Pathogenesis of necrotizing enterocolitis: modeling the innate immune response

Abstract

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. The pathophysiology is likely secondary to innate immune responses to intestinal microbiota by the premature infant's intestinal tract, leading to inflammation and injury. This review provides an updated summary of the components of the innate immune system involved in NEC pathogenesis. In addition, we evaluate the animal models that have been used to study NEC with regard to the involvement of innate immune factors and histopathological changes as compared to those seen in infants with NEC. Finally, we discuss new approaches to studying NEC, including mathematical models of intestinal injury and the use of humanized mice.

Figure 1

Examples of the various grades of morphological damage in hematoxylin and eosin–stained specimens. A–E: Representative samples of premature infants with necrotizing enterocolitis. A: Age-matched control from patient with jejunal atresia. B: Mild injury with hemorrhagic necrosis of mucosa and loss of villus tip architecture. C: Progressive injury with inflammatory infiltration of muscularis with complete villus destruction. D: Severe muscular and epithelial damage with complete loss of mucosa. E: Perforation with transmural necrosis with complete loss of epithelial and muscular architecture. F–J: Representative samples from intestinal injury secondary to gavage feeding in the setting of hypothermia and hypoxia in neonatal rats. F: Intact morphology, grade 0. G: Sloughing of villus tips, grade 1. H: Mid-villus necrosis, grade 2. I: Loss of villi, grade 3. J: Complete destruction of the mucosa, grade 4. Insets in F–J show higher magnified portions of the same sections, corresponding to the boxed regions. K–O: Representative images of tissue injury secondary to 60 minutes of intestinal ischemia and 90 minutes of reperfusion in 2-week-old mice. K: Sham-operated mice (no ischemia). L: Villus tip necrosis. M: Mid-villus necrosis. N: Loss of villus architecture. O: Complete loss of mucosal architecture. F–J, reprinted with permission from Nature Publishing Group. Scale bars = 50 μm (A–E, K–O). Original magnification, ×20 (A–O, main images, and F–J, insets).

Figure 2

The innate immune response in necrotizing enterocolitis (NEC. Top: hematoxylin and eosin stain of normal neonatal human small bowel. Middle: Mechanistic diagram of the factors that have been associated with the increased incidence of human NEC and the potential innate immune cells and molecules involved in the disease. In this diagram, prematurity, antibiotic use, method of delivery (vaginal versus Cesarean), and formal feeding can result in dysbiosis, altered barrier function, and altered growth factors and cytokines. The dashed arrows represent a reciprocal vicious cycle between dysbiosis and barrier function, and dysbiosis and altered growth factors and cytokines. All of these factors can lead to increased bacterial translocation, decreased enterocyte migration and to increased inflammation and necrosis, as evidenced in the hematoxylin and eosin panel (bottom), showing severe muscular and epithelial damage with complete loss of mucosa. EGF, epidermal growth factor; HB-EGF, heparin bound-epidermal growth factor; IGF, insulin-like growth factor; SIgA, secretory immunoglobulin A; TLR4, Toll-like receptor 4; and TGF, transforming growth factor.