Abstract
Bacterium-induced diarrhea results in 2 to 2.5 million deaths in the world each year. The mechanism needs to be further understood. Staphylococcus aureus infection has a close relation with diarrhea; its cell wall component peptidoglycan (PGN) has strong biological activity on immune cells and possibly plays a role in S. aureus-induced diarrhea. The present study showed that oral PGN-induced diarrhea in mice in a dose-dependent manner. Intestinal epithelial cells absorbed PGN via the intracellular pathway. Intestinal mast cells were activated after PGN gavage. Toll-like receptor (TLR)2 expression was detected in mast cells in the intestine as well as in the murine mast cell line p815 cells. Blocking TLR2 or nucleotide-binding oligomerization domain (NOD)1 with related antibodies or RNA interference abolished PGN-induced p815 cell activation. The mast cell mediator histamine and serotonin had synergistic effects in PGN-induced diarrhea. In summary, oral PGN can induce diarrhea in mice, and TLR2 and NOD1 mediate the PGN-induced mast cell activation that plays a critical role in diarrhea induction. Blockade of TLR2 or NOD1 or treating mice with a mast cell stabilizer can efficiently inhibit PGN-induced-diarrhea, providing potential therapeutic significance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Administration, Oral
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Animals
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Blotting, Western
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Cell Degranulation / drug effects
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Cells, Cultured
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Diarrhea / chemically induced*
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Diarrhea / metabolism
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Diarrhea / prevention & control
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Dose-Response Relationship, Drug
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Drug Synergism
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Gene Expression
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Histamine H1 Antagonists / pharmacology
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / ultrastructure
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Intracellular Fluid / metabolism
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Ketotifen / pharmacology
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Mast Cells / drug effects
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Mast Cells / metabolism
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Mast Cells / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, Knockout
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Microscopy, Electron
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Nod1 Signaling Adaptor Protein / genetics
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Nod1 Signaling Adaptor Protein / metabolism
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Peptidoglycan / administration & dosage
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Peptidoglycan / metabolism
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Peptidoglycan / toxicity*
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Reverse Transcriptase Polymerase Chain Reaction
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Serotonin Antagonists / pharmacology
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Staphylococcus aureus / chemistry*
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Histamine H1 Antagonists
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Nod1 Signaling Adaptor Protein
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Nod1 protein, mouse
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Peptidoglycan
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Serotonin Antagonists
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Ketotifen