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Abstract
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.
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Seyedmirzaee S, Hayatbakhsh MM, Ahmadi B, Baniasadi N, Bagheri Rafsanjani AM, Nikpoor AR, Mohammadi M. Serum immune biomarkers in irritable bowel syndrome. Clin Res Hepatol Gastroenterol 2016; 40:631-637. [PMID: 26850360 DOI: 10.1016/j.clinre.2015.12.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 11/25/2015] [Accepted: 12/07/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal (GI) disorder, which presents with abdominal pain and changes in the bowel habits. Although the exact cause of IBS remains uncertain, some studies have shown that the inflammation and cytokine imbalance may act as potential etiological factors. The aim of our study is to compare the serum levels of interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-α) in patients with IBS with the healthy controls. The other aim of this study is to evaluate possible association between above-mentioned cytokines and IBS subtypes. METHODS Seventy-four IBS patients diagnosed based on Rome III criteria and 75 gender and age-matched healthy controls were included in this study. Cytokines were measured in the serum using enzyme-linked immunosorbent assays (ELISA). RESULTS Patients were classified into groups of IBS with diarrhea (IBS-D): 34, IBS with constipation (IBS-C): 29, and IBS with mixed symptoms (IBS-M): 11. The serum levels of IL-6, IL-8 and TNF-α were significantly higher in patients with IBS as compared to controls (P<0.001). There was no difference in serum levels of cytokines based on IBS subtypes. CONCLUSIONS Higher serum level of IL-6, IL-8 and TNF-α in IBS suggests an important role of cytokines as immune mediators in the pathogenesis of this functional GI disorder. To understand any association between cytokines and IBS subtypes, further investigations with larger sample sizes are desired.
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Affiliation(s)
- Seyedmehdi Seyedmirzaee
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology sciences, Kerman University of medical Sciences, Kerman, Iran; Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Mahdi Hayatbakhsh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Bizhan Ahmadi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Nadieh Baniasadi
- Internal medicine department, Bam University of medical sciences, Bam, Iran.
| | | | - Amin Reza Nikpoor
- Department of immunology, School of medicine, Mashhad University of medical sciences, Mashhad, Iran.
| | - Mojgan Mohammadi
- Department of immunology, School of medicine, Mashhad University of medical sciences, Mashhad, Iran; Immunology research center, School of medicine, Mashhad University of medical sciences, Mashhad, Iran.
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Martinucci I, Blandizzi C, de Bortoli N, Bellini M, Antonioli L, Tuccori M, Fornai M, Marchi S, Colucci R. Genetics and pharmacogenetics of aminergic transmitter pathways in functional gastrointestinal disorders. Pharmacogenomics 2016; 16:523-39. [PMID: 25916523 DOI: 10.2217/pgs.15.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Functional gastrointestinal disorders (FGIDs) are highly prevalent syndromes, without evident underlying organic causes. Their pathogenesis is multifactorial in nature, with a combination of environmental and genetic factors contributing to their clinical manifestations, for which most of current treatments are not satisfactory. It is acknowledged that amine mediators (noradrenaline, dopamine and serotonin) play pivotal regulatory actions on gut functions and visceral sensation. In addition, drugs of therapeutic interest for FGIDs act on these transmitter pathways. The present article reviews current knowledge on the impact of genetics and pharmacogenetics of aminergic pathways on FGID pathophysiology, clinical presentations, symptom severity and medical management, in an attempt of highlighting the most relevant evidence and point out issues that should be addressed in future investigations.
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Affiliation(s)
- Irene Martinucci
- Gastroenterology Unit, Department of Translational Research & New Technologies in Medicine, University of Pisa, Via Paradisa 2, I-56124 Pisa, Italy
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Sarnelli G, D’Alessandro A, Pesce M, Palumbo I, Cuomo R. Genetic contribution to motility disorders of the upper gastrointestinal tract. World J Gastrointest Pathophysiol 2013; 4:65-73. [PMID: 24244875 PMCID: PMC3829454 DOI: 10.4291/wjgp.v4.i4.65] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/09/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Motility disorders of the upper gastrointestinal tract encompass a wide range of different diseases. Esophageal achalasia and functional dyspepsia are representative disorders of impaired motility of the esophagus and stomach, respectively. In spite of their variable prevalence, what both diseases have in common is poor knowledge of their etiology and pathophysiology. There is some evidence showing that there is a genetic predisposition towards these diseases, especially for achalasia. Many authors have investigated the possible genes involved, stressing the autoimmune or the neurological hypothesis, but there is very little data available. Similarly, studies supporting a post-infective etiology, based on an altered immune response in susceptible individuals, need to be validated. Further association studies can help to explain this complex picture and find new therapeutic targets. The aim of this review is to summarize current knowledge of genetics in motility disorders of the upper gastrointestinal tract, addressing how genetics contributes to the development of achalasia and functional dyspepsia respectively.
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Park CS, Uhm JH. Polymorphisms of the Serotonin Transporter Gene and G-Protein β3 Subunit Gene in Korean Children with Irritable Bowel Syndrome and Functional Dyspepsia. Gut Liver 2012; 6:223-8. [PMID: 22570752 PMCID: PMC3343161 DOI: 10.5009/gnl.2012.6.2.223] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 09/07/2011] [Accepted: 10/18/2011] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIMS Many candidate gene studies have revealed that polymorphisms of the 5'-flanking controlled SERT gene linked polymorphic region (5HTT-LPR) gene and G-protein β3 C825T gene might be associated with functional dyspepsia (FD) and irritable bowel syndrome (IBS). This study was performed to investigate polymorphisms of the 5HTT-LPR gene and G-protein β3 C825T gene in FD and IBS in Korean children. METHODS In total, 102 patients with FD, 72 patients with IBS based on the Rome III criteria and 148 healthy controls without gastrointestinal symptoms were included in the study to analyze 5HTT-LPR and G-protein β3 C825T polymorphisms. RESULTS 5HTT-LPR genotype analysis revealed no signifi cant differences in FD and IBS patients compared with controls. The GNβ3 C825T genotype distribution for CC, CT, and TT was 23.6%, 53.4%, and 23.0% in controls, 36.3%, 38.2%, and 25.5% in FD and 37.5%, 38.9%, and 23.6% in IBS, respectively. The CC genotype was more common in FD and IBS patients than controls (p<0.05). When the IBS patients were grouped according to IBS subtypes, CC genotype GNβ3 C825T was common in diarrhea-dominant IBS, and the TT genotype was common in constipation-dominant IBS (p<0.05). CONCLUSIONS The CC genotype of G-protein β3 C825T may be associated with FD and diarrhea-predominant IBS. The TT genotype may be associated with constipation-predominant IBS.
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Affiliation(s)
- Cheong Soo Park
- Department of Pediatrics, Eulji General Hospital, Eulji University College of Medicine, Seoul, Korea
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Cytokines and irritable bowel syndrome: where do we stand? Cytokine 2011; 57:201-9. [PMID: 22178716 DOI: 10.1016/j.cyto.2011.11.019] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2011] [Revised: 11/19/2011] [Accepted: 11/22/2011] [Indexed: 12/13/2022]
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, which presents with one or more gastrointestinal symptoms without any structural or organic abnormality. The etiology and pathophysiological mechanisms of IBS remain uncertain. Residual or reactivated inflammation at the molecular level is considered the underlying mechanism of post-infectious IBS. On the other hand, genetic variations in the immunological components of the body, including cytokine gene polymorphisms, are proposed as a potential mechanism of IBS even in patients without previous gastrointestinal infection. Several studies have suggested imbalanced cytokine signaling as an etiology for IBS. In this review, recent findings on cytokine profiles and cytokine gene polymorphisms in patients with IBS are described and the role of cytokines in animal models of IBS is discussed.
