Review Article: Intestinal Serotonin Signalling in Irritable Bowel Syndrome

G. M. Mawe; M. D. Coates; P. L. Moses

Disclosures

Aliment Pharmacol Ther. 2006;23(8):1067-1076. 

In This Article

Is Decreased SERT Expression in IBS Due to Genetic and/or Epigenetic Factors?

The 5-HT transporter, SERT, is a highly regulated protein. For example, the genetic make-up of an individual appears to influence their level of SERT expression.[18] Furthermore, activation of G-protein-coupled receptors can lead to changes in SERT by modulating its transcription by moving the transporter to or away from the plasma membrane, and by altering the phosphorylation state of the protein. It is therefore possible that genetic and/or epigenetic factors could affect SERT expression and function in the intestinal epithelium.

Genetic Factors

It is possible that individuals with IBS have a genetic predisposition for decreased SERT expression. The human SERT gene is located on human chromosome 17; it spans 37.8 kb and is composed of 14 exons that encode a 630 amino acid protein.[19,20] One possible explanation for the variability in SERT expression amongst individuals is the SERT gene-linked polymorphic region (SERT-LPR).[21] The SERT-LPR, comprising long (l) and short (s) variants, is located 1.2 kb upstream of the transcription start site in exon 1, and may influence the level of transcription. The l variant contains 16 copies of a 20–23 base pair sequence whereas the s variant contains 14 copies of this sequence. Lymphoblast transfection studies with expression vectors containing the long or short variants linked to a reporter gene indicate that the long variant directs higher levels of transcription compared with the short variant [see Murphy et al.[18] for review]. Consistent with this, higher SERT mRNA levels and higher rates of 5-HT uptake were measured in lymphoblasts of l/l homozygotes compared with those containing at least one copy of the s allele.[22] The l variant was also associated with higher rates of 5-HT uptake, and higher levels of 5-HT binding in platelets.[23,24,25]

It is important to note, however, that not all studies have reported a correlation between SERT-LPR alleles and SERT expression. Analysis of SERT mRNA levels in a large number of permanent lymphoblast cell lines failed to detect a correlation with SERT-LPR genotype.[26] In addition, no correlation between SERT-LPR alleles and promoter activity was observed with expression vectors assayed in COS-7[27,28] or PC12 cells.[22,27] Furthermore, no statistically significant correlations have been detected between SERT-LPR alleles and binding of SERT ligands in the brains of healthy volunteers.[29,30]

A number of studies have examined possible relationships between SERT-LPR alleles and psychiatric disorders, anxiety-related personality traits, suicide, alcoholism and response to antidepressants.[18] Although many studies have reported correlations between SERT-LPR alleles and a given clinical phenotype, others have not.

The relationship between SERT-LPR and IBS is unclear at this point, as data from the four studies conducted to date are somewhat contradictory. The first such study[31] examined possible associations between SERT-LPR and different clinical patterns of IBS, including IBS-C, IBS-D and IBS with alternating symptoms (IBS-A) in a Turkish population. The distributions of SERT polymorphisims were comparable between the healthy subjects and the IBS population as a whole. However, genotype variations were detected amongst the IBS populations, with the s/s genotype being more predominant in individuals with IBS-C and the l/s genotype being more predominant in individuals with IBS-D. The second study[32] investigated genotypes related to SERT-LPR and α2 adrenoreceptors in individuals in the upper Midwestern USA with lower GI symptoms (n = 274) that were divided into IBS-D, IBS-C, IBS-A and chronic pain. In this study, no difference was detected between the SERT-LPR genotypes of control individuals vs. the lower GI symptom population as a whole, or controls vs. IBS-D (n = 128), IBS-C (n = 90) or IBS-A (n = 38). Results of this study did identify combinations of polymorphisms that were associated with high symptom scores indicating that the SERT-LPR genotype may predispose a given individual to lower GI symptoms. The authors concluded that future studies of interactions between candidate genes associated with motor, sensory and/or behavioural functions would be of interest. A third study,[33] conducted in Korea, did not detect a relationship between SERT-LPR genotype in controls (n = 56) vs. the IBS population as a whole (n = 33) or the IBS-C (n = 12), IBS-D (n = 15) and IBS-A (n = 6) subgroups. They reported that s/s was the predominant genotype in healthy volunteers (n = 56) as well as in individuals with IBS. The fourth study[34] involved comparison of SERT-LPR genotype in a large cohort of North American Caucasian females with IBS-D (n = 194) vs. North American Caucasian female healthy volunteers (n = 448). In this investigation, a significant association was observed between IBS-D and the s/s genotype of SERT-LPR.

