title: Roles of nitric oxide and intestinal microbiota in the pathogenesis of necrotizing enterocolitis.
abstract: Necrotizing enterocolitis remains one of the most vexing problems in the neonatal intensive care unit. Risk factors for NEC include prematurity, formula feeding, and inappropriate microbial colonization of the GI tract. The pathogenesis of NEC is believed to involve weakening of the intestinal barrier by perinatal insults, translocation of luminal bacteria across the weakened barrier, an exuberant inflammatory response, and exacerbation of the barrier damage by inflammatory factors, leading to a vicious cycle of inflammation-inflicted epithelial damage. Nitric oxide (NO), produced by inducible NO synthase (iNOS) and reactive NO oxidation intermediates play a prominent role in the intestinal barrier damage by inducing enterocyte apoptosis and inhibiting the epithelial restitution processes, namely enterocyte proliferation and migration. The factors that govern iNOS upregulation in the intestine are not well understood, which hampers efforts in developing NO/iNOS-targeted therapies. Similarly, efforts to identify bacteria or bacterial colonization patterns associated with NEC have met with limited success, because the same bacterial species can be found in NEC and in non-NEC subjects. However, microbiome studies have identified the three important characteristics of early bacterial populations of the GI tract: high diversity, low complexity, and fluidity. Whether NEC is caused by specific bacteria remains a matter of debate, but data from hospital outbreaks of NEC strongly argue in favor of the infectious nature of this disease. Studies in Cronobacter muytjensii have established that the ability to induce NEC is the property of specific strains rather than the species as a whole. Progress in our understanding of the roles of bacteria in NEC will require microbiological experiments and genome-wide analysis of virulence factors.
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027; Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027. Electronic address: agrishin@chla.usc.edu.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Grishin
authors.affiliation: Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027. Electronic address: jbowling@chla.usc.edu.
authors.forename: Jordan
authors.initials: J
authors.lastname: Bowling
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. Electronic address: bbell@chla.usc.edu.
authors.forename: Brandon
authors.initials: B
authors.lastname: Bell
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. Electronic address: jinwang@chla.usc.edu.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027; Department of Surgery, Keck School of Medicine of the University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027. Electronic address: hford@chla.usc.edu.
authors.forename: Henri R
authors.initials: HR
authors.lastname: Ford
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D020345:Enterocolitis, Necrotizing / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology; D009569:Nitric Oxide / Q000378:metabolism*; D010539:Permeability
chemical_list: D015415:Biomarkers; D009569:Nitric Oxide
keywords: Bacteria; Gut barrier; Necrotizing enterocolitis; Nitric oxide