Development of the Neonatal Intestinal Microbiome and Its Association With Necrotizing Enterocolitis

Abstract

Purpose: Neonatal necrotizing enterocolitis (NEC) remains the most devastating gastrointestinal disease for premature infants. In the United States alone, NEC affects >4000 premature infants yearly, has a mortality rate of nearly 33%, and costs the health care system >$1 billion annually. Although NEC has been actively researched for several decades, its pathophysiology remains elusive. One potential mechanism suggests that disruption of the normal neonatal intestinal bacterial flora induces a proinflammatory state, allowing translocation of pathogens across the intestinal epithelia. Disruption of the normal intestinal flora (dysbiosis) is associated with many human diseases. Thus, it is a reasonable hypothesis that dysbiosis may play an important role in the development of NEC. This hypothesis is supported by evidence that probiotic use in premature infants can prevent the development of NEC. Although the role of probiotics and NEC is covered in other reviews, this review instead focuses on normal bacterial colonization in both term and preterm infants and on the association of dysbiosis and the development of NEC.

Methods: PubMed was queried with the use of the following key search terms: NEC, neonatal microbiome, fetal microbiome, maternal microbiome, neonatal dysbiosis, and microbiome ontogeny. Relevant literature was reviewed and selected for inclusion in accordance with the objectives of the article according to the authors' discretion. Articles that made key salient points in review articles were further pulled from PubMed.

Findings: Although the onset of NEC is thought to involve bacteria, the mechanisms behind their involvement remain unclear. Research to date has failed to identify a single causative organism, and current theories and data now indicate that a disruption of the host intestinal flora is associated with the onset of disease. Recent reports have found that a bloom of Proteobacteria, specifically Enterobacteriacae species, occurs just before the diagnosis of NEC. Whether this is a causative event or merely a marker of intestinal disease is still unclear.

Implications: Because of the complexity of these interactions, it is vital that we continue to investigate the host-bacterial axis in the developing intestine in both humans and in animal models.

Keywords: NEC; development; microbiome; neonate; pathogenesis.