Pathophysiology and Prevention of Neonatal Necrotizing Enterocolitis

Host Defense

Intestinal host defense involves a complex combination of factors that function to prevent intraluminal pathogens and toxins from resulting in disease while allowing for normal absorption of nutrients. This intricate system includes the following: (1) physical barriers such as skin, mucous membranes, intestinal epithelia and microvilli, epithelial cell tight junctions, and mucin; (2) immune cells such as polymorphonuclear leukocytes, macrophages, eosinophils, lymphocytes, as well as secretory immunoglobulin A (IgA); and (3) several biochemical factors shown to impact the development of NEC. Many of these important functions appear to be abnormal in the premature infant and may, therefore, put this population at risk for NEC. Intestinal permeability to macromolecules including immunoglobulins, proteins, and carbohydrates is known to be greater in neonates compared with older children and adults, and in premature infants, this permeability is more pronounced. Although mucosal permeability is beneficial for developing animals to augment passive immunity and nutrient absorption, the precise mechanisms accounting for these differences are poorly understood. The intestinal tight junctions that maintain the gut barrier may also be deficient in the premature infant. ^, It is known that intestinal mucus (a complex gel consisting of water, electrolytes, mucins, glycoprotein, immunoglobulins, and glycolipids) protects against bacterial and toxin invasion and the thickness of the mucus layer and expression of mucus glycoproteins are reduced in developing animals. In addition, key bacteriostatic proteins are secreted from epithelium, which bind to or inactivate the function of invading organisms. Intestinal trefoil factor is one such molecule that appears to be developmentally regulated and therefore deficient in the premature neonate. Human defensins (or cryptdins) are bacteriostatic proteins synthesized and secreted from Paneth cells that protect against bacterial translocation, and their expression is significantly decreased (200-fold lower) in the intestine of a premature infant compared to adults. ^, In contrast, during surgical NEC, the small intestinal mRNA expression of defensins 5 and 6 were upregulated compared to controls, which may perhaps be due to the timing of the resection relative to epithelial healing.

Immunologic host defense is abnormal in developing animals. For example, intestinal lymphocytes are decreased in neonates (B and T cells) and do not approach adult levels until 3 to 4 weeks of life. ^, Newborns also have markedly reduced secretory IgA in salivary samples, reflecting the decreased activity presumed in the intestine. Breast-milk feeding provides multiple immune factors; formula-fed neonates have impaired intestinal humoral immunity, and this deficiency may predispose to the increased incidence of NEC. ^, A complete review of the importance of breast milk in immunologic host defense can be found in Chapters 23 and 122 of this textbook.

Several biochemical factors that are present in the intestinal milieu play an important role in the maintenance of gut health and integrity. Examples are substances such as lactoferrin and glutamine, growth factors such as epidermal growth factor (EGF), transforming growth factor-β, and erythropoietin. ^, Lactoferrin is present in high concentrations in human milk and has been shown to reduce NEC severity in animal models of NEC, but did not prevent NEC in a large randomized controlled trial (RCT) of over 2000 infants. Interestingly, a meta-analysis that included six RCTs found that administration of lactoferrin decreased late-onset sepsis and Bell’s Stage II or III NEC, but the evidence was deemed low in quality. Another important component of human milk is the amino acid glutamine; higher concentrations of this can lead to increased weight gain and length in infants. ^, As with lactoferrin, glutamine also demonstrated efficacy in a neonatal rat model of NEC and can play a role in maintaining the integrity of the gut barrier, but in large RCTs failed to show a benefit against NEC in humans. An area of intense interest in preclinical studies has been the use of growth factors to attenuate intestinal inflammation in animal models of NEC. Treatment with EGF and heparin-bound EGF have been shown to protect against gut barrier failure in experimental NEC, decreased intestinal epithelial cell apoptosis, ^{, ,} and enhanced epithelial cell proliferation. ^, These studies suggest that growth factor administration may be beneficial in protecting against intestinal inflammation during NEC. In addition, other substances such as gastric acid, oligosaccharides, polyunsaturated fatty acids, and many others affect mucosal barrier function, intestinal inflammation, and the viability of intraluminal bacteria. Many of these factors are deficient or absent in the preterm neonate, especially in those patients not receiving breast-milk feedings. Intensive research is ongoing to define the specific role of each in gut barrier integrity and the development of intestinal inflammation and necrosis.