ArticleGastroenterology2012
Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice.
Article in Gastroenterology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 219 papers, 3 of them syntheses that pooled it.
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Who cites it
219 citing papers in PubMed, 3 syntheses or guidelines pooled it, 307 citations in OpenAlex.
- Research focus and emerging trends of the gut microbiome and infant: a bibliometric analysis from 2004 to 2024.Frontiers in microbiology · 2024Pooled it
- Enteral Feeding Interventions in the Prevention of Necrotizing Enterocolitis: A Systematic Review of Experimental and Clinical Studies.Nutrients · 2021Pooled it
- Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.Microbiome · 2017Pooled it
- Decoding the HMO‒microbiome axis: bridging maternal milk to infant health outcomes.Gut microbes · 2026Review
- Akkermansia muciniphila WW001 protects against DSS-induced colitis by restoring intestinal barrier integrity and modulating inflammatory responses.Folia microbiologica · 2026Article
- The central function and specific molecular mechanisms of the TLR4 pathway underlying impaired intestinal barrier in necrotizing enterocolitis.Biochemistry and biophysics reports · 2026Review
- The RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis.American journal of physiology. Gastrointestinal and liver physiology · 2026Article
- Deciphering the TLR4 and NLRP3 Inflammasome Crosstalk for Therapeutic Restoration of Intestinal and Systemic Immunity.Digestive diseases and sciences · 2026Review
- Diagnosis and Staging of Necrotizing Enterocolitis: Current Controversies and a Phenotype-Based Framework.Children (Basel, Switzerland) · 2026Review
- Necrotizing enterocolitis.Nature reviews. Disease primers · 2026Review
- Pathobiont-triggered induction of goblet cell response drives regional susceptibility to inflammatory bowel disease.The Journal of clinical investigation · 2026Article
- [Multicenter prospective study on the diagnostic value of syndecan-1 for necrotizing enterocolitis in preterm infants].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2026Article
- Performance of time-lapsed turbidimetry and agar plating as bacterial quantification methods.Microbiology spectrum · 2026Article
- The RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis.bioRxiv : the preprint server for biology · 2026Article
- Toll signalling controls intestinal regeneration in Drosophila.Development (Cambridge, England) · 2026Article
- Pathogenesis of necrotizing enterocolitis: mechanisms and mediators.World journal of pediatric surgery · 2026Review
- Intestinal epithelial cells in health and disease.Tissue barriers · 2026Review
- Neurodevelopmental impairment in infants with necrotizing enterocolitis: a comprehensive review of mechanisms, outcomes, and emerging strategies.World journal of pediatric surgery · 2026Review
- Article
- Elevated day-2 hemoglobin P₅₀ and risk of necrotizing enterocolitis in preterm infants: a pilot study.Pediatric surgery international · 2025Article
159 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsLittle is known about factors that regulate intestinal epithelial differentiation; microbial recognition receptors such as Toll-like receptor (TLR)4 might be involved. We investigated whether intestinal TLR4 regulates epithelial differentiation and is involved in development of necrotizing enterocolitis (NEC) of the immature intestine.
methodsMice with conditional disruption of TLR4 in the intestinal epithelium and TLR4 knockout (TLR4(-/-)) mice were generated by breeding TLR4(loxp/loxp) mice with villin-cre and Ella-cre, respectively. Enterocytes that did not express or overexpressed TLR4 were created by lentiviral or adenoviral transduction. Intestinal organoids were cultured on tissue matrices. Bile acids were measured by colorimetric assays, and microbial composition was determined by 16S pyrosequencing. NEC was induced in 7- to 10-day-old mice by induction of hypoxia twice daily for 4 days.
resultsTLR4(-/-) mice and mice with enterocyte-specific deletion of TLR4 were protected from NEC; epithelial differentiation into goblet cells was increased via suppressed Notch signaling in the small intestinal epithelium. TLR4 also regulates differentiation of goblet cells in intestinal organoid and enterocyte cell cultures; differentiation was increased on deletion of TLR4 and restored when TLR4 was expressed ectopically. TLR4 signaling via Notch was increased in intestinal tissue samples from patients with NEC, and numbers of goblet cells were reduced. 16S pyrosequencing revealed that wild-type and TLR4-deficient mice had similar microbial profiles; increased numbers of goblet cells were observed in mice given antibiotics. TLR4 deficiency reduced levels of luminal bile acids in vivo, and addition of bile acids to TLR4-deficient cell cultures prevented differentiation of goblet cells.
conclusionsTLR4 signaling and Notch are increased in intestinal tissues of patients with NEC and required for induction of NEC in mice. TLR4 prevents goblet cell differentiation, independently of the microbiota. Bile acids might initiate goblet cell development.
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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.