Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Serotonergic Integration In the Intestinal Mucosa

Author(s): Jackie D. Wood*

Volume 26, Issue 25, 2020

Page: [3010 - 3014] Pages: 5

DOI: 10.2174/1381612826666200612161542

Price: $65


Mucosal serotonin (5-HT) is a key paracrine signaling molecule in the integrated physiology of enterochromaffin cells, enteric mast cells, spinal afferent nerves and the enteric nervous system (ENS). Enterochromaffin cells release 5-HT as a paracrine signal to enteric mast cells, spinal afferents and neurons in the ENS. Enteric mast cells release multiple mediators of paracrine signaling, among which are histamine and the serine proteases, chymase and tryptase, as well as serotonin. Some of these mediators diffuse to receptors on afferent nociceptive and mechanosensitive terminals and sensitize the terminals in a manner that may underlie abdominal pain and distension induced pain in the irritable bowel syndrome. Substance P and calcitonin gene-related peptide (CGRP), released by spinal afferent innervation, degranulate enteric mast cells. Substance P and CGRP are significant factors in mucosal inflammation evoked by bacteria in the colonic microbiome. Binding of immunoglobulin antibodies to FcεRI receptors, on enteric mast cells, degranulate the mast cells and release paracrine mediators that overlay integrative microcircuitry in the ENS. An overlay of histamine “calls up” from the ENS library of programed gut behaviors, a defensive program consisting of a sequence of copious mucosal secretions, increased blood flow and powerful orthograde propulsion organized to move threats out of the colonic lumen. Symptoms of acute watery diarrhea, cramping abdominal pain and incontinence are associated with “running” of the defense program. Intestinal behavioral programs stored in the ENS library are described as working like digital “apps”.

Keywords: Mucosal epithelium, Enterochromaffin cells, Enteric mast cells, Spinal afferent neurons, Abdominal pain, Mucosal inflammation, Irritable bowel syndrome.

