Necrotizing enterocolitis: new insights into pathogenesis and mechanisms

Abstract

Necrotizing enterocolitis (NEC) is the most frequent and lethal disease of the gastrointestinal tract of preterm infants. At present, NEC is thought to develop in the premature host in the setting of bacterial colonization, often after administration of non-breast milk feeds, and disease onset is thought to be due in part to a baseline increased reactivity of the premature intestinal mucosa to microbial ligands as compared with the full-term intestinal mucosa. The increased reactivity leads to mucosal destruction and impaired mesenteric perfusion and partly reflects an increased expression of the bacterial receptor Toll-like receptor 4 (TLR4) in the premature gut, as well as other factors that predispose the intestine to a hyper-reactive state in response to colonizing microorganisms. The increased expression of TLR4 in the premature gut reflects a surprising role for this molecule in the regulation of normal intestinal development through its effects on the Notch signalling pathway. This Review will examine the current approach to the diagnosis and treatment of NEC, provide an overview of our current knowledge regarding its molecular underpinnings and highlight advances made within the past decade towards the development of specific preventive and treatment strategies for this devastating disease.

Figure 1. Factors that attenuate or prevent the development of NEC in experimental models

Activation of the innate immune receptor Toll-like receptor 4 (TLR4) plays an essential part in the development of necrotizing enterocolitis (NEC) by increasing enterocyte and intestinal stem cell apoptosis and impairing mucosal healing through decreased restitution and proliferation. These events lead to disruption of the epithelial barrier, which allows luminal bacteria to translocate and trigger a systemic inflammatory response, sepsis, multiple organ failure and death. Counter-regulatory factors can be exploited in order to dampen TLR4 signalling and expression to prevent the development of NEC. Natural factors include: epidermal growth factor (EGF)^,,,, heparin-binding EGF-like growth factor (HB-EGF)^–, nod-like receptor 2 (NOD2), Toll-like receptor 9 (TLR9)^,, Platelet-activating factor acetylhydrolase (PAF-AH). Exogenous factors include: the small-molecule TLR4 inhibitor C34 (REF. 68), bacterial (CpG) DNA^,, muramyl dipeptide (MDP), sodium nitrate, glutamine, celastrol (also known as tripterine) and dibenzazepine. EGFR, epidermal growth factor receptor; eNOS, endothelial nitric oxide synthase; Hsp70, heat shock protein 70; PAF, platelet-activating factor; SMAC, second mitochondria-derived activator of caspase (also known as Diablo homolog, mitochondrial).