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Li X, Chen H, Lu H, Li W, Chen X, Peng Y, Ge Z. The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. Scand J Gastroenterol 2010; 45:573-81. [PMID: 20163288 DOI: 10.3109/00365521003632576] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Functional dyspepsia is a common gastrointestinal disorder. The pathogenesis of functional dyspepsia remains unclear. Functional dyspepsia may begin after a bout of gastroenteritis (post-infectious functional dyspepsia) or de novo (nonspecific functional dyspepsia). The aim of this study was to investigate the prevalence and probable mechanisms of post-infectious functional dyspepsia. MATERIAL AND METHODS Functional dyspepsia patients with a history of unsanitary food intake and acute gastroenteritis 6-12 months ago were enrolled. (13)C-UBT confirmed absence of H. pylori infection. Controls consisted of healthy nondyspeptic volunteers and patients with nonspecific functional dyspepsia. Gastric biopsies were used for routine histology, immunohistochemistry, electron microscopy, ELISA, HPLC assays and Western blot examination. RESULTS Eighty-five subjects were entered including 35 with post-infectious functional dyspepsia, 30 with nonspecific functional dyspepsia, and 20 healthy controls. The number of mast cells in post-infectious functional dyspepsia and nonspecific functional dyspepsia were significantly greater than that in healthy controls. The number of enterochromaffin cells (ECs) in post-infectious functional dyspepsia was significantly higher than those in nonspecific functional dyspepsia or in healthy controls. The number of mast cells and ECs increased with the density of chronic inflammatory cells. The release of histamine and 5-hydroxytryptamine from gastric mucosa of post-infectious functional dyspepsia patients was significantly greater than those from nonspecific functional dyspepsia or healthy controls. Tryptase protein expression was higher in post-infectious functional dyspepsia and nonspecific functional dyspepsia than in healthy controls. The histological score of chronic gastric inflammation was greater in post-infectious functional dyspepsia versus patients with nonspecific functional dyspepsia or healthy controls. Electron microscopy showed secreting granules in the cytoplasm of both mast cells and ECs. The number of activated mast cells and Ecs at a distance of < 5 microm of nerve fibers were significantly greater in post-infectious functional dyspepsia versus nonspecific functional dyspepsia or controls. CONCLUSIONS Dyspepsia may occur after an acute onset of gastroenteritis in a part of patients. Potent chemicals derived from mast cells and ECs, including histamine, tryptase and 5-hydroxytryptamine may be involved in the pathogenesis of post-infectious functional dyspepsia.
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Affiliation(s)
- Xiaobo Li
- Department of Gastroenterology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
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Ochi M, Tominaga K, Iketani T, Kadouchi K, Tanigawa T, Shiba M, Watanabe T, Fujiwara Y, Oshitani N, Higuchi K, Kiriike N, Arakawa T. Perfectionism underlying psychological background correlated with the symptoms of functional dyspepsia. J Gastroenterol 2009; 43:699-704. [PMID: 18807131 DOI: 10.1007/s00535-008-2210-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2007] [Accepted: 04/15/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND Early satiety, bloating, and postprandial distress are common symptoms in patients with functional dyspepsia (FD) and anorexia nervosa (AN). Perfectionism is known to be associated with AN, accompanied by abnormal eating behavior. We analyzed perfectionism in FD as compared with that in AN, and investigated the correlation of perfectionism with abdominal symptoms. METHODS The study group comprised 168 patients with FD according to the Rome II criteria (65% females, mean age 47.7 years) and 101 with AN according to the DSM-IV criteria (100% females, mean age 23 years). As control, 130 healthy subjects (81% females, mean age 26.2 years) were studied. Frost's Multidimensional Perfectionism Scale (FMPS) was used to evaluate perfectionism. Abdominal symptoms were evaluated on the Gastrointestinal Symptoms Rating Scale (GSRS). RESULTS All subscale scores except for organization were significantly higher in patients with AN than in controls. The parental criticism (PC) score in patients with FD was also significantly higher than that in controls, but lower than that in patients with AN. PC was significantly correlated with the total GSRS, particularly indigestion scores of FD patients (P = 0.0476 and P = 0.0294). CONCLUSIONS Perfectionism such as PC underlying the psychological background of FD patients may be correlated with their abdominal symptoms.
