Bacterially Derived Tryptamine Increases Mucus Release by Activating a Host Receptor in a Mouse Model of Inflammatory Bowel Disease
Yogesh Bhattarai,
Si Jie,
David R. Linden,
Sayak Ghatak,
Ruben A.T. Mars,
Brianna B. Williams,
Meng Pu,
Justin L. Sonnenburg,
Michael A. Fischbach,
Gianrico Farrugia,
Lei Sha,
Purna C. Kashyap
Affiliations
Yogesh Bhattarai
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
Si Jie
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
David R. Linden
Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Sayak Ghatak
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
Ruben A.T. Mars
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
Brianna B. Williams
Department of Bioengineering and ChEM-H, Stanford University, CA 94305, USA
Meng Pu
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
Justin L. Sonnenburg
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94304, USA
Michael A. Fischbach
Department of Bioengineering and ChEM-H, Stanford University, CA 94305, USA
Gianrico Farrugia
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Lei Sha
Department of Pharmacy, Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, 77 Pu He Road, Shenbei New District, Shenyang 110122, P.R. China; Corresponding author
Purna C. Kashyap
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Corresponding author
Summary: 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.
