Skip to main content
SpringerLink
Log in

Association of Serotonin Transporter Promoter Polymorphism (5-HTTLPR) with Microscopic Colitis and Ulcerative Colitis

Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Serotonin (5-HT) release and serotonin reuptake transporter (5-HTT) expression have been reported to be decreased in experimental colitis, in interleukin-10 knockout-associated colitis, and in patients with ulcerative colitis. Serotonin is known to play an important role in the pathogenesis of colitis, but individual genetic variants of 5-HTT gene in microscopic colitis and ulcerative colitis are not known.

Aim

This study aimed to evaluate the association between the serotonin transporter gene promoter polymorphism (5-HTTLPR) and 5-HT concentration in microscopic colitis (MC) and ulcerative colitis (UC) patients.

Method

This prospective case–control study included 41 patients with microscopic colitis (age 19–82 years, mean 35 ± 13.6), 75 patients with ulcerative colitis (age 16–65 years, mean 38.5 ± 11.6), and 100 controls (age 20–64 years, mean 38 ± 11). 5-HTTLPR gene polymorphism was studied by polymerase chain reaction-based assay. 5-HT levels were measured by ELISA.

Results

The frequency of the 5-HTTLPR (SS) genotype was significantly lower in MC (12 %) patients compared to controls (30 %) (p < 0.05). When the L/L and L/S genotypes were combined into one group, the frequencies of the non-S genotype were significantly higher than those of S/S genotype between the MC patients and the controls (p < 0.05). 5-HT levels were significantly higher in UC and MC patients compared to healthy controls (p < 0.01).

Conclusions

A significant association was observed between LL genotype of 5-HTTLPR polymorphism and microscopic colitis, suggesting that 5-HTTLPR is a potential candidate gene involved in the pathogenesis of microscopic colitis. Serotonin levels were significantly higher in microscopic colitis and ulcerative colitis patients compared to healthy controls.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Gershon MD. Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord.. 2003;3:S25–S34.

    PubMed  Google Scholar 

  2. Ham TS. Regional distribution and relative frequency of gastrointestinal endocrine cells in large intestines of C57BL/6 mice. J Vet Sci. 2002;3:233–238.

    PubMed  Google Scholar 

  3. Khan WI, Ghia JE. Gut hormones: emerging role in immune activation and inflammation. Clin Exp Immunol. 2010;161:19–27.

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Kim DY, Camilleri M. Serotonin: a mediator of the brain-gut connection. Am J Gastroenterol. 2000;95:2698–2709.

    CAS  PubMed  Google Scholar 

  5. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.

    Article  CAS  PubMed  Google Scholar 

  6. 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:G433–G448.

    CAS  PubMed  Google Scholar 

  7. Heils A, Teufel A, Petri S, Stöber G, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996;66:2621–2624.

    Article  CAS  PubMed  Google Scholar 

  8. Lesch KP, Bengel D, Heils A, Sabol SZ, et al. Association of anxiety related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–1531.

    Article  CAS  PubMed  Google Scholar 

  9. Ahonen A, Kyösola K, Penttilä O. Enterochromaffin cells in macrophages in ulcerative colitis and irritable colon. Ann Clin Res.. 1976;8:1–7.

    CAS  PubMed  Google Scholar 

  10. Coates MD, Mahoney CR, Linden DR, Sampson JE, 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.

    Article  CAS  PubMed  Google Scholar 

  11. Magro F, Vieira-Coelho MA, Fraga S, Serrão MP, et al. Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci. 2002;47:216–224.

    Article  CAS  PubMed  Google Scholar 

  12. Ghia JE, Li N, Wang H, Collins M, et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology. 2009;137:1649–1660.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Oshima S, Fujimura M, Fukimiya M. Changes in number of serotonin-containing cells and serotonin levels in the intestinal mucosa of rats with colitis induced by dextran sodium sulfate. Histochem Cell Biol. 1999;112:257–263.

    Article  CAS  PubMed  Google Scholar 

  15. Minderhoud IM, Oldenburg B, Schipper ME, ter Linde JJ, Samsom M. Serotonin synthesis and uptake in symptomatic patients with Crohn’s disease in remission. Clin Gastroenterol Hepatol.. 2007;5:714–720.

    Article  CAS  PubMed  Google Scholar 

  16. Isgar B, Harman M, Kaye MD, Whorwell PJ. Symptoms of irritable bowel syndrome in ulcerative colitis in remission. Gut. 1983;24:190–192.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Nyhlin N, Bohr J, Eriksson S, Tysk C. Microscopic colitis: a common and an easily overlooked cause of chronic diarrhoea. Eur J Intern Med.. 2008;19:181–187.

    Article  PubMed  Google Scholar 

  18. Pardi DS, Smyrk TC, Tremaine WJ, Sandborn WJ. Microscopic colitis: a review. Am J Gastroenterol. 2002;97:794–802.

    Article  PubMed  Google Scholar 

  19. Bohr J. A review of collagenous colitis. Scand J Gastroenterol. 1998;33:2–29.

    Article  CAS  PubMed  Google Scholar 

  20. Fernández-Bañares F. Epidemiology of microscopic colitis. In: Colombel JF, Jewell DP, Pena AS, Tromm A, Warren BF, eds. Colitis: Diagnosis and Therapeutics Strategies. Falk symposia series 147. Dordrecht: Springer; 2006: 25–32.