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Affiliation(s)
- Masahiro Ochi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
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Thompson SK, Cai W, Jamieson GG, Zhang AY, Myers JC, Parr ZE, Watson DI, Persson J, Holtmann G, Devitt PG. Recurrent symptoms after fundoplication with a negative pH study--recurrent reflux or functional heartburn? J Gastrointest Surg 2009; 13:54-60. [PMID: 18712573 DOI: 10.1007/s11605-008-0653-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Accepted: 07/28/2008] [Indexed: 01/31/2023]
Abstract
INTRODUCTION A small cohort of patients present after antireflux surgery complaining of recurrent heartburn. Over two thirds of these patients will have a negative 24-h pH study. The aim of our study is to determine whether these patients have an associated functional disorder or abnormal cytokine activity and to examine the reproducibility of pH testing. METHODS A prospective analysis was carried out on a cohort of patients who had undergone a fundoplication and postoperative pH testing for recurrent heartburn: group A--patients with recurrent heartburn and a negative 24-h pH study and group B (control group)--patients with recurrent heartburn and a positive pH study. Questionnaires, a blood sample, and repeat pH testing were completed. RESULTS Sixty-nine patients were identified. Group A's depression score (8.6 +/- 4.1) was significantly higher than group B's (5.9 +/- 4.2; P = 0.03). Cytokine levels were similar in both groups. Forty-seven of 49 (96%) patients who underwent repeat pH testing had a negative study. Symptom-reflux correlation was highly significant (P < 0.001). CONCLUSION Some patients with recurrent heartburn and a negative pH study have associated functional or psychiatric comorbidities such as depression. Reproducibility of 24-h pH testing in these patients is excellent.
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Affiliation(s)
- Sarah K Thompson
- Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
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Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G. Immune activation in patients with irritable bowel syndrome. Gastroenterology 2007; 132:913-20. [PMID: 17383420 DOI: 10.1053/j.gastro.2007.01.046] [Citation(s) in RCA: 487] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Accepted: 12/07/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS We set out to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of proinflammatory cytokines. We further aimed to explore whether symptoms and psychiatric comorbidity in IBS are linked to the release of proinflammatory cytokines. METHODS We characterized basal and Escherichia coli lipopolysaccharide (LPS)-induced cytokine production in peripheral blood mononuclear cells (PBMCs) from 55 IBS patients (18 mixed-, 17 constipation-, 20 diarrhea-predominant) and 36 healthy controls (HCs). PBMCs were isolated by density gradient centrifugation and cultured for 24 hours with or without (1 ng/mL) LPS. Cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and IL-6) was measured by enzyme-linked immunosorbent assay. Abdominal symptoms and psychiatric comorbidities were assessed by using the validated Bowel Disease Questionnaire and the Hospital Anxiety and Depression Scale. RESULTS IBS patients showed significantly (P < .017) higher baseline TNF-alpha, IL-1beta, IL-6, and LPS-induced IL-6 levels compared with HCs. Analyzing IBS subgroups, all cytokine levels were significantly (P < .05) higher in diarrhea-predominant IBS (D-IBS) patients, whereas constipation-predominant IBS patients showed increased LPS-induced IL-1beta levels compared with HCs. Baseline TNF-alpha and LPS-induced TNF-alpha and IL-6 levels were significantly higher in patients reporting more than 3 bowel movements per day, urgency, watery stools, and pain associated with diarrhea compared with patients without these symptoms (all P < .05). LPS-induced TNF-alpha production was associated significantly (r = 0.59, P < .001) with anxiety in patients with IBS. CONCLUSIONS Patients with D-IBS display enhanced proinflammatory cytokine release, and this may be associated with symptoms and anxiety.
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Affiliation(s)
- Tobias Liebregts
- Department of Gastroenterology and Hepatology, University of Adelaide, Royal Adelaide Hospital, South Australia, Australia
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Mizuta Y, Shikuwa S, Isomoto H, Mishima R, Akazawa Y, Masuda JI, Omagari K, Takeshima F, Kohno S. Recent insights into digestive motility in functional dyspepsia. J Gastroenterol 2006; 41:1025-40. [PMID: 17160514 DOI: 10.1007/s00535-006-1966-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2006] [Accepted: 10/02/2006] [Indexed: 02/04/2023]
Abstract
Functional gastrointestinal disorders, such as functional dyspepsia (FD) and irritable bowel syndrome, are common pathologies of the gut. FD is a clinical syndrome defined as chronic or recurrent pain or discomfort of unknown origin in the upper abdomen. The pathophysiological mechanisms responsible for FD have not been fully elucidated, but new ideas regarding its pathophysiology and the significance of the pathophysiology with respect to the symptom pattern of FD have emerged. In particular, there is growing interest in alterations in gastric motility, such as accommodation to a meal or gastric emptying, and visceral sensation in FD. The mechanisms underlying impaired gastroduodenal motor function are unclear, but possible factors include abnormal neurohormonal function, autonomic dysfunction, visceral hypersensitivity to acid or mechanical distention, Helicobacter pylori infection, acute gastrointestinal infection, psychosocial comorbidity, and stress. Although the optimum treatment for FD is not yet clearly established, acid-suppressive drugs, prokinetic agents, eradication of H. pylori, and antidepressants have been widely used in the management of patients with FD. The therapeutic efficacy of prokinetics such as itopride hydrochloride and mosapride citrate in the treatment of FD is supported by the results of relatively large and well-controlled studies. In addition, recent research has yielded new therapeutic agents and modalities for dysmotility in FD, including agonists/antagonists of various sensorimotor receptors, activation of the nitrergic pathway, kampo medicine, acupuncture, and gastric electric stimulation. This review discusses recent research on the pathophysiology of and treatment options for FD, with special attention given to digestive dysmotility.
