Mechanisms of gut barrier failure in the pathogenesis of necrotizing enterocolitis: Toll-like receptors throw the switch

Research output: Contribution to journalArticle

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal causes in premature infants, and its overall survival has not improved in the past three decades. While the precise cause of NEC remains incompletely understood, we and others have shown that a major predisposing factor in the development and propagation of NEC is a breakdown of the intestinal barrier which leads to bacterial translocation and systemic sepsis. In seeking to identify the causes involved, we and others have also determined that activation of the receptor for bacterial endotoxin, namely toll-like receptor 4 (TLR4), is required for the development of intestinal barrier failure leading to NEC. We have also shown that the premature infant is endowed with strategies that can either limit or promote the extent of TLR4 signaling within the gut, which together determine the relative propensity with which NEC develops. In this review, we highlight the evidence for TLR4 signaling in the pathogenesis of NEC through a survey of its effects on gut barrier failure. We identify how TLR4 regulation within the gut can explain the unique susceptibility of the premature infant to the development of NEC, and highlight how strategies to limit the degree of TLR4 signaling can serve as novel therapeutic approaches for this devastating disease.

Original languageEnglish (US)
Pages (from-to)76-82
Number of pages7
JournalSeminars in Pediatric Surgery
Volume22
Issue number2
DOIs
StatePublished - May 2013
Externally publishedYes

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Necrotizing Enterocolitis
Toll-Like Receptors
Toll-Like Receptor 4
Premature Infants
Bacterial Translocation
Child Development
Causality
Cause of Death
Sepsis

Keywords

  • Bacterial translocation
  • Necrotizing enterocolitis
  • Neonatal intestinal barrier
  • Toll-like receptor 4 regulation (TLR4)

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Surgery

Cite this

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abstract = "Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal causes in premature infants, and its overall survival has not improved in the past three decades. While the precise cause of NEC remains incompletely understood, we and others have shown that a major predisposing factor in the development and propagation of NEC is a breakdown of the intestinal barrier which leads to bacterial translocation and systemic sepsis. In seeking to identify the causes involved, we and others have also determined that activation of the receptor for bacterial endotoxin, namely toll-like receptor 4 (TLR4), is required for the development of intestinal barrier failure leading to NEC. We have also shown that the premature infant is endowed with strategies that can either limit or promote the extent of TLR4 signaling within the gut, which together determine the relative propensity with which NEC develops. In this review, we highlight the evidence for TLR4 signaling in the pathogenesis of NEC through a survey of its effects on gut barrier failure. We identify how TLR4 regulation within the gut can explain the unique susceptibility of the premature infant to the development of NEC, and highlight how strategies to limit the degree of TLR4 signaling can serve as novel therapeutic approaches for this devastating disease.",
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