Correlative support for a genetic predisposition for decreased SERT expression comes from a study that involved an analysis of SERT-binding kinetics in platelets. Similar to serotonergic neurones and intestinal epithelial cells, platelets express SERT on their outer membranes and they act as sponges for 5-HT that enters the bloodstream. In a study by Bellini et al., SERT-binding kinetics of platelets from individuals with IBS-D were compared with those of healthy volunteers.[35] Both the maximal binding capacity and dissociation constant were lower in individuals with IBS-D, suggesting a lower density of SERT of platelets in individuals with IBS-D.

The study demonstrating the most dramatic correlation between IBS and SERT-LPR was the study performed by Hicks and colleagues[34] that involved the largest sample size and this study involved a relatively homogeneous population (North American Caucasian females). The finding that a link between SERT-LPR and a specific subtype of IBS, but not in IBS as a whole, or subtypes of IBS in heterogeneous populations supports the concept that a universal aetiology for IBS does not exist. It is likely that a variety of conditions, triggers and contributing factors result in the wide array of symptoms that are grouped into the descriptor, IBS. While it is not yet possible to draw a firm conclusion regarding a genetic predisposition for IBS, this is clearly a promising avenue to explore, and any links that are discovered could possibly lead to more effective treatment plans.

Epigenetic Factors

In addition to being influenced by means of genetic polymorphisms, SERT expression and function can also be modulated via second messengers that are activated by homologous (5-HT) and heterologous receptors.[8,36] For example, 5-HT, cholera toxin and forskolin increase SERT expression, while cyclic adenosine monophosphate (cAMP) activators increase SERT activity. SSRIs decrease SERT expression, and PKC activation decreases SERT activity. Furthermore, adenosine receptor stimulation activates two different protein kinase G (PKG)-dependent pathways that increase 5-HT uptake by moving SERT to the cytosolic membrane and by phosphorylating SERT via a mitogen activated protein (MAP) kinase-dependent mechanism.

Various elements of 5-HT signalling are altered in IBD[5,37,38,39] (see Table 4 ). In addition, 5-HT content, EC cell numbers, release and SERT expression are altered in a number animal models of intestinal inflammation, including trinitro benzenesulphonic acid (TNBS) colitis[40] and ileitis[41] in guinea-pig, TNBS colitis in mouse,[42]Trichinella spiralis ileitis in mouse,[43]Citrobacter rodentium colitis in mouse[44] and dextran sodium sulphate colitis in rat[45] (see Table 5 ).

The changes that have been detected in the EC cell population and 5-HT levels in postinfectious IBS (PI-IBS) may be brought on by the inflammatory response associated with the infection. The data from experimental animals, which represent genetically homogeneous populations, indicate that the inflammatory process can lead to changes in EC cells as well as SERT expression by enterocytes. This concept is supported by data we presented at the 2005 meeting of the American Motility Society demonstrating that tumour necrosis factor alpha and γ-interferon decrease SERT function in CACO-2 cells, a human colonic epithelial cell line.[46] Furthermore, the decrease in SERT immunoreactivity that is detected in T. spiralis-infected mouse intestine persists following recovery from inflammation.[43] It is worth noting that EC cells and mucosal 5-HT levels are consistently found to be elevated in animal models of intestinal inflammation and in PI-IBS ( Table 4 and Table 5 ), whereas this trend is either not detected or not as consistently observed in IBD, IBS-D or IBS-C ( Table 1 , Table 2 , and Table 3 ). As the animal models and PI-IBS involve relatively short time points, it is possible that EC cell hyperplasia occurs and 5-HT levels are elevated during the inflammatory response and then rebound to normal or below normal levels over time.

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