Abstract
Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand ("A18") that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Basic Helix-Loop-Helix Transcription Factors / agonists
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / immunology
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Cytochrome P-450 CYP1A1 / genetics
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Cytochrome P-450 CYP1A1 / immunology
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Diet / methods
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Disease Models, Animal
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Enterocolitis, Necrotizing / genetics*
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Enterocolitis, Necrotizing / immunology
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Enterocolitis, Necrotizing / pathology
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Enterocolitis, Necrotizing / prevention & control
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Female
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Gene Expression Regulation
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Humans
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Indoles / administration & dosage*
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Infant, Newborn
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Infant, Premature
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / immunology
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Intestinal Mucosa / pathology
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Ligands
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Maternal Exposure
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Mice
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Milk, Human / physiology*
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Pregnancy
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Receptors, Aryl Hydrocarbon / agonists
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Receptors, Aryl Hydrocarbon / genetics*
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Receptors, Aryl Hydrocarbon / immunology
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Signal Transduction
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Swine
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Toll-Like Receptor 4 / genetics*
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Toll-Like Receptor 4 / immunology
Substances
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AHR protein, human
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Ahr protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Indoles
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Ligands
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Receptors, Aryl Hydrocarbon
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TLR4 protein, human
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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indole-3-carbinol
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Cyp1a1 protein, mouse
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Cytochrome P-450 CYP1A1