Enteric Colonization in Sporadic Neonatal Necrotizing Enterocolitis

Blakey, Joan L.; Lubitz, Lionel; Campbell, Neil; Gillam, G. L.; Bishop, Ruth F.; Barnes, Graeme L.

doi:10.1097/00005176-198508000-00017

Cited by 70 publications

(39 citation statements)

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“…Although the precise pathways leading to the development of NEC is incompletely understood, evidence points to a clear role for the interaction between the intestinal microbial flora and the host immune system in its pathogenesis. Specifically, the onset of NEC occurs at a time when the intestinal lumen is colonized by Gram-negative flora (54,55), which usually occurs at ϳ8 -10 days after birth (56 -58). Additional evidence for a role for bacteria in the pathogenesis of NEC is found in the fact that NEC outbreaks occur in clusters within neonatal intensive care units in a pattern that is indicative of an infective etiology (59) and that NEC clinically responds to the administration of broad-spectrum antibiotic therapy (60,61).…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

Leaphart

Cavallo

Gribar

et al. 2007

The Journal of Immunology

427

507

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Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in preterm infants and is characterized by translocation of LPS across the inflamed intestine. We hypothesized that the LPS receptor (TLR4) plays a critical role in NEC development, and we sought to determine the mechanisms involved. We now demonstrate that NEC in mice and humans is associated with increased expression of TLR4 in the intestinal mucosa and that physiological stressors associated with NEC development, namely, exposure to LPS and hypoxia, sensitize the murine intestinal epithelium to LPS through up-regulation of TLR4. In support of a critical role for TLR4 in NEC development, TLR4-mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates. TLR4 activation in vitro led to increased enterocyte apoptosis and reduced enterocyte migration and proliferation, suggesting a role for TLR4 in intestinal repair. In support of this possibility, increased NEC severity in C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation after mucosal injury compared with mutant mice. TLR4 signaling also led to increased serine phosphorylation of intestinal focal adhesion kinase (FAK). Remarkably, TLR4 coimmunoprecipitated with FAK, and small interfering RNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. These findings demonstrate a critical role for TLR4 in the development of NEC through effects on enterocyte injury and repair, identify a novel TLR4-FAK association in regulating enterocyte migration, and suggest TLR4/FAK as a therapeutic target in this disease.

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Section: Discussionmentioning

confidence: 99%

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

Leaphart

Cavallo

Gribar

et al. 2007

The Journal of Immunology

427

507

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“…A controversial role for clostridia in pathogenesis of NEC dates back to the 1970's. 7,14,[18][19][20][21][22] Clostridia are reported to be associated with NEC more frequently than any other group of bacteria. Interpretation of these studies however has been mired by inconsistent use of anaerobic cultures, the frequent isolation of clostridia from infants without NEC, variation in the species of clostridia associated with NEC, and frequent reports of NEC in the absence of clostridia.…”

Section: Discussionmentioning

confidence: 99%

Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria

et al. 2011

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“…Most studies on the composition of the gut microflora in neonates who go on to develop NEC have been carried out using traditional techniques of culture (11)(12)(13)(14). Some studies have found an association between various bacterial species and NEC (15)(16)(17)(18)(19)(20), whereas others did not observe any association between NEC and any specific bacterial species (8,21).…”

Section: Discussionmentioning

confidence: 99%

Investigation of the early intestinal microflora in premature infants with/without necrotizing enterocolitis using two different methods

et al. 2011

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Enteric Colonization in Sporadic Neonatal Necrotizing Enterocolitis

Cited by 70 publications

References 0 publications

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria

Investigation of the early intestinal microflora in premature infants with/without necrotizing enterocolitis using two different methods

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