteria that are in close contact with the intestinal surface.…”

The role of intestinal epithelial barrier function in the development of NEC

“…Coutinho, et. al, found decreased numbers of [93][94][95] While Salzman, et. al, showed increased Paneth cell numbers, defensin production from these cells was deficient.…”

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

“…For example, a significant component is the pattern recognition of pathogens through Toll-like receptor (TLR)-4 (3,4). Also, a reduction in Paneth and in mucin-producing goblet cells (5,6) and an increase in proinflammatory mediators (i.e., TNF-α, IL-1, -6, -8, and platelet-activating factor) are associated with NEC (7).However, less attention has been given to the adaptive immune system. The fact that NEC usually occurs at least a week after birth and after the initiation of enteral feedings is consistent with the idea that the adaptive immune system is also of significance.…”

“…For example, a significant component is the pattern recognition of pathogens through Toll-like receptor (TLR)-4 (3,4). Also, a reduction in Paneth and in mucin-producing goblet cells (5,6) and an increase in proinflammatory mediators (i.e., TNF-α, IL-1, -6, -8, and platelet-activating factor) are associated with NEC (7).…”