Abstract
Intestinal epithelial cells (IECs) form a physical and immunological barrier that separates the vast gut microbiota from host tissues. MyD88-dependent Toll-like receptor signaling is a key mediator of microbial-host cross-talk. We examined the role of epithelial MyD88 expression by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88(ΔIEC)). Loss of epithelial MyD88 signaling resulted in increased numbers of mucus-associated bacteria; translocation of bacteria, including the opportunistic pathogen Klebsiella pneumoniae, to mesenteric lymph nodes; reduced transmucosal electrical resistance; impaired mucus-associated antimicrobial activity; and downregulated expression of polymeric immunoglobulin receptor (the epithelial IgA transporter), mucin-2 (the major protein of intestinal mucus), and the antimicrobial peptides RegIIIγ and Defa-rs1. We further observed significant differences in the composition of the gut microbiota between MyD88(ΔIEC) mice and wild-type littermates. These physical, immunological, and microbial defects resulted in increased susceptibility of MyD88(ΔIEC) mice to experimental colitis. We conclude that MyD88 signaling in IECs is crucial for maintenance of gut homeostasis.
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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Cell Line
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Colitis / complications
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Colitis / immunology*
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Down-Regulation
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Homeostasis
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Humans
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Immunity, Mucosal
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism*
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Klebsiella Infections / complications
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Klebsiella Infections / immunology*
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Klebsiella pneumoniae / immunology*
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Metagenome / genetics
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Metagenome / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Animal
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Mucin-2 / genetics
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Mucin-2 / metabolism
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism*
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Opportunistic Infections / complications
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Opportunistic Infections / immunology*
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Pancreatitis-Associated Proteins
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Proteins / genetics
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Proteins / metabolism
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RNA, Small Interfering / genetics
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Receptors, Polymeric Immunoglobulin / genetics
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Receptors, Polymeric Immunoglobulin / metabolism
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Sequence Deletion / genetics
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Signal Transduction / genetics
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Signal Transduction / immunology
Substances
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Mucin-2
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Myeloid Differentiation Factor 88
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Pancreatitis-Associated Proteins
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Peptide Fragments
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Proteins
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RNA, Small Interfering
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Receptors, Polymeric Immunoglobulin
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Reg3g protein, mouse