Serotonin (5-hydroxytryptamine; 5-HT) is a bioamine neurotransmitter classically recognized for its importance in central nervous system (CNS) functions. Nevertheless, most of the body’s serotonin is peripherally located, with over 95 % of the body’s 5-HT produced in the intestine, where it modulates motility and secretion [1]. Intestinal 5-HT has also been demonstrated to play a major role in enteric nervous system development, intestinal epithelial homeostasis, and the modulation of intestinal inflammation [2–5]. Despite the recognition that intestinal inflammatory diseases such as ulcerative colitis (UC) can have strong genetic components [6], genetic polymorphisms linked with serotonin have not been associated with these disease states. In this issue of Digestive Diseases and Sciences, Sikander et al. [7] conducted the first prospective case–control study to demonstrate that there may be a potential association between polymorphisms in the 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) of the serotonin transporter (SERT) gene promoter and the intestinal inflammatory diseases UC and microscopic colitis (MC).
In the intestine, 5-HT is produced by two different isoforms of the same biosynthetic enzyme, tryptophan hydroxylase (TPH). The vast majority (90 %) of 5-HT is produced by TPH1 in the enterochromaffin (EC) cells (and mast cells in rodents). The remainder is synthesized by TPH2 in enteric neurons [8]. TPH2 is also located in the neurons of the CNS. Under normal conditions, SERT terminates the action of released intestinal 5-HT via uptake into mucosal enterocytes and serotonergic neurons. The remaining 5-HT diffuses into the systemic circulation where it is taken up primarily by platelets which also contain SERT. Because 5-HT does not cross the blood–brain barrier, virtually all 5-HT present in blood is synthesized in the intestine [1, 9, 10]. Further, because platelets do not contain the synthetic machinery necessary to produce 5-HT (TPH), all platelet 5-HT is the result of SERT-mediated uptake. SERT is thus essential for intestinal and blood 5-HT homeostasis. The expression of SERT is regulated in part by a polymorphism in the 5-HTTLPR which has two predominant variant alleles: a short (S) allele and long (L) allele. The S allele is associated with reduced transcriptional efficiency and lower functional expression of SERT relative to the L allele [11]. It is therefore possible that intestinal and platelet 5-HT levels would be abnormal in individuals harboring an S allele.
Abnormal concentrations of 5-HT could affect an individual’s predisposition to or severity of intestinal inflammatory disease. Human studies have revealed a potential role for mucosal 5-HT in intestinal inflammation. Increased enteric 5-HT concentrations are present in patients with Crohn’s disease (CD), UC and MC [12–14]. This elevation is associated with significantly increased EC cell numbers and decreased SERT transcription in some studies [15, 16]. Studies have been conflicting, however, in UC where decreased amounts of mucosal 5-HT, TPH1 and SERT immunoreactivity and decreased EC cell numbers have also been observed [16].
Murine models have further supported the contribution of 5-HT toward intestinal inflammation. Mice that lack SERT, and thus have an increase in available intestinal 5-HT, develop more severe colitis when induced by trinitrobenzene sulfonic acid (TNBS) [17]. These mice also develop a more severe spontaneous colitis that arises as a result of interleukin (IL)-10 deletion [18]. Mice that do not produce intestinal mucosal 5-HT because they lack TPH1 are resistant to dinitrobenzene sulfonic acid-induced colitis [19]. Mice or guinea pigs with TNBS-induced colitis also demonstrate SERT downregulation and an increase in EC cell number and/or 5-HT release [9, 20–22].
Extensive research has elucidated part of the complex interrelationship between 5-HT and the immune system. SERT and/or 5-HT receptors are expressed on many cells involved in innate and adaptive immunity, including macrophages, mast cells, dendritic cells, basophils, neutrophils, eosinophils, natural killer cells, B cells and T cells [23]. The modulation of immune cells by 5-HT can have opposing effects; immune cell activation can trigger NF-kB and/or other proinflammatory signaling pathways, thereby stimulating production of proinflammatory mediators [24]. Conversely, activation of the 5-HT7 receptor, expressed on dendritic cells, helps ameliorate chemically induced colitis [25]. The immune system likewise exerts effects on 5-HT homeostasis. The proinflammatory mediators interferon-γ and tumor necrosis factor-α decrease SERT function in colonic adenocarcinoma Caco2 cells [26]. Moreover, IL-1β and lipopolysaccharide-induced 5-HT secretion is significantly increased in EC cells derived from patients with CD compared with a control population [24].
