New insights into the pathogenesis and treatment of necrotizing enterocolitis: Toll-like receptors and beyond

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in the preterm infant. The dismal results of current treatment for NEC highlight the urgent need for greater understanding of the pathogenesis of this disease, and the importance of discovering novel, molecular-specific therapies for it. Current dogma indicates that NEC development reflects an abnormal response by the premature infant to the microbial flora that colonizes the gastrointestinal tract, although the mechanisms that mediate these abnormal bacterial-enterocyte interactions and the reasons for the particularly increased susceptibility of the premature infant to the development of NEC remain incompletely explained. Recent evidence has shed light on an emerging role for the Toll-like receptors (TLRs) of the innate immune system as central players in the pathways that signal in response to enteric bacteria resulting in the development of NEC. We now review recent advances in the field of NEC and identify several exciting potential avenues for novel treatments by focusing on abnormal TLR4 signaling in the premature intestine in the pathogenesis of NEC. In so doing, we seek to offer new hope to the patients and their families who are affected by this devastating disorder.

Figure 1

The role of TLR4 signaling in the pathogenesis of necrotizing enterocolitis. As described in the text, hypoxia, infection and prematurity together increase the expression of TLR4 in the intestinal mucosa, whose subsequent activation by enteric bacteria leads to increased barrier injury and reduced epithelial repair. Inhibition of TLR4, as may occur via activation of the cytoplasmic innate immune receptors NOD2 and TLR9 leads to an inhibition of TLR4, restoration of the intestinal epithelial barrier, and a reduction in the severity of NEC.