Key Points
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Serotonin is an important molecule that was first discovered in the gut and contributes to the activation of intrinsic and extrinsic gastrointestinal reflexes
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Enterochromaffin cells are the major source of serotonin in the gut and in platelets, but we now know that serotonin is also synthesized in other peripheral tissues
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Serotonin synthesis and release by enterochromaffin cells is influenced by gut microorganisms via the generation of short-chain fatty acids
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In the intestinal mucosa, serotonin can act to promote inflammation, but also to protect from and reverse inflammation through activation of dendritic cell 5-HT7 receptors and epithelial 5-HT4 receptors, respectively
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Serotonin influences metabolic homeostasis through actions in pancreatic islets, in the liver and in adipose tissue
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Within bone, serotonin acts both in the bone marrow to stimulate haematopoiesis and also in osseous tissue to influence bone metabolism
Abstract
Serotonin was first discovered in the gut, and its conventional actions as an intercellular signalling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signalling pharmacotherapeutic targets for treatment of nausea, diarrhoea or constipation. The latest discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the gastrointestinal tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro-inflammatory and anti-inflammatory signalling molecule in the intestinal mucosa via activation of serotonin receptors (5-HT7 or 5-HT4 receptors, respectively). For decades, serotonin receptors have been known to exist in a variety of tissues other than the gut, but studies have now provided strong evidence for physiological roles of serotonin in several important processes, including haematopoiesis, metabolic homeostasis and bone metabolism. Furthermore, evidence for serotonin synthesis in peripheral tissues outside of the gut is emerging. In this Review, we expand the discussion beyond gastrointestinal functions to highlight the roles of peripheral serotonin in colitis, haematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiota.
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References
Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20, 14–21 (2013).
Erspamer, V. Experimental research on the biological significance of enterochromaffin cells [Italian]. Arch. Fisiol. 37, 156–159 (1937). This report represents the discovery of serotonin.
Erspamer, V. & Asero, B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169, 800–801 (1952).
Mawe, G. M. & Hoffman, J. M. Serotonin signalling in the gut — functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 10, 473–486 (2013).
Smith, T. K. & Gershon, M. D. CrossTalk proposal: 5-HT is necessary for peristalsis. J. Physiol. 593, 3225–3227 (2015). This paper provides one side of the story regarding the roles of mucosal serotonin in activating motility reflexes.
Spencer, N. J., Sia, T. C., Brookes, S. J., Costa, M. & Keating, D. J. CrossTalk opposing view: 5-HT is not necessary for peristalsis. J. Physiol. 593, 3229–3231 (2015). This paper provides the other side of the story regarding the roles of mucosal serotonin in activating motility reflexes.
Page, I. H., Rapport, M. M. & Green, A. A. The crystallization of serotonin. J. Lab. Clin. Med. 33, 1606 (1948). This paper demonstrates that the structure of serotonin is 5-hydroxytryptamine.
Rapport, M. M., Green, A. A. & Page, I. H. Partial purification of the vasoconstrictor in beef serum. J. Biol. Chem. 174, 735–741 (1948).
Bertaccini, G. Tissue 5-hydroxytryptamine and urinary 5-hydroxyindoleacetic acid after partial or total removal of the gastro-intestinal tract in the rat. J. Physiol. 153, 239–249 (1960).
Cote, F. et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl Acad. Sci. USA 100, 13525–13530 (2003). This paper demonstrates that peripheral serotonin production is not limited to the gastrointestinal tract.
Walther, D. J. & Bader, M. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673–1680 (2003).
Kim, H. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat. Med. 16, 804–808 (2010).
Paulmann, N. et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 7, e1000229 (2009).
Stunes, A. K. et al. Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation. Diabetes Obes. Metab. 13, 551–558 (2011).
Chabbi-Achengli, Y. et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc. Natl Acad. Sci. USA 109, 2567–2572 (2012). This paper demonstrates that serotonin, synthesized in bone, can act to promote bone accrual.
Neunlist, M. & Schemann, M. Nutrient-induced changes in the phenotype and function of the enteric nervous system. J. Physiol. 592, 2959–2965 (2014).
Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 29, 1395–1403 (2015).
