SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome patients regardless of visceral sensitivity state in large intestine

Kerckhoffs, Angèle P. M.; Linde, José J.M. ter; Akkermans, L.M.A.; Samsom, Melvin

doi:10.1152/ajpgi.00153.2011

Cited by 82 publications

(88 citation statements)

References 53 publications

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“…While Camilleri and colleagues did not detect a change in mucosal SERT mRNA in their population of IBS-D patients 50 , decreased SERT expression in IBS-D has been reported by others in adults 40, 51 as well as children 41 . In patients with IBS-C, no change was detected in the study by Camilleri 50 .…”

Section: Alterations In Mucosal 5-ht Signaling In Pathophysiologicalmentioning

confidence: 64%

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

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

871

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 Pathophysiologicalmentioning

confidence: 64%

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

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

871

783

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“…Serotonin plays a crucial part in the regulation of gastro intestinal secretion, motility, perception and central nervous system function 115,116 , and several drugs used for treating functional dyspepsia target 5-HT receptors 117 (see below). In one study 118 of polymorphisms in candidate genes for different 5-HT receptors, cholecystokinin receptors and GNB3 as well as in the promoters of the genes encoding cholecystokinin and the sodium-dependent serotonin transporter, only the role of GNB3 in functional dyspepsia was confirmed.…”

Section: Genetic Contributionsmentioning

confidence: 99%

Functional dyspepsia

Enck¹,

Azpiroz

Boeckxstaens

et al. 2017

Nat Rev Dis Primers

253

247

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| Functional dyspepsia is one of the most prevalent functional gastrointestinal disorders. Functional dyspepsia comprises three subtypes with presumed different pathophysiology and aetiology: postprandial distress syndrome (PDS), epigastric pain syndrome (EPS) and a subtype with overlapping PDS and EPS features. Functional dyspepsia symptoms can be caused by disturbed gastric motility (for example, inadequate fundic accommodation or delayed gastric emptying), gastric sensation (for example, sensations associated with hypersensitivity to gas and bloating) or gastric and duodenal inflammation. A genetic predisposition is probable but less evident than in other functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Psychiatric comorbidity and psychopathological state and trait characteristics could also play a part, although they are not specific to functional dyspepsia and are less pronounced than in IBS. Possible differential diagnoses include Helicobacter pylori infection and peptic ulceration. Pharmacological therapy is mostly based on the subtype of functional dyspepsia, such as prokinetic and fundus-relaxing drugs for PDS and acid-suppressive drugs for EPS, whereas centrally active neuromodulators and herbal drugs play a minor part. Psychotherapy is effective only in a small subset of patients, whereas quality of life can be severely affected in nearly all patients. Future therapies might include novel compounds that attempt to treat the underlying gastric and duodenal inflammation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17081 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .standard therapy for gastro -oesophageal reflux disease. Paediatric dyspeptic symptoms are being addressed in a separate classification effort 10 . This Primer covers functional dyspepsia in adults only, although we sporadically refer to paediatric functional dyspepsia when similarities exist. EpidemiologyThe population prevalence of functional dyspepsia is quite variable across the globe, with overall high numbers (10-40%) in Western countries and low numbers (5-30%) in Asia, independent of the respective functional dyspepsia definitions 11 . A large-scale health and nutrition survey from France 12 (which involved >35,000 people) identified that 15% of individuals had suspected functional dyspepsia, 28% had irritable bowel syndrome (IBS) and 6% had both. The population of patients who are affected by both IBS and functional dyspepsia has been reported to range between 10% and 27% in previous studies 13 and to approach 30% in popu lation samples; it could be even higher in specific populations 14,15 . This observation has given rise to the term 'overlap syndrome' (REF. 13), which calls into question the sensitivity and specificity of the Rome criteria, at least for IBS and functional dyspepsia. This argument is also supported by the observation that patients with functional dyspepsia m...

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“…Quantitative real-time PCR was employed to assess the expression of TPH1 due to its role as the rate-limiting biosynthetic enzyme involved in serotonin production within the enterochromaffin cells of the gut 17 and its proposed link with IBS pathophysiology. 18 We compared TPH1 expression in individual gut tissue samples of the IBS cohort to the expression profile obtained from a pooled RNA sample comprised of 8 individuals from the asymptomatic cohort selected at random. The results from this analysis for each IBS cohort sample were plotted against each patient's serum vitamin D concentration (Fig.…”

Section: Evaluation Of Tryptophan Hydroxylase-1 Expression Within Thementioning

confidence: 99%

Gene Expression Profiling and Assessment of Vitamin D and Serotonin Pathway Variations in Patients With Irritable Bowel Syndrome

Dussik

Hockley

Grozić

et al. 2018

J Neurogastroenterol Motil

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Background/AimsIrritable bowel syndrome (IBS) is a multifaceted disorder that afflicts millions of individuals worldwide. IBS is currently diagnosed based on the presence/duration of symptoms and systematic exclusion of other conditions. A more direct manner to identify IBS is needed to reduce healthcare costs and the time required for accurate diagnosis. The overarching objective of this work is to identify gene expression-based biological signatures and biomarkers of IBS. MethodsGene transcripts from 24 tissue biopsy samples were hybridized to microarrays for gene expression profiling. A combination of multiple statistical analyses was utilized to narrow the raw microarray data to the top 200 differentially expressed genes between IBS versus control subjects. In addition, quantitative polymerase chain reaction was employed for validation of the DNA microarray data. Gene ontology/pathway enrichment analysis was performed to investigate gene expression patterns in biochemical pathways. Finally, since vitamin D has been shown to modulate serotonin production in some models, the relationship between serum vitamin D and IBS was investigated via 25-hydroxyvitamin D (25[OH]D) chemiluminescence immunoassay. ResultsA total of 858 genetic features were identified with differential expression levels between IBS and asymptomatic populations. Gene ontology enrichment analysis revealed the serotonergic pathway as most prevalent among the differentially expressed genes. Further analysis via real-time polymerase chain reaction suggested that IBS patient-derived RNA exhibited lower levels of tryptophan hydroxylase-1 expression, the enzyme that catalyzes the rate-limiting step in serotonin biosynthesis. Finally, mean values for 25(OH)D were lower in IBS patients relative to non-IBS controls. Conclusions IntroductionIrritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders afflicting between 10-15% of the global population.1 Primary symptoms associated with IBS include abdominal pain and irregular bowel movements that, based upon the predominant symptom pattern, may be utilized to subdivide the syndrome into 3 classifications: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), and mixed IBS (IBS-M).2 However, the subtype of IBS that an individual is classified does not necessarily remain static; patients can evolve over time from diarrheic or mixed type to constipative. The chronic and erratic nature of IBS can lead to a multitude of secondary effects, such as depression, anxiety, poor quality of life, insomnia, and sexual dysfunction. 3Using the current diagnostic model for IBS, the Rome IV criteria, symptoms must be present for 3 months or longer before diagnoses can be established. 4 Other disorders with IBS-like symptoms that should be excluded include celiac disease, inflammatory bowel disease (IBD), malabsorptive disorders, pelvic floor disorders, and colon cancer. Further, once diagnosed, treatment for IBS patients may be mostly palliative in nature with dietary changes...

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SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome patients regardless of visceral sensitivity state in large intestine

Cited by 82 publications

References 53 publications

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

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

Functional dyspepsia

Gene Expression Profiling and Assessment of Vitamin D and Serotonin Pathway Variations in Patients With Irritable Bowel Syndrome

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