Evidence map›Paper›PMID 25899687›Full record

ArticleMucosal immunology2015

Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor.

M Good, C P Sodhi, C E Egan, A Afrazi, H Jia, Y Yamaguchi, P Lu, M F Branca, C Ma, T Prindle and 5 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Mucosal immunology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 143 papers.

0numbers the graph read from it
0cells of the map it votes in
143citing papers in PubMed
15.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

143 citing papers in PubMed, 221 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Necrotizing enterocolitis.Nature reviews. Disease primers · 2026
    Review
  5. Review
  6. Time-dependent Amino Acid Crosstalk Shapes Macrophage Responses in Necrotizing Enterocolitis.Cellular and molecular gastroenterology and hepatology · 2026
    Article
  7. Review
  8. Review
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  12. Review
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83 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors at 6 institutions in 1 country.

M Good1] Division of Newborn Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
C P Sodhi1] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland, USA [2] Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
C E Egan1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
A Afrazi1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
H Jia1] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland, USA [2] Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
Y Yamaguchi1] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland, USA [2] Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
P Lu1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
M F Branca1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
C Ma1] Division of Newborn Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
T Prindle1] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland, USA [2] Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
S Mielo1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
A Pompa1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Z Hodzic1] Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J A Ozolek1] Division of Pediatric Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
D J Hackam1] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland, USA [2] Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
University of Pittsburgh · USChildren's Hospital of Pittsburgh · USJohns Hopkins Hospital · USBloomberg (United States) · USJohns Hopkins Children's Center · USJohns Hopkins University · US

Funding

TLR4 Signaling in the Pathogenesis of Surgical Necrotizing EnterocolitisR01GM078238 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HACKAM, DAVID J · 2006 to 2019
$3.9M
Modulation of TLR4 and TLR9 Signaling in NECR01DK083752 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HACKAM, DAVID J · 2008 to 2016
$3.4M
Training in Renal, GI, Endocrine, and Epithelial BiologyT35DK065521 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DEFRANCO, DONALD B, JURCZAK, MICHAEL J. · 2004 to 2024
$811k
Novel Anti-Inflammatory Properties of Breast Milk in Necrotizing EnterocolitisK08DK101608 · NIDDK · WASHINGTON UNIVERSITY · PI GOOD, MISTY L · 2014 to 2017
$584k
NIDDK NIH HHS K08 DK101608NIDDK NIH HHS K08DK101608NIDDK NIH HHS R01 DK083752NIDDK NIH HHS R01DK083752NIDDK NIH HHS T35 DK065521NIGMS NIH HHS R01 GM078238NIGMS NIH HHS R01GM078238
6 · The paper itself

Abstract

Breast milk is the most effective strategy to protect infants against necrotizing enterocolitis (NEC), a devastating disease that is characterized by severe intestinal necrosis. Previous studies have demonstrated that the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) plays a critical role in NEC development via deleterious effects on mucosal injury and repair. We now hypothesize that breast milk protects against NEC by inhibiting TLR4 within the intestinal epithelium, and sought to determine the mechanisms involved. Breast milk protected against NEC and reduced TLR4 signaling in wild-type neonatal mice, but not in mice lacking the epidermal growth factor receptor (EGFR), whereas selective removal of EGF from breast milk reduced its protective properties, indicating that breast milk inhibits NEC and attenuates TLR4 signaling via EGF/EGFR activation. Overexpression of TLR4 in the intestinal epithelium reversed the protective effects of breast milk. The protective effects of breast milk occurred via inhibition of enterocyte apoptosis and restoration of enterocyte proliferation. Importantly, in IEC-6 enterocytes, breast milk inhibited TLR4 signaling via inhibition of glycogen synthase kinase-3β (GSK3β). Taken together, these findings offer mechanistic insights into the protective role for breast milk in NEC, and support a link between growth factor and innate immune receptors in NEC pathogenesis.

Indexed as

AnimalsApoptosisCell LineEnterocolitis, NecrotizingEnterocytesEpidermal Growth FactorErbB ReceptorsFemaleGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaMiceMilkSignal TransductionToll-Like Receptor 4EGFR protein, mouseEpidermal Growth FactorErbB ReceptorsGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaGsk3b protein, mouseTlr4 protein, mouseToll-Like Receptor 4

Identifiers

PMID25899687
PMCPMC4540669
OpenAlexW2072852259

What OpenQuestion holds

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Registered trials

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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.