Jones, R. M. The influence of the gut microbiota on host physiology: in pursuit of mechanisms. Yale J. Biol. Med. 89, 285–297 (2016).
Hurst, N. R., Kendig, D. M., Murthy, K. S. & Grider, J. R. The short chain fatty acids, butyrate and propionate, have differential effects on the motility of the guinea pig colon. Neurogastroenterol. Motil. 26, 1586–1596 (2014).
Hoffman, J. M. et al. Activation of colonic mucosal 5-HT4 receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142, 844–854.e4 (2012). This paper demonstrates that 5-HT 4 receptors are highly expressed in the epithelial layer of the colon, and that activation of these receptors could be a mechanism of the prokinetic actions of 5-HT 4 agonists.
Wang, F. et al. Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces. J. Physiol. 595, 79–91 (2017).
Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).
Aherne, C. M., Collins, C. B. & Eltzschig, H. K. Netrin-1 guides inflammatory cell migration to control mucosal immune responses during intestinal inflammation. Tissue Barriers 1, e24957 (2013).
Bischoff, S. C. et al. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G685–G695 (2009).
Ghia, J. E. et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137, 1649–1660 (2009). References 24 and 25 provide evidence for a pro-inflammatory action of mucosal 5-HT in the intestines.
Kim, J. J. et al. Blocking peripheral serotonin synthesis by telotristat etiprate (LX1032/LX1606) reduces severity of both chemical- and infection-induced intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G455–G465 (2015).
Margolis, K. G. et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 63, 928–937 (2014).
Li, N. et al. Serotonin activates dendritic cell function in the context of gut inflammation. Am. J. Pathol. 178, 662–671 (2011).
Kim, J. J. et al. Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation. J. Immunol. 190, 4795–4804 (2013).
Gershon, M. D. Serotonin is a sword and a shield of the bowel: serotonin plays offense and defense. Trans. Am. Clin. Climatol. Assoc. 123, 268–280 (2012).
Motomura, Y. et al. Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in Th1 and Th2 dominant environments. Gut 57, 475–481 (2008).
Foley, K. F., Pantano, C., Ciolino, A. & Mawe, G. M. IFN-gamma and TNF-alpha decrease serotonin transporter function and expression in Caco2 cells. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G779–G784 (2007).
Spohn, S. N. et al. Protective actions of epithelial 5-hydroxytryptamine 4 receptors in normal and inflamed colon. Gastroenterology 151, 933–944 (2016). This paper demonstrates that activation of mucosal 5-HT 4 receptors can accelerate recovery from colitis.
Li, Z. et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J. Neurosci. 31, 8998–9009 (2011).
Liu, M. T., Kuan, Y. H., Wang, J., Hen, R. & Gershon, M. D. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29, 9683–9699 (2009).
Margolis, K. G. et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J. Clin. Invest. 126, 2221–2235 (2016).
Bianco, F. et al. Prucalopride exerts neuroprotection in human enteric neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G768–G775 (2016).
Belkind-Gerson, J. et al. Colitis induces enteric neurogenesis through a 5-HT4-dependent mechanism. Inflamm. Bowel Dis. 21, 870–878 (2015).
Matsuyoshi, H. et al. A 5-HT4-receptor activation-induced neural plasticity enhances in vivo reconstructs of enteric nerve circuit insult. Neurogastroenterol. Motil. 22, 806–e226 (2010). This paper demonstrates that compromised enteric reflexes regenerate faster when 5-HT 4 receptors in the region are activated.
Tharayil, V. S. et al. Lack of serotonin 5-HT2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo . Neurogastroenterol. Motil. 22, 462–e110 (2010).
Lowy, P. H., Keighley, G. & Cohen, N. S. Stimulation by serotonin of erythropoietin-dependent erythropoiesis in mice. Br. J. Haematol. 19, 711–718 (1970).
Yang, M. et al. Promoting effects of serotonin on hematopoiesis: ex vivo expansion of cord blood CD34+ stem/progenitor cells, proliferation of bone marrow stromal cells, and antiapoptosis. Stem Cells 25, 1800–1806 (2007). This paper deomonstrates a role for serotonin in bone marrow on haematopoiesis.
