Abstract
Because of their importance in the regulation of gut functions, several therapeutic targets involving serotonin-related proteins have been developed or repurposed to treat motility disorders, including serotonin transporter inhibitors, tryptophan hydroxylase blockers, 5-HT3 antagonists, and 5-HT4 agonists. This chapter focuses on our discovery of 5-HT4 receptors in the epithelial cells of the colon and our efforts to evaluate the effects of stimulating these receptors. 5-HT4 receptors appear to be expressed by all epithelial cells in the mouse colon, based on expression of a reporter gene driven by the 5-HT4 receptor promoter. Application of 5-HT4 agonists to the mucosal surface causes serotonin release from enterochromaffin cells, mucus secretion from goblet cells, and chloride secretion from enterocytes. Luminal administration of 5-HT4 agonists speeds up colonic motility and suppresses distention-induced nociceptive responses. Luminal administration of 5-HT4 agonists also decreases the development of, and improves recovery from, experimental colitis. Recent studies determined that the prokinetic actions of minimally absorbable 5-HT4 agonists are just as effective as absorbable compounds. Collectively, these findings indicate that targeting epithelial receptors with non-absorbable 5-HT4 agonists could offer a safe and effective strategy for treating constipation and colitis.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Chey WD, Pare P, Viegas A, Ligozio G, Shetzline MA (2008) Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial. Am J Gastroenterol 103:1217–1225
Greenwood-Van Meerveld B, Venkova K, Hicks G, Dennis E, Crowell MD (2006) Activation of peripheral 5-HT receptors attenuates colonic sensitivity to intraluminal distension. Neurogastroenterol Motil 18:76–86
Hennessey A, Robertson NP, Swingler R, Compston DA (1999) Urinary, faecal and sexual dysfunction in patients with multiple sclerosis. J Neurol 246:1027–1032
Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Johnson AC, Brooks EM, Zhao H, Swain GM, Moses PL, Galligan JJ (2012) Activation of colonic mucosal 5-HT4 receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142:844–854. e844
Jin J-G, Foxx-Orenstein AE, Grider J (1999) Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors. J Pharmacol Exp Ther 288:93–97
Jin JG, Foxx-Orenstein AE, Grider JR (1997) Stimulation of colonic propulsion by 5-HT4 receptor agonists: synergism by delta opioid receptor antagonists. Gastroenterology 112:A754
Johansson ME, Gustafsson JK, Holmen-Larsson J, Jabbar KS, Xia L, Xu H, Ghishan FK, Carvalho FA, Gewirtz AT, Sjovall H, Hansson GC (2014) Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63:281–291
Konen JR, Haag MM, Guseva D, Hurd M, Linton AA, Lavoie B, Kerrigan CB, Joyce E, Bischoff SC, Swann S, Griffin L, Matsukawa J, Falk MD, Gibson TS, Hennig GW, Wykosky J, Mawe GM (2021) Prokinetic actions of luminally acting 5-HT4 receptor agonists. Neurogastroenterol Motil 33:e14026
Mawe GM, Hoffman JM (2013) Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10:473
Patel BA, Patel N, Fidalgo S, Wang C, Ranson RN, Saffrey MJ, Yeoman MS (2014) Impaired colonic motility and reduction in tachykinin signalling in the aged mouse. Exp Gerontol 53:24–30
Spear E, Holt E, Joyce E, Haag M, Mawe S, Hennig G, Lavoie B, Applebee A, Teuscher C, Mawe G (2018) Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil 30:e13349
Spohn SN, Bianco F, Scott RB, Keenan CM, Linton AA, O’Neill CH, Bonora E, Dicay M, Lavoie B, Wilcox RL, MacNaughton WK, De Giorgio R, Sharkey KA, Mawe GM (2016) Protective actions of epithelial 5-hydroxytryptamine 4 receptors in normal and inflamed colon. Gastroenterology 151:933–944 e933
Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Buller HA, Dekker J, Van Seuningen I, Renes IB, Einerhand AW (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131:117–129
West CL, Amin JY, Farhin S, Stanisz AM, Mao YK, Kunze WA (2019) Colonic motility and Jejunal vagal afferent firing rates are decreased in aged adult male mice and can be restored by an aminosterol. Front Neurosci 13:955
Funding Support
Funding for the studies described here that were performed in the Mawe Laboratory was obtained from the NIH (DK113800 and DK62267) and from Takeda Pharmaceuticals.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this paper
Cite this paper
Mawe, G.M., Hurd, M., Hennig, G.W., Lavoie, B. (2022). Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation. In: Spencer, N.J., Costa, M., Brierley, S.M. (eds) The Enteric Nervous System II. Advances in Experimental Medicine and Biology, vol 1383. Springer, Cham. https://doi.org/10.1007/978-3-031-05843-1_30
Download citation
DOI: https://doi.org/10.1007/978-3-031-05843-1_30
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-05842-4
Online ISBN: 978-3-031-05843-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)