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Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling.

Abstract

BACKGROUND & AIMS
Altered gastrointestinal motility is associated with significant morbidity and health care costs. Toll-like receptors (TLR) regulate intestinal homeostasis. We examined the roles of TLR4 signaling in survival of enteric neurons and gastrointestinal motility.
METHODS
We assessed changes in intestinal motility by assessing stool frequency, bead expulsion, and isometric muscle recordings of colonic longitudinal muscle strips from mice that do not express TLR4 (Tlr4(Lps-d) or TLR4(-/-)) or Myd88 (Myd88(-/-)), in wild-type germ-free mice or wild-type mice depleted of the microbiota, and in mice with neural crest-specific deletion of Myd88 (Wnt1Cre(+/-)/Myd88(fl/fl)). We studied the effects of the TLR4 agonist lipopolysaccharide (LPS) on survival of cultured, immortalized fetal enteric neurons and enteric neuronal cells isolated from wild-type and Tlr4(Lps-d) mice at embryonic day 13.5.
RESULTS
There was a significant delay in gastrointestinal motility and reduced numbers of nitrergic neurons in TLR4(Lps-d), TLR4(-/-), and Myd88(-/-) mice compared with wild-type mice. A similar phenotype was observed in germ-free mice, mice depleted of intestinal microbiota, and Wnt1Cre(+/-)/Myd88(fl/fl) mice. Incubation of enteric neuronal cells with LPS led to activation of the transcription factor nuclear factor (NF)-κB and increased cell survival.
CONCLUSIONS
Interactions between enteric neurons and microbes increases neuron survival and gastrointestinal motility in mice. LPS activation of TLR4 and NF-κB appears to promote survival of enteric neurons. Factors that regulate TLR4 signaling in neurons might be developed to alter gastrointestinal motility.

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  • Authors

    Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S

    Source

    Gastroenterology 143:4 2012 Oct pg 1006-16.e4

    MeSH

    Analysis of Variance
    Animals
    Anti-Bacterial Agents
    Apoptosis
    Cell Survival
    Cells, Cultured
    Cholinergic Neurons
    Colon
    Defecation
    Eating
    Endotoxins
    Enteric Nervous System
    Feces
    Female
    Gastrointestinal Motility
    Lipopolysaccharides
    Male
    Metagenome
    Mice
    Mice, Knockout
    Models, Animal
    Muscle Contraction
    Muscle, Smooth
    Myeloid Differentiation Factor 88
    Nitrergic Neurons
    Phenotype
    Signal Transduction
    Toll-Like Receptor 4

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, U.S. Gov't, Non-P.H.S.

    Language

    eng

    PubMed ID

    22732731