Yang, M., Srikiatkhachorn, A., Anthony, M. & Chong, B. H. Serotonin stimulates megakaryocytopoiesis via the 5-HT2 receptor. Blood Coagul. Fibrinolysis 7, 127–133 (1996).
Amireault, P. et al. Serotonin is a key factor for mouse red blood cell survival. PLoS ONE 8, e83010 (2013).
Amireault, P. et al. Ineffective erythropoiesis with reduced red blood cell survival in serotonin-deficient mice. Proc. Natl Acad. Sci. USA 108, 13141–13146 (2011). This paper demonstrates a role for serotonin in erythrocyte survivial.
Breum, L., Rasmussen, M. H., Hilsted, J. & Fernstrom, J. D. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am. J. Clin. Nutr. 77, 1112–1118 (2003).
Kim, H. J. et al. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J. Proteome Res. 10, 722–731 (2011).
Bertrand, R. L. et al. A Western diet increases serotonin availability in rat small intestine. Endocrinology 152, 36–47 (2011).
Voigt, J. P. & Fink, H. Serotonin controlling feeding and satiety. Behav. Brain Res. 277, 14–31 (2015).
Kim, K. et al. Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 156, 444–452 (2015).
Zelkas, L. et al. Serotonin-secreting enteroendocrine cells respond via diverse mechanisms to acute and chronic changes in glucose availability. Nutr. Metab. (Lond.) 12, 55 (2015).
Sumara, G., Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. 16, 588–600 (2012).
Oh, C. M. et al. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat. Commun. 6, 6794 (2015).
Crane, J. D. et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat. Med. 21, 166–172 (2015).
Siddiqui, J. A. & Partridge, N. C. Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology (Bethesda) 31, 233–245 (2016).
Yadav, V. K. et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138, 976–989 (2009).
Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).
Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).
Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008). This paper demonstrates that gut-derived serotonin can influence bone density by supressing the proliferation of pre-osteoblasts.
Kode, A. et al. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. J. Clin. Invest. 122, 3490–3503 (2012).
Yadav, V. K. et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat. Med. 16, 308–312 (2010).
Blazevic, S., Erjavec, I., Brizic, M., Vukicevic, S. & Hranilovic, D. Molecular background and physiological consequences of altered peripheral serotonin homeostasis in adult rats perinatally treated with tranylcypromine. J. Physiol. Pharmacol. 66, 529–537 (2015).
Erjavec, I. et al. Constitutively elevated blood serotonin is associated with bone loss and type 2 diabetes in rats. PLoS ONE 11, e0150102 (2016).
Cui, Y. et al. Lrp5 functions in bone to regulate bone mass. Nat. Med. 17, 684–691 (2011).
Rizzoli, R. et al. Antidepressant medications and osteoporosis. Bone 51, 606–613 (2012).
Mezuk, B., Eaton, W. W. & Golden, S. H. Depression and osteoporosis: epidemiology and potential mediating pathways. Osteoporos Int. 19, 1–12 (2008).
Warden, S. J., Robling, A. G., Sanders, M. S., Bliziotes, M. M. & Turner, C. H. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146, 685–693 (2005).
Garfield, L. D. et al. Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults. World J. Biol. Psychiatry 15, 404–410 (2014).
Suarez-Trujillo, A. & Casey, T. M. Serotoninergic and circadian systems: driving mammary gland development and function. Front. Physiol. 7, 301 (2016).
Durk, T. et al. Production of serotonin by tryptophan hydroxylase 1 and release via platelets contribute to allergic airway inflammation. Am. J. Respir. Crit. Care Med. 187, 476–485 (2013).
Huang, Y. J. et al. Mouse taste buds use serotonin as a neurotransmitter. J. Neurosci. 25, 843–847 (2005).
Erspamer, V. Pharmacology of indolealkylamines. Pharmacol. Rev. 6, 425–487 (1954).
Berger, M., Gray, J. A. & Roth, B. L. The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009).
Langer, C. et al. Atrial fibrillation in carcinoid heart disease: the role of serotonin. A review of the literature. Clin. Res. Cardiol. 96, 114–118 (2007).
de Jong, J. S. & Dekker, L. R. Platelets and cardiac arrhythmia. Front. Physiol. 1, 166 (2010).
