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.

Links

Publisher Full Text

Authors

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

Institution

Division of Digestive Diseases, Emory University, Atlanta, Georgia.

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