HHS Public Access Author manuscript Cell, Author manuscript; available in PMC 2016 April 09 Published in final edited form as Cell2015Aprl9161(2):264-276.doi:10.1016/cl2015.02047 Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis Jessica M Yano, Kristie Yu, Gregory P. Donaldson, Gauri G. Shastri, Phoebe Ann' Liang Ma2, Cathryn R Nagler, Rustem F Ismagilov, Sarkis K Mazmanian, and Elaine Y. 1Division of Biology Biological Engineering, California Institute of Technology, Pasadena, CA 91125.USA E9乙 Division of Chemistry and Chemical Engineering California Institute of Technology, Pasadena CA 91125 USA 3Department of Pathology and Department of Medicine, The Unit of Chicago, Chicago, IL 60637.USA SUMMARY The gastrointestinal(GI) tract contains much of the bodys serotonin (5-hydroxytryptamine, 5- IT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here we demonstrate that the microbiota plays a critical role in regulating host 5-HT Indigenous spore- forming bacteria(Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells(ECs), which supply 5-HT to the mucosa, lumen and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating Gl motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECS. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT, and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes INTRODUCTION In addition to its role as a brain neurotransmitter, the monoamine serotonin(5- hydroxytryptamine, 5-HT) is an important regulatory factor in the gastrointestinal(Gi)tract 0 2015 Published by Elsevier Inc. to ehsiaoacaltec Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of he resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain AUTHORS CONTRIBUTIONS J M.Y., K.Y., G.P. D, G.G.S., P.A., L.M. and E.Y. H. performed the experiments and analyzed the data, J M.Y. and E.Y. H. designed he study, C.R. N.,R. F I and S K M. provided novel reagents, R F I. and s K M. provided valuable support and contributed equally J M.Y. and E.Y. H. wrote the manuscript. All authors discussed the results and commented on the manuscript.Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis Jessica M. Yano1, Kristie Yu1, Gregory P. Donaldson1, Gauri G. Shastri1, Phoebe Ann1, Liang Ma2, Cathryn R. Nagler3, Rustem F. Ismagilov2, Sarkis K. Mazmanian1, and Elaine Y. Hsiao1,* 1Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA 2Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA 3Department of Pathology and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA SUMMARY The gastrointestinal (GI) tract contains much of the body’s serotonin (5-hydroxytryptamine, 5- HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore￾forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT, and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes. INTRODUCTION In addition to its role as a brain neurotransmitter, the monoamine serotonin (5- hydroxytryptamine, 5-HT) is an important regulatory factor in the gastrointestinal (GI) tract © 2015 Published by Elsevier Inc. *Correspondence to: ehsiao@caltech.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AUTHORS CONTRIBUTIONS J.M.Y., K.Y., G.P.D., G.G.S., P.A., L.M. and E.Y.H. performed the experiments and analyzed the data, J.M.Y. and E.Y.H. designed the study, C.R.N., R.F.I and S.K.M. provided novel reagents, R.F.I. and S.K.M. provided valuable support and contributed equally, J.M.Y. and E.Y.H. wrote the manuscript. All authors discussed the results and commented on the manuscript. HHS Public Access Author manuscript Cell. Author manuscript; available in PMC 2016 April 09. Published in final edited form as: Cell. 2015 April 9; 161(2): 264–276. doi:10.1016/j.cell.2015.02.047. Author Manuscript Author Manuscript Author Manuscript Author Manuscript