  21. Fernández-Bañares F, Esteve M, Espinós JC, et al. Drug consumption and the risk of microscopic colitis. Am J Gastroenterol. 2007;102:324–330.

    Article  PubMed  Google Scholar 

  22. Beaugerie L, Pardi D. Review article: drug-induced microscopic colitis—a proposal for a scoring system and review of the literature. Alimen Pharm Therap.. 2005;22:277–284.

    Article  CAS  Google Scholar 

  23. Tagkalidis P, Bhathal P, Gibson P. Microscopic colitis. J Gastroenterol Hepatol. 2002;17:236–248.

    Article  PubMed  Google Scholar 

  24. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6.

    Article  CAS  PubMed  Google Scholar 

  25. Lahiri DK, Nurhberger JI. A rapid non enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acid Res. 1991;19:5444.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Sikander A, Rana SV, Sinha SK, et al. Serotonin transporter promoter variant: analysis in Indian IBS patients and control population. J Clin Gastroenterol. 2009;43:957–961.

    Article  CAS  PubMed  Google Scholar 

  27. Gershon MD. Plasticity in serotonin control mechanisms in the gut. Curr Opin Pharmacol. 2003;3:600–607.

    Article  CAS  PubMed  Google Scholar 

  28. Kellum JM, Albuquerque FC, Stoner MC, Harris RP. Stroking human jejunal mucosa induces 5-HT release and Cl- secretion via afferent neurons and 5-HT4 receptors. Am J Physiol. 1999;277:G515–G520.

    CAS  PubMed  Google Scholar 

  29. El-Salhy M, Danielsson A, Stenling R, Grimelius L. Colonic endocrine cells in inflammatory bowel disease. J Intern Med. 1997;242:413–419.

    Article  CAS  PubMed  Google Scholar 

  30. Stoyanova II, Gulubova MV. Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem. 2002;104:185–192.

    Article  CAS  PubMed  Google Scholar 

  31. Bishop AE, Pietroletti R, Taat CW, Brummelkamp WH, Polak JM. Increased populations of endocrine cells in Crohn’s ileitis. Virchows Arch A Pathol Anat Histopathol.. 1987;410:391–396.

    Article  CAS  PubMed  Google Scholar 

  32. Wisniewska-Jarosinska M, Boznanska-Swietaszek P, Harasiuk A, Mokwinska M, Stec-Michalska K, Chojnacki J. 24-hour urinary 5-hydroxyindole acetic acid excretion in patients with ulcerative colitis. Pol Merkur Lekarski.. 2009;26:452–454.

    CAS  PubMed  Google Scholar 

  33. Verity MA, Mellunkoff SM, Frankland M, Greipel M. Serotonin content and argentaffin and Paneth cell changes in ulcerative colitis. Gastroenterology. 1962;43:24–31.

    CAS  PubMed  Google Scholar 

  34. Baez-Giangreco A, Afzal M, Antonious J, Laajam MA, Zargar SA. Collagenous colitis: a case report with study of the neuroendocrine markers. Saudi J Gastroenterol.. 1999;5:36–39.

    CAS  PubMed  Google Scholar 

  35. Docherty M. Elevated serotonin associated with collagenous colitis. Am J Gastroenterol. 2010;105:1449.

    Article  PubMed  Google Scholar 

  36. Narla NP, Smyrk TC, Pardi DS, Tung J. Clinical features and treatment responses in pediatric lymphocytic and collagenous colitis. J Pediatr Gastroenterol Nutr. 2013;57:557–561.

    Article  PubMed  Google Scholar 

  37. Nakamura M, Ueno S, Sano A, Tanabe H. The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry. 2000;5:32–38.

    Article  CAS  PubMed  Google Scholar 

  38. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet. 2006;78:815–826.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Shiotani A, Kusunoki H, Kimura Y, Ishii M, et al. S100A expression and interleukin-10 polymorphisms are associated with ulcerative colitis and diarrhea predominant irritable bowel syndrome. Dig Dis Sci. 2013;58:2314–2323.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. College of Applied Medical Sciences, Jazan University, Post Box No. 114, Jazan, 45142, K.S.A

    Arbab Sikander

  2. Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Saroj Kant Sinha, Kaushal Kishor Prasad & Satya Vati Rana

  3. House # 137, Sector 15-A, Chandigarh, 160015, India

    Satya Vati Rana

Authors
  1. Arbab Sikander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saroj Kant Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaushal Kishor Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satya Vati Rana
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satya Vati Rana.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sikander, A., Sinha, S.K., Prasad, K.K. et al. Association of Serotonin Transporter Promoter Polymorphism (5-HTTLPR) with Microscopic Colitis and Ulcerative Colitis. Dig Dis Sci 60, 887–894 (2015). https://doi.org/10.1007/s10620-014-3482-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-014-3482-y

Keywords

Search

Navigation