Necrotizing enterocolitis (NEC) is the leading cause of death and disability from gastrointestinal disease in premature infants. Recent discoveries have shed light on a unifying theorem to explain the pathogenesis of NEC, suggesting that specific treatments might finally be forthcoming. A variety of experiments have highlighted how the interaction between bacterial signalling receptors on the premature intestine and an abnormal gut microbiota incites a pro-inflammatory response in the intestinal mucosa and its underlying endothelium that leads to NEC. Central amongst the bacterial signalling receptors implicated in NEC development is the lipopolysaccharide receptor Toll-like receptor 4 (TLR4), which is expressed at higher levels in the premature gut than in the full-term gut. The high prenatal intestinal expression of TLR4 reflects the role of TLR4 in the regulation of normal gut development, and supports additional studies indicating that NEC develops in response to signalling events that occur in utero. This Review provides new evidence explaining the pathogenesis of NEC, explores new findings indicating that NEC development has origins before birth, and discusses future questions and opportunities for discovery in this field.
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