**5. Pathogenesis**

The pathogenesis of NEC is complex, multifactorial, and incompletely defined. The disorder is believed to be a composite result of intestinal immaturity, aberrant immunological response, and gut microbial dysbiosis [3, 4, 23, 24]. It almost never occurs when the intestinal immune system is mature and intact, even when other risk factors are present. Experimental NEC does not occur in sterile environment. Research support the hypothesis that NEC in the preterm infant results from a multifactorial process that requires the concurrent presence of an immature intestinal tract and immune system leading to increased susceptibility, factors causing disruption of the normal intestinal bacterial microbiome with growth of potentially pathogenic bacteria, and an exaggerated inflammatory host response with the release of cytokines and chemokines (**Figure 2**). A genetically determined predisposition to necrotizing enterocolitis has been also proposed implying the contribution of genetic polymorphisms in the pro-inflammatory cytokines associated with NEC [25]. The combination of compromised intestinal epithelial barrier; underdeveloped and anomalous immune defense; abnormal mesenteric vascular development, tone, and flow; and altered luminal microbiota shaped by formula feedings, antibiotic exposure, and cesarean delivery presumably leads to intestinal inflammation and gangrene. NEC is triggered when several risk factors heighten neonatal intestinal inflammation and an irreversible borderline is surpassed.