Brattelid, T. et al. Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure. Naunyn Schmiedebergs Arch. Pharmacol. 370, 157–166 (2004).
Connolly, J. M. et al. Fenfluramine disrupts the mitral valve interstitial cell response to serotonin. Am. J. Pathol. 175, 988–997 (2009).
Rothman, R. B. et al. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102, 2836–2841 (2000).
Esteve, J. M., Launay, J. M., Kellermann, O. & Maroteaux, L. Functions of serotonin in hypoxic pulmonary vascular remodeling. Cell Biochem. Biophys. 47, 33–44 (2007).
Launay, J. M. et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 8, 1129–1135 (2002).
Bolte, A. C., van Geijn, H. P. & Dekker, G. A. Pathophysiology of preeclampsia and the role of serotonin. Eur. J. Obstet. Gynecol. Reprod. Biol. 95, 12–21 (2001).
Bonnin, A. et al. A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350 (2011).
Jeffrey, J. J., Ehlich, L. S. & Roswit, W. T. Serotonin: an inducer of collagenase in myometrial smooth muscle cells. J. Cell. Physiol. 146, 399–406 (1991).
Matsuda, M. et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6, 193–203 (2004).
de Jong, T. R., Veening, J. G., Waldinger, M. D., Cools, A. R. & Olivier, B. Serotonin and the neurobiology of the ejaculatory threshold. Neurosci. Biobehav. Rev. 30, 893–907 (2006).
Giuliano, F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci. 30, 79–84 (2007).
Ramage, A. G. The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control of micturition. Br. J. Pharmacol. 147 (Suppl. 2), S120–S131 (2006).
Sommer, C. Serotonin in pain and analgesia: actions in the periphery. Mol. Neurobiol. 30, 117–125 (2004).
Braz, J. M. & Basbaum, A. I. Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits. J. Comp. Neurol. 507, 1990–2003 (2008).
Jann, M. W. & Slade, J. H. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 27, 1571–1587 (2007).
Acknowledgements
G.M.M. is supported by NIH grant DK62267. The authors thank E. Spear and B. Lavoie for editorial assistance.
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S.N.S. and G.M.M. both contributed to formulating the outline, conducting literature searches, writing and editing the manuscript.
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Glossary
- Neurotransmitter
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Compounds that are released from neurons that can affect the physiology of nearby cells.
- Enterochromaffin cell
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A subset of enteroendocrine cells in the gastrointestinal epithelium that produce, store and release serotonin.
- Enteric neuron
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Neurons located in the myenteric or submucosal plexuses that are part of the enteric nervous system.
- β cells
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Pancreatic β cells are endocrine cells in the pancreas that produce insulin.
- Enteric nervous system
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Third division of the autonomic nervous system, along with the sympathetic and parasympathetic divisions; consists of the ganglia and nerves within the wall of the gut, and it is unique in that it contains intrinsic reflex circuitry that can locally regulate motility, secretion and blood flow.
- Short-chain fatty acid
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Fatty acid with a backbone consisting of 2–6 carbon atoms; also known as volatile fatty acid.
- Myenteric plexus
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A ganglionated plexus of the enteric nervous system that is situated between the circular and longitudinal muscle layers; neural circuits in this plexus provide output to the muscle layers and are responsible for generating motility patterns in the gastrointestinal tract.
- Glial cell
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Non-neuronal cells in neural tissues that provide structural and functional support that aids in proper neurotransmission.
- Serotonylation
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A process in which serotonin affects the physiology of cells via mechanisms that do not involve activation of cell surface receptors.
- Adipose tissue
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Tissue that consists primarily of adipocytes, which are cells that store fat for energy and insulation.
- Leptin
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A hormone produced in adipose tissue that regulates fat storage in the body as well as appetite.
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Spohn, S., Mawe, G. Non-conventional features of peripheral serotonin signalling — the gut and beyond. Nat Rev Gastroenterol Hepatol 14, 412–420 (2017). https://doi.org/10.1038/nrgastro.2017.51
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DOI: https://doi.org/10.1038/nrgastro.2017.51
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