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

doi:10.1016/j.chom.2018.05.004

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

Cell Host Microbe. 2018 Jun 13;23(6):775-785.e5. doi: 10.1016/j.chom.2018.05.004.

Authors

Affiliations

¹ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
² Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.
³ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94304, USA.
⁴ Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
⁵ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
⁶ Department of Medicine, School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 90073, USA; Brentwood Biomedical Research Institute, Los Angeles, CA 90073, USA.
⁷ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
⁸ Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Medicine, School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 90073, USA; Brentwood Biomedical Research Institute, Los Angeles, CA 90073, USA; Department of Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA; Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL 32224, USA.
¹¹ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: kashyap.purna@mayo.edu.

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.

Keywords: Bacteroides thetaiotaomicron; GI transit; IBS; constipation; genetically engineered; microbiome; motility; phage promoter; secretion; tryptophan.

Publication types

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

MeSH terms

Animals
Bacteroides thetaiotaomicron / genetics
Bacteroides thetaiotaomicron / physiology
Colon / microbiology
Colon / physiology*
Epithelium / drug effects
Feces / microbiology
Gastrointestinal Microbiome / genetics
Gastrointestinal Microbiome / physiology*
Humans
Intestinal Secretions*
Mice
Mice, 129 Strain
Mice, Knockout
Primary Cell Culture
Receptors, Serotonin, 5-HT4 / metabolism*
Sex Factors
Specific Pathogen-Free Organisms
Tryptamines / metabolism*

Substances

Tryptamines
Receptors, Serotonin, 5-HT4
tryptamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding