Formula feeding and immature gut microcirculation promote intestinal hypoxia, leading to necrotizing enterocolitis.
Animals
Animals, Newborn
Disease Models, Animal
Endothelial Cells
/ pathology
Enterocolitis, Necrotizing
/ pathology
Humans
Hypoxia
/ pathology
Infant Formula
/ chemistry
Intestinal Mucosa
/ physiopathology
Intestines
/ blood supply
Lipopolysaccharides
Mice
Mice, Inbred C57BL
Microcirculation
Microscopy, Fluorescence
Milk, Human
/ chemistry
Nitric Oxide
/ metabolism
RNA-Seq
Vasoconstriction
Hypoxia
Microvascular flow dynamics
Microvasculature dilation
Necrotizing enterocolitis
Premature intestine circulation
Vascular maturation
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
09 12 2019
09 12 2019
Historique:
received:
18
06
2019
accepted:
28
10
2019
pubmed:
11
11
2019
medline:
18
6
2020
entrez:
10
11
2019
Statut:
epublish
Résumé
Major risk factors for necrotizing enterocolitis (NEC) are formula feeding and prematurity; however, their pathogenic mechanisms are unknown. Here, we found that insufficient arginine/nitric oxide synthesis limits blood flow in the intestinal microvasculature, leading to hypoxia, mucosal damage and NEC in the premature intestine after formula feeding. Formula feeding led to increased intestinal hypoxia in pups at postnatal day (P)1 and P5, but not in more mature pups at P9. Accordingly, blood flow in the intestinal microvasculature increased after formula feeding in P9 pups only. mRNA profiling revealed that regulators of arginine/nitric oxide synthesis are at higher levels in endothelial cells of the intestine in P9 than in P1 pups. Importantly, arginine supplementation increased intestinal microvasculature blood flow and prevented NEC, whereas an arginine antagonist exacerbated NEC. Our results suggest that balancing intestinal oxygen demand and supply in the premature intestine by modulating arginine/nitric oxide could be used to prevent NEC.This article has an associated First Person interview with the first author of the paper.
Identifiants
pubmed: 31704804
pii: dmm.040998
doi: 10.1242/dmm.040998
pmc: PMC6918740
pii:
doi:
Substances chimiques
Lipopolysaccharides
0
Nitric Oxide
31C4KY9ESH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : 353857
Pays : Canada
Organisme : CIHR
ID : 162208
Pays : Canada
Organisme : CIHR
ID : PJT-149046
Pays : Canada
Informations de copyright
© 2019. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing or financial interests.
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