Post-infectious irritable bowel syndrome (IBS) may represent a low-grade inflammatory state and has been associated with increased peak postprandial 5-HT release and EC cell hyperplasia [27, 28]. In investigations of SERT polymorphisms in IBS, a meta-analysis of seven studies concluded that 5-HTTPLR genotypes are unrelated to IBS, while others reported evidence of an association when patients were stratified by predominant clinical symptoms [29]. The most recent meta-analysis of 25 such studies concluded that the L/L genotype of 5-HTTLPR is associated with an increased risk of developing constipation-predominant IBS (IBS-C) [30]. 5-HTTLPR genetic polymorphisms also may provide evidence for the efficacy of serotonin-based therapies for specific subtypes of IBS. In comparison with individuals with S/S or S/L genotypes, diarrhea-predominant IBS patients with the L/L genotype demonstrated a greater response to alosetron, a 5HT3 antagonist, while IBS-C patients with the L/L genotype had less of a response to the 5HT4 agonist tegaserod [31, 32].
Sikander et al. [7] conducted a prospective case–control study in which they sought to evaluate the association between the 5-HTTLPR promoter polymorphism and serum 5-HT concentrations in UC and MC. By evaluation of the 5-HTTLPR gene polymorphism in patients categorized as active UC, UC in remission, MC or in healthy controls, the authors found that the frequency of the S/S genotype was significantly lower in patients with MC or UC in remission, relative to healthy controls. They also determined that serum 5-HT levels, as measured by ELISA, were significantly higher in individuals with MC or UC when compared to the control population. More specifically, MC patients with the L/S or S/S genotype had significantly increased serum 5-HT concentrations compared with controls with similar genotypes. Similarly, active UC patients with the S/S genotype had increased serum 5-HT concentrations compared with S/S controls. Mean 5-HT concentrations were highest in individuals expressing the S/S genotype.
This is the first study to suggest that 5-HTTLPR polymorphisms may contribute to the pathogenesis of MC and UC and that these polymorphisms may correlate with serum 5-HT concentrations. Intestinal inflammation could be initiated by the increased amount of available enteric mucosal 5-HT due to a SERT polymorphism. Individuals in this study with the S/S genotype had the highest mean 5-HT levels. It is therefore interesting that individuals with intestinal inflammatory diseases (MC or UC in remission) exhibit the S/S genotype less frequently than controls. This observation is consistent with the hypothesis that 5-HTTLPR might represent only one of the contributing factors to disease severity.
This study describes a novel association between 5-HT, genetic susceptibility variants and intestinal inflammatory disease. Future studies in the field can span into multiple directions. It may be of interest to measure concentrations of free 5-HT in plasma of individuals with intestinal inflammatory diseases. Although only ≈ 0.1 % of 5-HT released can be measured as free 5-HT [33], this pool is accessible to sites of action and receptors that may be important for intestinal serotonergic functions. It would also be interesting to evaluate whether 5-HTTLPR polymorphisms are associated with changes in other important intestinal markers of serotonin homeostasis such as TPH1, 5-HT receptors and mucosal SERT expression as well as EC cell number. Further, the observation that >50 % of the controls in this study have the S/S genotype demonstrates that the development of MC and UC is not exclusively dependent on the presence of a 5-HTTPLR polymorphism. Future studies may focus on the evaluation of the relationship between 5-HTTLPR polymorphisms and epigenetic factors as well as rare variations in SERT that have been recently discovered [34]. The current study represents an important step toward understanding the complex genetic basis of intestinal inflammatory diseases.
References
Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 2013;20:14–21.
Li Z, Chalazonitis A, Huang YY, et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci. 2011;31:8998–9009.
Gross ER, Gershon MD, Margolis KG, et al. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology. 2012;143:408–417 e402.
Khan WI, Ghia JE. Gut hormones: emerging role in immune activation and inflammation. Clin Exp Immunol. 2010;161:19–27.
Margolis KG, Stevanovic K, Li Z, et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut. 2014;63:928–937.
Van Limbergen J, Radford-Smith G, Satsangi J. Advances in IBD genetics. Nat Rev Gastroenterol Hepatol. 2014;11:372–385.
