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

Gastroenterology. 2012 Oct;143(4):1006-16.e4. doi: 10.1053/j.gastro.2012.06.034. Epub 2012 Jun 23.


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.

Publication types

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

MeSH terms

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


  • Anti-Bacterial Agents
  • Endotoxins
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptor 4