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Affiliation(s)
- Yohei Mizuta
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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Andresen V, Camilleri M, Kim HJ, Stephens DA, Carlson PJ, Talley NJ, Saito YA, Urrutia R, Zinsmeister AR. Is there an association between GNbeta3-C825T genotype and lower functional gastrointestinal disorders? Gastroenterology 2006; 130:1985-94. [PMID: 16762621 DOI: 10.1053/j.gastro.2006.03.017] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2005] [Accepted: 03/09/2006] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS GNbeta3 influences G-protein translation of a majority of ligand-receptor activations. It has been reported that functional dyspepsia (FD) is associated with homozygous genotypes of the C825T polymorphism in the GNbeta3 gene. It is unknown whether the GNbeta3 genotype is associated with lower functional gastrointestinal disorders (FGID). We aimed to compare the prevalence of the different GNbeta3-C825T genotypes in patients with lower FGID and healthy controls and to test the associations of these genetic variations with subgroups of irritable bowel syndrome (IBS), functional abdominal pain (FAP), lower FGID-FD overlap, and high somatic symptom scores. METHODS GNbeta3-C825T polymorphism was analyzed in DNA from blood samples of 233 patients with lower FGID and 152 healthy controls. A validated bowel questionnaire characterized the FGID phenotype: 82 with IBS constipation, 94 with IBS diarrhea, 38 with IBS alternating bowel function, and 19 with FAP. There were 159 patients with lower FGID and overlap FD using Rome II criteria. Regression analyses assessed associations of the GNbeta3 genotypes with lower FGID as a group, and subgroups of FGID and somatic symptom scores. RESULTS GNbeta3-C825T genotype distributions were similar between healthy controls (50.7% CC, 40.8% TC) and patients with lower FGID (8.6% TT, 51.5% CC, 40.8% TC, and 7.7% TT). There were no significant associations of GNbeta3-C825T polymorphism with lower FGID overall or with the separate symptom subgroups including IBS, FAP, lower FGID-FD overlap, or high somatic symptom scores. CONCLUSIONS In contrast to the reported association with FD, GNbeta3-C825T polymorphism is not associated significantly with lower FGID, with different IBS or FAP phenotypes, or lower FGID-FD overlap.
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Affiliation(s)
- Viola Andresen
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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O'Mahony S, Dinan TG, Keeling PW, Chua ASB. Central serotonergic and noradrenergic receptors in functional dyspepsia. World J Gastroenterol 2006; 12:2681-7. [PMID: 16718753 PMCID: PMC4130975 DOI: 10.3748/wjg.v12.i17.2681] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Functional dyspepsia is a symptom complex characterised by upper abdominal discomfort or pain, early satiety, motor abnormalities, abdominal bloating and nausea in the absence of organic disease. The central nervous system plays an important role in the conducting and processing of visceral signals. Alterations in brain processing of pain, perception and affective responses may be key factors in the pathogenesis of functional dyspepsia. Central serotonergic and noradrenergic receptor systems are involved in the processing of motor, sensory and secretory activities of the gastrointestinal tract. Visceral hypersensitivity is currently regarded as the mechanism responsible for both motor alterations and abdominal pain in functional dyspepsia. Some studies suggest that there are alterations in central serotonergic and noradrenergic systems which may partially explain some of the symptoms of functional dyspepsia. Alterations in the autonomic nervous system may be implicated in the motor abnormalities and increases in visceral sensitivity in these patients. Noradrenaline is the main neurotransmitter in the sympathetic nervous system and again alterations in the functioning of this system may lead to changes in motor function. Functional dyspepsia causes considerable burden on the patient and society. The pathophysiology of functional dyspepsia is not fully understood but alterations in central processing by the serotonergic and noradrenergic systems may provide plausible explanations for at least some of the symptoms and offer possible treatment targets for the future.