Sikander A, Sinha SK, Prasad KK, Rana SV. Association of serotonin transporter promoter polymorphism (5-HTTLPR) with microscopic colitis and ulcerative colitis. Dig Dis Sci. (Epub ahead of print). doi:10.1007/s10620-014-3482-y.
Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.
Margolis KG, Pothoulakis C. Serotonin has a critical role in the pathogenesis of experimental colitis. Gastroenterology. 2009;137:1562–1566.
Margolis KG, Gershon MD. Neuropeptides and inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25:503–511.
Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996;66:2621–2624.
El-Salhy M, Danielsson A, Stenling R, Grimelius L. Colonic endocrine cells in inflammatory bowel disease. J Intern Med. 1997;242:413–419.
El-Salhy M, Gundersen D, Hatlebakk JG, Hausken T. High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis. World J Gastroenterol. 2012;18:6070–6075.
Belai A, Boulos PB, Robson T, Burnstock G. Neurochemical coding in the small intestine of patients with Crohn’s disease. Gut. 1997;40:767–774.
Bishop AE, Pietroletti R, Taat CW, Brummelkamp WH, Polak JM. Increased populations of endocrine cells in Crohn’s ileitis. Virchows Archiv A Pathol Anat Histopathol. 1987;410:391–396.
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;126:1657–1664.
Bischoff SC, Mailer R, Pabst O, 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. 2009;296:G685–G695.
Haub S, Ritze Y, Bergheim I, et al. Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter. Neurogastroenterol Motil. 2010;22:826–834 e229.
Ghia JE, Li N, Wang H, et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology. 2009;137:1649–1660.
Linden DR, Foley KF, McQuoid C, et al. Serotonin transporter function and expression are reduced in mice with TNBS-induced colitis. Neurogastroenterol Motil. 2005;17:565–574.
Linden DR, Chen JX, Gershon MD, Sharkey KA, Mawe GM. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol. 2003;285:G207–G216.
O’Hara JR, Ho W, Linden DR, Mawe GM, Sharkey KA. Enteroendocrine cells and 5-HT availability are altered in mucosa of guinea pigs with TNBS ileitis. Am J Physiol Gastrointest Liver Physiol. 2004;287:G998–G1007.
Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci. 2013;4:48–63.
Kidd M, Gustafsson BI, Drozdov I, Modlin IM. IL1beta- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn’s disease. Neurogastroenterol Motil. 2009;21:439–450.
Kim JJ, Bridle BW, Ghia JE, et al. Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation. J Immunol. 2013;190:4795–4804.
Foley KF, Pantano C, Ciolino A, Mawe GM. IFN-gamma and TNF-alpha decrease serotonin transporter function and expression in Caco2 cells. Am J Physiol Gastrointest Liver Physiol. 2007;292:G779–G784.
Spiller R. Serotonin, inflammation, and IBS: fitting the jigsaw together? J Pediatr Gastroenterol Nutr. 2007;45:S115–S119.
Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J Clin Gastroenterol. 2005;39:S184–S193.
Colucci R, Blandizzi C, Bellini M, et al. The genetics of the serotonin transporter and irritable bowel syndrome. Trends Mol Med. 2008;14:295–304.
Zhang ZF, Duan ZJ, Wang LX, et al. The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies. BMC Gastroenterol. 2014;14:23.
Li Y, Nie Y, Xie J, et al. The association of serotonin transporter genetic polymorphisms and irritable bowel syndrome and its influence on tegaserod treatment in Chinese patients. Dig Dis Sci. 2007;52:2942–2949.
Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2002;123:425–432.
Brand T, Anderson GM. The measurement of platelet-poor plasma serotonin: a systematic review of prior reports and recommendations for improved analysis. Clin Chem. 2011;57:1376–1386.
Prasad HC, Steiner JA, Sutcliffe JS, Blakely RD. Enhanced activity of human serotonin transporter variants associated with autism. Philos Trans R Soc Lond B Biol Sci. 2009;364:163–173.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Goldner, D., Margolis, K.G. Association of Serotonin Transporter Promoter Polymorphism (5HTTLPR) with Microscopic Colitis and Ulcerative Colitis: Time to Be AsSERTive?. Dig Dis Sci 60, 819–821 (2015). https://doi.org/10.1007/s10620-015-3598-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-015-3598-8