Wood JD. Cellular neurophysiology of enteric neuronsPhysiology of the Gastrointestinal Tract. 5th ed. San Diego: Elsevier 2012; pp. 629-69.
Wood JD. Pathophysiology underlying the irritable bowel syndrome.Johnson LR, Kaunitz JD, Ghishan FK, Merchant JL, Said HM, Wood JD, Eds. Physiology of the Gastrointestinal Tract. 5th. San Diego: Elsevier 2012; pp. 2157-77.
Frieling T, Cooke HJ, Wood JD. Serotonin receptors on submucous neurons in guinea pig colon. Am J Physiol 1991; 261(6 Pt. 1): G1017-23.
[PMID: 1767843]
Camilleri M, Chey WY, Mayer EA, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001; 161(14): 1733-40.
[] [PMID: 11485506]
Bearcroft CP, Perrett D, Farthing MJ. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998; 42(1): 42-6.
[] [PMID: 9505884]
O’Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000; 12(5): 449-57.
[] [PMID: 11012945]
Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.
[] [PMID: 14988823]
Chen JX, Pan H, Rothman TP, Wade PR, Gershon MD. Guinea pig 5-HT transporter: cloning, expression, distribution, and function in intestinal sensory reception. Am J Physiol 1998; 275(3): G433-48.
[PMID: 9724254]
Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 2004; 126(7): 1657-64.
[] [PMID: 15188158]
Frieling T, Palmer JM, Cooke HJ, Wood JD. Neuroimmune communication in the submucous plexus of guinea pig colon after infection with Trichinella spiralis. Gastroenterology 1994; 107(6): 1602-9.
[] [PMID: 7525397]
Liu S, Hu HZ, Gao N, et al. Neuroimmune interactions in guinea pig stomach and small intestine. Am J Physiol Gastrointest Liver Physiol 2003; 284(1): G154-64.
[] [PMID: 12388180]
Wood JD. Enteric nervous system: Brain-in-the-gutPhysiology of the Gastrointestinal Tract. 6th ed. San Diego: Academic Press 2018; pp. 361-72.
MacQueen G, Marshall J, Perdue M, Siegel S, Bienenstock J. Pavlovian conditioning of rat mucosal mast cells to secrete rat mast cell protease II. Science 1989; 243(4887): 83-5.
[] [PMID: 2911721]
Santos J, Saperas E, Mourelle M, Antolín M, Malagelada JR. Regulation of intestinal mast cells and luminal protein release by cerebral thyrotropin-releasing hormone in rats. Gastroenterology 1996; 111(6): 1465-73.
[] [PMID: 8942724]
Söderholm JD, Perdue MH. Stress and gastrointestinal tract. II. Stress and intestinal barrier function. Am J Physiol Gastrointest Liver Physiol 2001; 280(1): G7-G13.
[] [PMID: 11123192]
Liu S, Wood JD. Neurobiology of corticotropin- releasing factor in the enteric nervous system during stressCell/Tissue Injury and Cytoprotection / Organoprotection in the Gastrointestinal Tract: Mechanisms, Prevention and Treatment Front Gastrointest Res. Basel: Karger 2012; pp. 115-23.
Wood JD, Peck OC, Tefend KS, et al. Evidence that colitis is initiated by environmental stress and sustained by fecal factors in the cotton-top tamarin (Saguinus oedipus). Dig Dis Sci 2000; 45(2): 385-93.
[] [PMID: 10711456]
Wood JD, Peck OC, Sharma HS, et al. A non-peptide neurokinin 1 (NK-1) receptor antagonist suppresses initiation of acute inflammation in the colon of the cotton-top tamarin model for spontaneous colitis and colon cancer. Gastroenterology 1996; 110: A1047.
Wang GD, Wang XY, Zou F, et al. Mast cell expression of the serotonin1A receptor in guinea pig and human intestine. Am J Physiol Gastrointest Liver Physiol 2013; 304(10): G855-63.
[] [PMID: 23518679]
Harrington AM, Castro J, Erickson A, Grundy L, Brierley SM. Physiology of the Gastrointestinal Tract. 6th ed. San Diego: Academic Press 2018; pp. 387-418.
Coelho AM, Fioramonti J, Bueno L. Mast cell degranulation induces delayed rectal allodynia in rats: role of histamine and 5-HT. Dig Dis Sci 1998; 43(4): 727-37.
[] [PMID: 9558027]
Hillsley K, Kirkup AJ, Grundy D. Direct and indirect actions of 5-hydroxytryptamine on the discharge of mesenteric afferent fibres innervating the rat jejunum. J Physiol 1998; 506(Pt. 2): 551-61.
[] [PMID: 9490878]
Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973; 14(2): 125-32.
[] [PMID: 4696535]
Castagliuolo I, LaMont JT, Letourneau R, et al. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 1994; 107(3): 657-65.
[] [PMID: 7915699]
Castagliuolo I, Riegler M, Pasha A, et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis. J Clin Invest 1998; 101(8): 1547-50.
[] [PMID: 9541482]
Pothoulakis C, Castagliuolo I, LaMont JT, et al. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc Natl Acad Sci USA 1994; 91(3): 947-51.
[] [PMID: 7508124]
Pothoulakis C, Karmeli F, Kelly CP, et al. Ketotifen inhibits Clostridium difficile toxin A-induced enteritis in rat ileum. Gastroenterology 1993; 105(3): 701-7.
[] [PMID: 8395445]
Wershil BK, Castagliuolo I, Pothoulakis C. Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice. Gastroenterology 1998; 114(5): 956-64.
[] [PMID: 9558284]
Cocchiara R, Albeggiani G, Azzolina A, et al. Effect of substance P on uterine mast cell cytokine release during the reproductive cycle. J Neuroimmunol 1995; 60(1-2): 107-15.
[] [PMID: 7543905]
Cocchiara R, Albeggiani G, Lampiasi N, Bongiovanni A, Azzolina A, Geraci D. Histamine and tumor necrosis factor-alpha production from purified rat brain mast cells mediated by substance P. Neuroreport 1999; 10(3): 575-8.
[] [PMID: 10208592]
Cocchiara R, Bongiovanni A, Albeggiani G, et al. Inhibitory effect of neuraminidase on SP-induced histamine release and TNF-alpha mRNA in rat mast cells: evidence of a receptor-independent mechanism. J Neuroimmunol 1997; 75(1-2): 9-18.
[] [PMID: 9143232]
Xia Y, Hu HZ, Liu S, Pothoulakis C, Wood JD. Clostridium difficile toxin A excites enteric neurones and suppresses sympathetic neurotransmission in the guinea pig. Gut 2000; 46(4): 481-6.
[] [PMID: 10716676]
Wang GD, Wang XY, Liu S, et al. Innervation of enteric mast cells by primary spinal afferents in guinea pig and human small intestine. Am J Physiol Gastrointest Liver Physiol 2014; 307(7): G719-31.
[] [PMID: 25147231]
Gao C, Liu S, Hu H-Z, et al. Serine proteases excite myenteric neurons through protease-activated receptors in guinea pig small intestine. Gastroenterology 2002; 123(5): 1554-64.
[] [PMID: 12404230]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy