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

Mallappa Anitha, Matam Vijay-Kumar, Shanthi V. Sitaraman, Andrew T. Gewirtz, Shanthi Srinivasan

Research output: Contribution to journalArticlepeer-review

175 Scopus citations


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 (Tlr4Lps-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+/-/Myd88fl/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 Tlr4Lps-d mice at embryonic day 13.5. RESULTS: There was a significant delay in gastrointestinal motility and reduced numbers of nitrergic neurons in TLR4Lps-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+/-/ Myd88fl/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.

Original languageEnglish (US)
Pages (from-to)1006-10163.e4
Issue number4
StatePublished - Oct 2012

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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