Pathogenesis of necrotizing enterocolitis: mechanisms and mediators

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of preterm neonatal infants. The hallmarks of the disease include severe intestinal necrosis and systemic inflammation leading to overwhelming sepsis. There remains significant morbidity and mortality attributed to NEC, raising the urgency to investigate potential causative mechanisms in order to treat and potentially prevent the disease. This review will summarize the established and emerging mechanisms leading to NEC, including toll-like receptor 4 activation by gram-negative bacteria, microbial dysbiosis, a maladapted immune response, impairment in the enteric nervous system and mitochondrial damage. Overriding each of these factors are potential genetic and epigenetic modulators, which may drive each of the above processes. Importantly, results of experiments from a variety of laboratories have suggested that an understanding of processes may lead to the development of novel preventative or treatment modalities, including small molecules and stem cells that can interfere with the deleterious pathways. By summarizing the latest mechanistic and therapeutic advances, this review hopes to provide insights into the ultimate goal of improving outcomes for patients with this devastating disease.