biostudies-literatureYe LBLRD VANCCIH NIH HHSNIDDK NIH HHSPew Charitable TrustsNIEHS NIH HHSNHLBI NIH HHSNational Institutes of HealthU.S. Department of Veterans AffairsNIH HHSNIGMS NIH HHSAustralian Research Council179-196.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC7997396biostudies-literatureUnknown29(2)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.Cell host & microbeEnteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways.PMC7997396R01 DK093399S10 OD020010U01 ES030672K01 DK125527F32 AT010415I01 BX002230R01 GM074057R01 DK109368R35 HL150713T32 DK007568Keating DJThorpe DWCassilly CDJabba SVLickwar CRMartin AMLu HYWang JYe LClardy JThompson JDLiddle RARawls JFBae MJordt SEPoss KDfalseEnteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways.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.2021-01-01T00:00:00Z2021 Feb2026-06-01T03:04:20.954Z2026-04-08T09:14:50.851ZS-EPMC79973963335210910.1016/j.chom.2020.11.011