Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways

Cell Host Microbe. 2021 Feb 10;29(2):179-196.e9. doi: 10.1016/j.chom.2020.11.011. Epub 2020 Dec 21.


The intestinal epithelium senses nutritional and microbial stimuli using epithelial sensory enteroendocrine cells (EEC). EECs communicate nutritional information to the nervous system, but whether they also relay signals from intestinal microbes remains unknown. Using in vivo real-time measurements of EEC and nervous system activity in zebrafish, we discovered that the bacteria Edwardsiella tarda activate EECs through the receptor transient receptor potential ankyrin A1 (Trpa1) and increase intestinal motility. Microbial, pharmacological, or optogenetic activation of Trpa1+EECs directly stimulates vagal sensory ganglia and activates cholinergic enteric neurons by secreting the neurotransmitter 5-hydroxytryptamine (5-HT). A subset of indole derivatives of tryptophan catabolism produced by E. tarda and other gut microbes activates zebrafish EEC Trpa1 signaling. These catabolites also directly stimulate human and mouse Trpa1 and intestinal 5-HT secretion. These results establish a molecular pathway by which EECs regulate enteric and vagal neuronal pathways in response to microbial signals.

Keywords: Danio rerio; bacterial tryptophan catabolism; enteroendocrine cells; gut microbes; gut-brain axis communication; indole; indole-3-carboxaldehyde; intestinal peristalsis; serotonin.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cholinergic Neurons / metabolism
  • Edwardsiella tarda / metabolism*
  • Enteric Nervous System / cytology
  • Enteric Nervous System / metabolism*
  • Enteroendocrine Cells / physiology*
  • Gastrointestinal Motility / physiology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / innervation
  • Intestinal Mucosa / metabolism*
  • Proto-Oncogene Proteins c-ret / genetics
  • Serotonin / metabolism
  • Signal Transduction
  • TRPA1 Cation Channel / metabolism*
  • Tryptophan / metabolism
  • Zebrafish
  • Zebrafish Proteins / genetics


  • TRPA1 Cation Channel
  • Zebrafish Proteins
  • Serotonin
  • Tryptophan
  • Proto-Oncogene Proteins c-ret
  • Ret protein, zebrafish