ArticleProceedings of the National Academy of Sciences of the United States of America2013
Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 146 papers, 1 of them a synthesis that pooled it.
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Who cites it
146 citing papers in PubMed, 1 synthesis or guideline pooled it, 233 citations in OpenAlex.
- Comparative efficacy of different single drugs to prevent necrotizing enterocolitis in preterm infants: an update systematic review and network meta-analysis.Frontiers in nutrition · 2024Pooled it
- Candidate gene analysis in pathogenesis of surgically and non-surgically treated necrotizing enterocolitis in preterm infants.Molecular and cellular biochemistry · 2018Trial
- The gut-lung axis in early life: microbiome-associated mechanisms and clinical relevance.European respiratory review : an official journal of the European Respiratory Society · 2026Review
- The gut-brain ConNECtion: exploring the developmental impact of necrotizing enterocolitis on the neonatal brain.Pediatric research · 2026Review
- Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice.Nature communications · 2026Article
- Necrotizing enterocolitis.Nature reviews. Disease primers · 2026Review
- Variation in antiviral immunity and inflammation pathways precedes HIV-1 infection in a high-risk African cohort.The Journal of clinical investigation · 2026Article
- Supplementary parenteral arginine corrects hypoargininaemia and rebalances plasma amino acid profiles in very preterm infants receiving parenteral nutrition: A prospective study.Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition · 2026Article
- Beyond the Gut: Necrotizing Enterocolitis as a Gut-Brain Axis Disorder of Neurodevelopment.Biomedicines · 2026Article
- Endothelial Cell Secretome Alterations Induced by Inflammatory Stress.bioRxiv : the preprint server for biology · 2026Article
- Vitamins as modulators of neonatal intestinal injury.Frontiers in nutrition · 2026Review
- Advancing precision triage in strangulated small bowel obstruction: from static scores to dynamic multiparametric models.Frontiers in surgery · 2026Review
- Pathogenesis of necrotizing enterocolitis: mechanisms and mediators.World journal of pediatric surgery · 2026Review
- Investigation of the putative mechanism by whichFrontiers in pharmacology · 2026Article
- Postoperative hyperinflammation and recovery challenges in necrotizingenterocolitis.World journal of pediatric surgery · 2026Review
- Ferroptosis in necrotizing enterocolitis: iron overload-driven intestinal injury and mechanistic insights.Frontiers in pediatrics · 2026Review
- Digging deeper into necrotizing enterocolitis: bridging clinical, microbial, and molecular perspectives.Gut microbes · 2025Review
- Dynamic Interactions between the Gut Microbiome, Health, and Metabolic Disorders in Preterm Infants.Journal of microbiology and biotechnology · 2025Review
- The pioneering gut microbiome acquired via different delivery modes in neonates shapes distinct immune and metabolic environments.medRxiv : the preprint server for health sciences · 2025Article
- Necrotizing enterocolitis: specific human milk oligosaccharides prevent enteric glia loss and hypomotility.Pediatric research · 2025Article
86 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
Abstract
Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS(-/-) mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate--a precursor for enteral generation of nitrite and nitric oxide--and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate-nitrite-NO signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.