@article{e064da653fa34491b8fc1ca49675aca2,
title = "Bacterially Derived Tryptamine Increases Mucus Release by Activating a Host Receptor in a Mouse Model of Inflammatory Bowel Disease",
abstract = "Recent studies emphasize the role of microbial metabolites in regulating gastrointestinal (GI) physiology through activation of host receptors, highlighting the potential for inter-kingdom signaling in treating GI disorders. In this study, we show that tryptamine, a tryptophan-derived bacterial metabolite, stimulates mucus release from goblet cells via activation of G-protein-coupled receptor (GPCR) 5-HT4R. Germ-free mice colonized with engineered Bacteroides thetaiotaomicron optimized to produce tryptamine (Trp D+) exhibit decreased weight loss and increased mucus release following dextran sodium sulfate treatment when compared with mice colonized with control B. thetaiotaomicron (Trp D-). Additional beneficial effects in preventing barrier disruption and lower disease activity index were seen only in female mice, highlighting sex-specific effects of the bacterial metabolite. This study demonstrates potential for the precise modulation of mucus release by microbially produced 5-HT4 GPCR agonist as a therapeutic strategy to treat inflammatory conditions of the GI tract.",
keywords = "Microbiology, Rodent Gastroenterology",
author = "Yogesh Bhattarai and Si Jie and Linden, {David R.} and Sayak Ghatak and Mars, {Ruben A.T.} and Williams, {Brianna B.} and Meng Pu and Sonnenburg, {Justin L.} and Fischbach, {Michael A.} and Gianrico Farrugia and Lei Sha and Kashyap, {Purna C.}",
note = "Funding Information: We would like to thank Dr. Val{\'e}rie Compan for providing 5-HT4R KO mice, Dr. Beverley Greenwood-Van Meerveld for helpful discussions, and Lyndsay Busby for administrative assistance and copyediting. We would like to thank Sarah Becker for technical assistance. We acknowledge the help of Jenny Kirkpatrick and Boyd Palmer from Mayo Clinic Histopathology Core Facility located in Scottsdale, Arizona. We thank Lisa Till and Will Moor with their assistance in the GF facility. This work was made possible by funding from NIH DK114007, Minnesota Partnership for Biotechnology and Medical Genomics and the Center for Individualized Medicine, Mayo Clinic, Rochester, MN. Y.B. S.J. L.S. and P.C.K. designed the experiments and the overall data analysis; S.J. Y.B. and D.R.L. contributed to the mouse experiments; S.G. D.R.L. Y.B. and S.J. contributed to development of novel histochemistry-based digital image analysis algorithm for assessing mucus release; B.B.W. M.A.F. J.S. S.J. and Y.B. contributed to bacterial engineering and determining culture conditions; R.A.T.M. contributed to tryptamine measurement from fecal pellets; D.R.L. and M.P. contributed to histopathological damage assessment from H&E stained colon slides; and Y.B. and P.C.K. wrote the manuscript with input from all co-authors who read, revised, and approved the manuscript. P.C.K. reports being on the Advisory Board of Novome Biotechnologies and an ad hoc consultant for Pendulum Therapeutics, IP group, and Otsuka Pharmaceuticals. P.C.K. holds patent US20170042860A1 for use of tryptamine producing bacteria (“Transparent Methods for using Ruminococcus gnavus or Clostridium sporogenes to treat gastrointestinal disorders”), and P.C.K. and Mayo Clinic have a financial interest related to this research. These interests have been reviewed and managed in accordance with Mayo Clinic conflict of interest policies. M.A.F. reports being a co-founder and director of Federation Bio. Y.B. is currently a scientist at Takeda Pharmaceuticals. J.L.S. reports being a founder of Novome Biotechnologies, Inc. Funding Information: We would like to thank Dr. Val{\'e}rie Compan for providing 5-HT4R KO mice, Dr. Beverley Greenwood-Van Meerveld for helpful discussions, and Lyndsay Busby for administrative assistance and copyediting. We would like to thank Sarah Becker for technical assistance. We acknowledge the help of Jenny Kirkpatrick and Boyd Palmer from Mayo Clinic Histopathology Core Facility located in Scottsdale, Arizona. We thank Lisa Till and Will Moor with their assistance in the GF facility. This work was made possible by funding from NIH DK114007 , Minnesota Partnership for Biotechnology and Medical Genomics and the Center for Individualized Medicine, Mayo Clinic , Rochester, MN. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = dec,
day = "18",
doi = "10.1016/j.isci.2020.101798",
language = "English (US)",
volume = "23",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "12",
}