TY - JOUR
T1 - Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion
AU - Bhattarai, Yogesh
AU - Williams, Brianna B.
AU - Battaglioli, Eric J.
AU - Whitaker, Weston R.
AU - Till, Lisa
AU - Grover, Madhusudan
AU - Linden, David R.
AU - Akiba, Yasutada
AU - Kandimalla, Karunya K.
AU - Zachos, Nicholas C.
AU - Kaunitz, Jonathan D.
AU - Sonnenburg, Justin L.
AU - Fischbach, Michael A.
AU - Farrugia, Gianrico
AU - Kashyap, Purna C.
N1 - Funding Information:
We would like to thank Bradley Schmidt, Nella Gabrielová Cheryl Bernard, and William Moor for technical assistance; Dr. Lisa M. Wolfe and Dr. Corey Broeckling from the metabolomics facility at Colorado State University for assistance with metabolomics analysis; Dr. John Grider for valuable scientific discussions; Dr.Valérie Compan for providing 5-HT
Funding Information:
We would like to thank Bradley Schmidt, Nella Gabrielová, Cheryl Bernard, and William Moor for technical assistance; Dr. Lisa M. Wolfe and Dr. Corey Broeckling from the metabolomics facility at Colorado State University for assistance with metabolomics analysis; Dr. John Grider for valuable scientific discussions; Dr.Valérie Compan for providing 5-HT 4 R −/− mice; Julie Nielsen and Donna T DeSmet for help with figures; and Lyndsay Busby for administrative assistance. Figures for graphical abstract and animation for Figure360 were made using Biomedical PowerPoint Toolkit Suite ( http://www.motifolio.com ). Funding: this work was made possible by funding from NIH DK100638 , DK111850 , and DK114007 (P.C.K.), NIDDK K23 103911 (M.G.), Integrated Physiology Core of the Hopkins Conte Digestive Disease Basic and Translational Research Core Center ( P30 DK-089502 ), the Global Probiotic Council (P.C.K.), the Center for Individualized Medicine, Mayo Clinic , Rochester, MN (P.C.K.), and VA merit review funds (J.D.K.).
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/6/13
Y1 - 2018/6/13
N2 - 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.
AB - 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.
KW - Bacteroides thetaiotaomicron
KW - GI transit
KW - IBS
KW - constipation
KW - genetically engineered
KW - microbiome
KW - motility
KW - phage promoter
KW - secretion
KW - tryptophan
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UR - http://www.scopus.com/inward/citedby.url?scp=85048206165&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2018.05.004
DO - 10.1016/j.chom.2018.05.004
M3 - Article
C2 - 29902441
AN - SCOPUS:85048206165
SN - 1931-3128
VL - 23
SP - 775-785.e5
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -