Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis

Semin Pediatr Surg. 2005 Feb;14(1):49-57. doi: 10.1053/j.sempedsurg.2004.10.025.


Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates, and is characterized by the development of diffuse intestinal necrosis in the stressed, pre-term infant. Systemic stress causes a breakdown in the intestinal mucosal barrier, which leads to translocation of bacteria and endotoxin and the initiation of a signaling response within the enterocyte. This review summarizes recent evidence defining a clear role that defective enterocyte signaling plays in the pathogenesis of NEC through the following mechanisms: 1) The localized production of nitric oxide by villus enterocytes results in an increase in enterocyte apoptosis and impaired proliferation; 2) The translocation of endotoxin results in a PI3K-dependent activation of RhoA-GTPase within the enterocyte leading to decreased enterocyte migration and impaired restitution; 3) Dysregulated sodium-proton exchange within the enterocyte by endotoxin renders the enterocyte monolayer more susceptible to damage in the face of the acidic microenvironment characteristic of systemic sepsis; and 4) Endotoxin causes a p38-dependent release of the pro-inflammatory molecule COX-2 by the enterocyte, which potentiates the systemic inflammatory response. An understanding of the mechanisms by which disordered enterocyte signaling contributes to the pathogenesis of barrier failure and NEC--through these and other mechanisms--may lead to the identification of novel therapeutic approaches for this devastating disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Bacterial Translocation
  • Cyclooxygenase 2
  • Endotoxins / pharmacology
  • Enterocolitis, Necrotizing / immunology
  • Enterocolitis, Necrotizing / pathology
  • Enterocolitis, Necrotizing / physiopathology*
  • Enterocytes / physiology*
  • Humans
  • Infant, Newborn
  • Intestinal Mucosa / pathology
  • Lipopolysaccharides
  • Membrane Proteins
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase
  • Prostaglandin-Endoperoxide Synthases / metabolism


  • Endotoxins
  • Lipopolysaccharides
  • Membrane Proteins
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases