Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion

Yogesh Bhattarai, Brianna B. Williams, Eric J. Battaglioli, Weston R. Whitaker, Lisa Till, Madhusudan Grover, David R Linden, Yasutada Akiba, Karunya K. Kandimalla, Nicholas C. Zachos, Jonathan D. Kaunitz, Justin L. Sonnenburg, Michael A. Fischbach, Gianrico Farrugia, Purna C Kashyap

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HT4R activation and is blocked by 5-HT4R antagonist and absent in 5-HT4R−/− mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. Video Abstract: [Figure presented] Bhattarai et al. uncovered the mechanism by which a bacteria-derived small molecule can alter host gastrointestinal function. Tryptamine produced by bacterial decarboxylation of dietary tryptophan accelerates gastrointestinal transit by activating the epithelial G-protein-coupled receptor (GPCR) serotonin receptor-4 (5-HT4R) and increasing anion-dependent fluid secretion in the proximal colon.

Original languageEnglish (US)
Pages (from-to)775-785.e5
JournalCell Host and Microbe
Volume23
Issue number6
DOIs
StatePublished - Jun 13 2018

Keywords

  • Bacteroides thetaiotaomicron
  • constipation
  • genetically engineered
  • GI transit
  • IBS
  • microbiome
  • motility
  • phage promoter
  • secretion
  • tryptophan

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Fingerprint Dive into the research topics of 'Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion'. Together they form a unique fingerprint.

  • Cite this

    Bhattarai, Y., Williams, B. B., Battaglioli, E. J., Whitaker, W. R., Till, L., Grover, M., Linden, D. R., Akiba, Y., Kandimalla, K. K., Zachos, N. C., Kaunitz, J. D., Sonnenburg, J. L., Fischbach, M. A., Farrugia, G., & Kashyap, P. C. (2018). Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. Cell Host and Microbe, 23(6), 775-785.e5. https://doi.org/10.1016/j.chom.2018.05.004