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  • Review Article
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Non-conventional features of peripheral serotonin signalling — the gut and beyond

Nature Reviews Gastroenterology & Hepatology volume 14, pages 412–420 (2017)Cite this article

Subjects

Key Points

  • Serotonin is an important molecule that was first discovered in the gut and contributes to the activation of intrinsic and extrinsic gastrointestinal reflexes

  • 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

  • Serotonin synthesis and release by enterochromaffin cells is influenced by gut microorganisms via the generation of short-chain fatty acids

  • 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

  • Serotonin influences metabolic homeostasis through actions in pancreatic islets, in the liver and in adipose tissue

  • 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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Figure 1: Serotonin signalling in the gut is influenced by the gut microbiota and their by-products.
Figure 2: Serotonin can act through different mechanisms to influence inflammation.
Figure 3: Serotonin influences many peripheral tissues.

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References

  1. Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20, 14–21 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 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.

    Google Scholar 

  3. Erspamer, V. & Asero, B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169, 800–801 (1952).

    CAS  PubMed  Google Scholar 

  4. Mawe, G. M. & Hoffman, J. M. Serotonin signalling in the gut — functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 10, 473–486 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    CAS  PubMed  Google Scholar 

  8. Rapport, M. M., Green, A. A. & Page, I. H. Partial purification of the vasoconstrictor in beef serum. J. Biol. Chem. 174, 735–741 (1948).

    CAS  PubMed  Google Scholar 

  9. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Walther, D. J. & Bader, M. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673–1680 (2003).

    CAS  PubMed  Google Scholar 

  12. Kim, H. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat. Med. 16, 804–808 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Paulmann, N. et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 7, e1000229 (2009).

    PubMed  PubMed Central  Google Scholar 

  14. Stunes, A. K. et al. Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation. Diabetes Obes. Metab. 13, 551–558 (2011).

    CAS  PubMed  Google Scholar 

  15. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Neunlist, M. & Schemann, M. Nutrient-induced changes in the phenotype and function of the enteric nervous system. J. Physiol. 592, 2959–2965 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

  18. Jones, R. M. The influence of the gut microbiota on host physiology: in pursuit of mechanisms. Yale J. Biol. Med. 89, 285–297 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. Wang, F. et al. Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanical forces. J. Physiol. 595, 79–91 (2017).

    CAS  PubMed  Google Scholar 

  22. Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    PubMed  PubMed Central  Google Scholar 

  24. 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).

    CAS  PubMed  Google Scholar 

  25. 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.

    CAS  PubMed  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. Margolis, K. G. et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 63, 928–937 (2014).

    CAS  PubMed  Google Scholar 

  28. Li, N. et al. Serotonin activates dendritic cell function in the context of gut inflammation. Am. J. Pathol. 178, 662–671 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. 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).

    PubMed  PubMed Central  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. 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.

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Margolis, K. G. et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J. Clin. Invest. 126, 2221–2235 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Bianco, F. et al. Prucalopride exerts neuroprotection in human enteric neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G768–G775 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Belkind-Gerson, J. et al. Colitis induces enteric neurogenesis through a 5-HT4-dependent mechanism. Inflamm. Bowel Dis. 21, 870–878 (2015).

    PubMed  Google Scholar 

  39. 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.

    CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. Lowy, P. H., Keighley, G. & Cohen, N. S. Stimulation by serotonin of erythropoietin-dependent erythropoiesis in mice. Br. J. Haematol. 19, 711–718 (1970).

    CAS  PubMed  Google Scholar 

  42. 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.

    CAS  PubMed  Google Scholar 

  43. Yang, M., Srikiatkhachorn, A., Anthony, M. & Chong, B. H. Serotonin stimulates megakaryocytopoiesis via the 5-HT2 receptor. Blood Coagul. Fibrinolysis 7, 127–133 (1996).

    CAS  PubMed  Google Scholar 

  44. Amireault, P. et al. Serotonin is a key factor for mouse red blood cell survival. PLoS ONE 8, e83010 (2013).

    PubMed  PubMed Central  Google Scholar 

  45. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. 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).

    CAS  PubMed  Google Scholar 

  48. Bertrand, R. L. et al. A Western diet increases serotonin availability in rat small intestine. Endocrinology 152, 36–47 (2011).

