Redefining the role of intestinal microbes in the pathogenesis of NEC: future developments

The importance of bacterial colonization as a predisposing factor to necrotizing enterocolitis (NEC) was first described several decades ago and, since that first report, evidence supporting the role of bacteria in the pathogenesis of NEC has continued to grow. Established clinical evidence includes the common findings of bacteremia and endotoxinemia in affected neonates, imaging finding of pneumatosis intestinalis likely due to submucosal gas produced by bacterial fermentation, and the efficacy of antibiotic therapy and probiotic administration in many cases of NEC. Clinical findings were confirmed by laboratory studies showing that molecules of the immune system recognizing microbic determinants are involved in NEC pathophysiology and that inducible nitric oxide synthetases are upregulated in the presence of microbes in experimental models of NEC.
Despite the strong evidence linking microbes to the pathogenesisi of NEC, no conclusive data are available on the organisms that are causally linked with the disease. In general, microbial species identified in cultures from patients with NEC have not been significantly different from species generally considered "normal" within the gastrointestinal tract of hospitalized patients. Therefore, it is possible to suggest that no single causative pathogen is responsible for NEC pathogenesis. Moreover, some studies demonstrated the presence of different viruses in infants with NEC, even if the precise role of viruses in NEC pathogenesis remains uncertain.
Recently, knowledge of microbes present within the human gastrointestinal tract has expanded dramatically thanks to the advent of molecular culture-independent microbiological techniques. These studies have indicated that the distal gastrointestinal tract of preterm infants during the first weeks of life may contain fewer than 20 bacterial species, whereas the bacterial load in the adult intestine is estimated to include 100-1000 species. Moreover, profiles of gut microbes in the first months of life are characterized by a remarkable inter-individual variability, which becomes less pronounced by 6 or 12 months of life. These results suggest an instability of the gut flora in newborns, which may correlate with the onset of NEC.
Further breakthroughs are expected from the introduction of high-throughput techniques that will allow extensive microbiological analysis at the molecular level. Although these approaches have not yet been exploited to study the microbiology of NEC, the simplicity of the infant intestinal tract may allow for successful completion of such studies in coming years and may help addressing some open issues related to NEC pathogenesis, such as the role of formula feeding and the potential benefits of probiotics.

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