Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients

Wang, Y. M.; Chang, Young Eun; Cheng, Juei-Tang; Li, J.; Wang, T.; Zhang, Q. Y.; Liang, De‐Yong; Sun, Bei; Wang, B. M.

doi:10.1111/j.1365-2982.2012.01902.x

Cited by 36 publications

(44 citation statements)

References 39 publications

(89 reference statements)

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“…A possible relationship exists between SERT-LPR alleles and psychiatric disorders, anxiety-related personality traits, suicide, alcoholism, and responsiveness to antidepressants 65 . Studies of the SERT-LPR in humans with IBS have demonstrated trends in some populations, but a meta-analysis of these findings failed to detect a clear relationship between the SERT-LPR and IBS 66 , although SERT expression level in the gut does appear to be influenced by the SERT-LPR genotype 67 . Furthermore, there appears to be a relationship between the SERT-LPR genotype and depressive symptoms with IBS, with IBS sufferers with the short allele being more likely to have a history of depression 68 .…”

Section: Alterations In Mucosal 5-ht Signaling In Pathophysiological mentioning

confidence: 98%

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

877

783

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Serotonin (5-HT) has been recognized for decades as an important signaling molecule in the gut, but it is still revealing its secrets. We continue to discover novel gastrointestinal (GI) functions of 5-HT, as well as actions of gut-derived 5-HT outside of the gut, and we are learning how 5-HT signaling is altered in GI disorders. Furthermore, new therapeutic targets related to 5-HT signaling are being identified that can hopefully be exploited to alleviate the symptoms of functional GI disorders. Conventional functions of 5-HT in the gut involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion, and vasodilation. Activation of extrinsic vagal and spinal afferent fibers results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts non-conventional actions that include serving as a pro-inflammatory signaling molecule and as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, which comes from the gut, can promote hemostasis, influence bone development, and contribute to allergic airway inflammation. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhea or constipation, respectively. More recently, the synthetic enzyme, tryptophan hydroxylase has been targeted, and there are recent findings suggesting that epithelial 5-HT4 receptors could be targeted to provide a safe and effective treatment for constipation. Here we provide an overview of these serotonergic actions and treatment strategies.

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Section: Alterations In Mucosal 5-ht Signaling In Pathophysiological mentioning

confidence: 98%

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

877

783

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“…Once serotonin is secreted from EC cells, SERT will be activated to reuptake serotonin back into EC cells and attenuate the effect of serotonin in GI tracts subsequently [8]. The L variation of 5-HTTLPR is found to increase the expression of SERT gene and enhance SERT activity consequently [9-11,34]. The enhanced SERT activity would take up serotonin and weaken its effects in promoting gut secretion and motility.…”

Section: Discussionmentioning

confidence: 99%

The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies

et al. 2014

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BackgroundThe results of previous studies assessing the association between the 5-HTTLPR polymorphism of serotonin transporter gene and irritable bowel syndrome (IBS) are inconsistent. The aim of this study was to clarify the association between the 5-HTTLPR mutation and the presence of IBS and its subtypes with a meta-analysis of 25 studies.MethodsA thorough search for case–control studies evaluating the association between the 5-HTTLPR polymorphism of serotonin transporter gene and the presence of IBS was carried out in four electronic databases. A meta-analysis was performed in accordance with the Cochrane Handbook for systemic reviews.ResultsA total of 25 articles with 3443 IBS cases and 3359 controls were included into our meta-analysis. No significant association was found between this polymorphism and IBS in all populations. Whereas the LL genotype was demonstrated to be a risk factor for constipation predominant IBS (IBS-C) development in the overall population (LL vs SS: OR = 1.570, 95% CI = 1.147-2.148, P = 0.005, Bon = 0.030; LL vs LS: OR = 1.658, 95% CI = 1.180-2.331, P = 0.004, Bon = 0.024; LL vs LS/SS: OR = 1.545, 95% CI = 1.187-2.012, P = 0.001, Bon = 0.006). In the analysis of different ethnicities, L allele and LL genotype were significantly associated with increased IBS-C risk in the East Asian population (L vs S: OR = 1.487, 95% CI = 1.139-1.941, P = 0.003, Bon = 0.018; LL vs SS: OR = 2.575, 95% CI = 1.741-3.808, P = 0.000, Bon = 0.000; LL vs LS: OR = 3.084, 95% CI = 2.017-4.715, P = 0.000, Bon = 0.000; LL vs LS/SS: OR = 2.759, 95% CI = 1.933-3.938, P = 0.000, Bon = 0.000), but not in the Caucasian population.ConclusionsDifferent from the conclusions of the earlier meta-analyses, the 5-HTTLPR mutation affects IBS-C but not IBS-D and IBS-M development and this effect only exists in the East Asian population but not other populations.

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“…However, subsequent studies reported inconsistent results. Kumar et al [102] did show that a SLC6A4 polymorphism was significantly associated with IBS, and Wang et al [103] found that different SERT genotypes could influence SLC6A4 promoter efficiency and SERT mRNA and protein expression in the colonic mucosa.…”

Section: Neurotransmitters and Cytokinesmentioning

confidence: 99%

Irritable bowel syndrome: Emerging paradigm in pathophysiology

Lee

Park

2014

WJG

135

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Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.

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Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients

Abstract: Polymorphism in the promoter region of the SERT gene can influence the expression of SERT mRNA and the levels of the SERT protein in the colonic mucosa, thereby playing a key role in motility-related symptoms of IBS patients.

Cited by 36 publications

References 39 publications

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies

Irritable bowel syndrome: Emerging paradigm in pathophysiology

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