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Affiliation(s)
- S O'Mahony
- Department of Psychiatry, Alimentary Pharmabiotic Centre, University College Cork, Ireland
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Abstract
The pathogenesis of Functional Dyspepsia (FD) remains unclear, appears diverse and is thus inadequately understood. Akin to other functional gastrointestinal disorders, research has demonstrated an association between this common diagnosis and psychosocial factors and psychiatric morbidity. Conceptualising the relevance of these factors within the syndrome of FD requires application of the biopsychosocial model of disease. Using this paradigm, dysregulation of the reciprocal communication between the brain and the gut is central to symptom generation, interpretation and exacerbation. Appreciation and understanding of the neurobiological correlates of various psychological states is also relevant. The view that psychosocial factors exert their influence in FD predominantly through motivation of health care seeking also persists. This appears too one-dimensional an assertion in light of the evidence available supporting a more intrinsic aetiological link. Evolving understanding of pathogenic mechanisms and the heterogeneous nature of the syndrome will facilitate effective management. Co-morbid psychiatric illness warrants treatment with conventional therapies. Acknowledging the relevance of psychosocial variables in FD, the degree of which is subject to variation, has implications for assessment and management. Available evidence suggests psychological therapies may benefit FD patients particularly those with chronic symptoms. The rationale for use of psychotropic medications in FD is apparent but the evidence base to support the use of antidepressant pharmacotherapy is to date limited.
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Affiliation(s)
- Sandra Barry
- Department of Psychiatry, Alimentary Pharmacobiotic Centre, University College Cork, Cork, Ireland
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Camilleri CE, Carlson PJ, Camilleri M, Castillo EJ, Locke GR, Geno DM, Stephens DA, Zinsmeister AR, Urrutia R. A study of candidate genotypes associated with dyspepsia in a U.S. community. Am J Gastroenterol 2006; 101:581-92. [PMID: 16464220 DOI: 10.1111/j.1572-0241.2006.00481.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The role of genetic predisposition to the development of dyspepsia is unclear. Recently, a significant association was reported with CC genotype of GNbeta3. AIM To explore the association of candidate genotypes altering adrenergic, serotonergic, CCKergic, and G protein functions, and dyspepsia in a sample from a U.S. community. METHODS Dyspeptics and healthy controls were identified among community respondents who had been randomly selected to complete validated questionnaires. Other diseases were excluded by face-to-face history and physical examination. Polymorphisms of candidate genes for alpha(2A), alpha(2C), 5-HT(1A), 5-HT(2A), 5-HT(2C), CCK-1 receptors and CCK promoter, GNbeta3 protein, and SERT-promoter (SERT-P) were studied. The association between polymorphisms and meal-related or meal-unrelated dyspepsia, high somatic symptom scores, and somatization were evaluated using Fisher's exact test. RESULTS DNA was available from 41 dyspeptics and 47 healthy controls from Olmsted County. Community dyspepsia unrelated to meals was associated with both homozygous GNbeta3 protein 825T and C alleles. There were no significant associations with meal-related dyspepsia. Using Rome II subgroups, the same genotype was associated with dysmotility-like and other dyspepsia. Higher somatization scores were not significantly associated with any of the candidate genes when considered as single factors. CONCLUSION Meal-unrelated dyspepsia in a U.S. community study is associated with the homozygous 825T or C alleles of GNbeta3 protein. Candidate genes controlling adrenergic, serotonergic, and CCKergic functions do not appear to be associated with dyspepsia.
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Affiliation(s)
- Christopher E Camilleri
- Gastroenterology Research Unit, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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