    CAS  PubMed  Google Scholar 

  49. Voigt, J. P. & Fink, H. Serotonin controlling feeding and satiety. Behav. Brain Res. 277, 14–31 (2015).

    CAS  PubMed  Google Scholar 

  50. Kim, K. et al. Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology 156, 444–452 (2015).

    PubMed  Google Scholar 

  51. 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).

    Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Oh, C. M. et al. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat. Commun. 6, 6794 (2015).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. Siddiqui, J. A. & Partridge, N. C. Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology (Bethesda) 31, 233–245 (2016).

    CAS  Google Scholar 

  56. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).

    CAS  PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kode, A. et al. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. J. Clin. Invest. 122, 3490–3503 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

  63. Erjavec, I. et al. Constitutively elevated blood serotonin is associated with bone loss and type 2 diabetes in rats. PLoS ONE 11, e0150102 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. Cui, Y. et al. Lrp5 functions in bone to regulate bone mass. Nat. Med. 17, 684–691 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Rizzoli, R. et al. Antidepressant medications and osteoporosis. Bone 51, 606–613 (2012).

    CAS  PubMed  Google Scholar 

  66. Mezuk, B., Eaton, W. W. & Golden, S. H. Depression and osteoporosis: epidemiology and potential mediating pathways. Osteoporos Int. 19, 1–12 (2008).

    CAS  PubMed  Google Scholar 

  67. 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).

    CAS  PubMed  Google Scholar 

  68. 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).

    PubMed  Google Scholar 

  69. Suarez-Trujillo, A. & Casey, T. M. Serotoninergic and circadian systems: driving mammary gland development and function. Front. Physiol. 7, 301 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. 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).

    PubMed  Google Scholar 

  71. Huang, Y. J. et al. Mouse taste buds use serotonin as a neurotransmitter. J. Neurosci. 25, 843–847 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Erspamer, V. Pharmacology of indolealkylamines. Pharmacol. Rev. 6, 425–487 (1954).

    CAS  PubMed  Google Scholar 

  73. Berger, M., Gray, J. A. & Roth, B. L. The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. de Jong, J. S. & Dekker, L. R. Platelets and cardiac arrhythmia. Front. Physiol. 1, 166 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  PubMed  Google Scholar 

  77. Connolly, J. M. et al. Fenfluramine disrupts the mitral valve interstitial cell response to serotonin. Am. J. Pathol. 175, 988–997 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. Launay, J. M. et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 8, 1129–1135 (2002).

    CAS  PubMed  Google Scholar 

  81. 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).

    CAS  PubMed  Google Scholar 

  82. Bonnin, A. et al. A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  Google Scholar 

  84. Matsuda, M. et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6, 193–203 (2004).

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Giuliano, F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci. 30, 79–84 (2007).

    CAS  PubMed  Google Scholar 

  87. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Sommer, C. Serotonin in pain and analgesia: actions in the periphery. Mol. Neurobiol. 30, 117–125 (2004).

    CAS  PubMed  Google Scholar 

  89. 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).

    PubMed  PubMed Central  Google Scholar 

  90. Jann, M. W. & Slade, J. H. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 27, 1571–1587 (2007).

    CAS  PubMed  Google Scholar 

Download references

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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Authors and Affiliations

  1. Department of Neurological Sciences, D403A Given Building, University of Vermont, Vermont, 05405, USA

    Stephanie N. Spohn & Gary M. Mawe

  2. Department of Internal Medicine, Division of Infectious Disease, 1518 Medical Science Research Building 1, 1150 W. Medical Center Drive, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Stephanie N. Spohn

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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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Correspondence to Gary M. Mawe.

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PowerPoint slides

Glossary

Neurotransmitter

Compounds that are released from neurons that can affect the physiology of nearby cells.

Enterochromaffin cell

A subset of enteroendocrine cells in the gastrointestinal epithelium that produce, store and release serotonin.

Enteric neuron

Neurons located in the myenteric or submucosal plexuses that are part of the enteric nervous system.

β cells

Pancreatic β cells are endocrine cells in the pancreas that produce insulin.

Enteric nervous system

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

Fatty acid with a backbone consisting of 2–6 carbon atoms; also known as volatile fatty acid.

Myenteric plexus

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

Non-neuronal cells in neural tissues that provide structural and functional support that aids in proper neurotransmission.

Serotonylation

A process in which serotonin affects the physiology of cells via mechanisms that do not involve activation of cell surface receptors.

Adipose tissue

Tissue that consists primarily of adipocytes, which are cells that store fat for energy and insulation.

Leptin

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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