The Role of the Intestinal Barrier in the Pathogenesis of Necrotizing Enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates and is increasing in frequency because of recent advances in neonatal care. NEC develops in a stressed preterm infant in the setting of intestinal barrier disruption, systemic inflammation, and leads to, multisystem organ failure. The intestinal barrier lies at the interface between microbes within the intestinal lumen and the immune system of the host, and has both immunological and mechanical components. These components serve to protect the host from invading pathogens and, at the same time, provide a surface area for nutrient absorption. Factors that lead to impairments in the function of the intestinal barrier may predispose the host to the invasion of gut-derived microbes and to the development of systemic inflammatory disease. This process, termed "bacterial translocation," may be compounded during instances in which the mechanisms that regulate the repair of the intestinal barrier are disrupted. Bacterial translocation is of particular concern to the newborn patient, in which immaturity of the mechanical barrier and incomplete development of the host immune system combine to render the host at particular risk for the development of intestinal inflammation. This review will serve to provide an overview of recent evidence regarding the components of the intestinal barrier, and the mechanisms by which disruptions in barrier function may contribute to the pathogenesis of NEC.

Antenatal antibiotic exposure in preterm infants with necrotizing enterocolitis

“…Both patients with stage I disease, which can be difficult to distinguish from suspected bacteremia/sepsis unrelated to the gastrointestinal system, and patients with isolated spontaneous bowel perforations were excluded from analysis. 6 Each baby with NEC was compared only with the control infant with whom she/he was matched and not with other subjects with differing levels of confounding variables (for example, GA, BW, multiplicity of gestation and year of birth).…”

“…5 Suggested pathophysiological mechanisms for NEC (alone or in combination) include enteral feedings superimposed upon immature intestinal function, increased intestinal oxygen demand required for nutrient absorption, activation of cytokine-induced inflammatory cascades, and abnormal microbial colonization and proliferation. 4,[6][7][8][9][10] The neonatal microbiota is influenced by exposure to maternal vaginal and gastrointestinal flora. 9,11,12 Maternal treatment with broad-spectrum antibiotics can have an impact on the biodiversity of the newborn's postnatal microbial flora.…”

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

“…This defensive role is particularly relevant to the mucosa of the gastrointestinal tract, the pulmonary system, and the urinary tract, each of which is particularly susceptible to the development of inflammatory diseases due to their role as a barrier that must not only protect, but also serve the physiological function of each of the organ systems. In the case of the gastrointestinal tract, mucosal inflammation is manifest as inflammatory bowel disease (including Crohn's disease and ulcerative colitis) (1-3) or necrotizing enterocolitis (NEC), a leading cause of death in preterm infants (4). In the case of the pulmonary system, mucosal inflammation may be manifest as pneumonitis, pneumonia, or asthma (5-7), acute and chronic pulmonary conditions that have a high degree of morbidity and potential mortality.…”

Increased expression and internalization of the endotoxin coreceptor CD14 in enterocytes occur as an early event in the development of experimental necrotizing enterocolitis

“…NEC is characterized by local and systemic inflammation which may progress to intestinal necrosis and perforation, overwhelming sepsis and death (4). The pathophysiology of NEC is incompletely understood, yet recent evidence indicates this disease develops after an episode of stress to the intestinal barrier, leading to impaired healing and a prolonged breakdown of the gut barrier (5). This leads to bacterial translocation from the intestinal lumen and leukocyte activation, stimulating local and systemic cytokine release.…”