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- Beyder, Arthur, et al.
(författare)
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Loss-of-Function of the Voltage-Gated Sodium Channel Na(V)1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome
- 2014
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 146:7, s. 1659-1668
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na(V)1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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| 2. |
- Beyder, Arthur, et al.
(författare)
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Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
- 2014
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 146:7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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| 6. |
- Jones, Michael P., et al.
(författare)
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Clusters of community-dwelling individuals empirically derived from stool diaries correspond with clinically meaningful outcomes
- 2021
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Ingår i: European Journal of Gastroenterology and Hepathology. - : Lippincott Williams & Wilkins. - 0954-691X .- 1473-5687. ; 33:1S, s. e740-e745
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Tidskriftsartikel (refereegranskat)abstract
- Background Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability.Methods As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis.Results The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46–0.74), self-rated health (d = −0.42) and depression (d = −0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P < 0.0001).Conclusion A naturalistic classification of individuals challenges consensus criteria in showing that some IBS individuals have a symptom experience not unlike health. The proposed approach has demonstrated temporal stability over time, unlike consensus criteria. A naturalistic disease classification system may have practical advantages over consensus criteria when supported by a decision-analytic system.
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| 7. |
- Talley, Nicholas J., et al.
(författare)
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Ileocolonic Histopathological and Microbial Alterations in the Irritable Bowel Syndrome : A Nested Community Case-Control Study
- 2021
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Ingår i: Clinical and Translational Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Histopathological alterations in the ileum and colon in irritable bowel syndrome (IBS) are controversial, and normal values are poorly established. We hypothesized that changes in mucosal immune cells characterize IBS and key changes in immune composition are associated with the mucosa-associated microbiota (MaM).METHODS: A nested case-control study (48 IBS and 106 controls included) from 745 colonoscopy participants in a random population sample. Intraepithelial lymphocytes (IELs)/100 enterocytes and eosinophils/5 nonoverlapping high-power fields counted; mast cells identified by immunocytochemistry (CD117)/5 high-power fields. Paneth cells quantified per 5 crypts. 16S rRNA gene amplicon sequencing performed on available sigmoid MaM, n = 55 and fecal microbiota, n = 20. Microbiota profiles compared between samples with high and low IEL counts.RESULTS: IBS had increased IELs in the terminal ileum (relative risk ratio = 1.70, 95% confidence interval 1.08–2.76, P = 0.022 adjusted for age, sex, and smoking). Cecal IELs were increased in IBS—diarrhea (relative risk ratio = 2.03, 95% confidence interval 1.13–3.63, P = 0.017). No difference was observed in alpha diversity of MaM or fecal microbiota based on IEL count. There was no difference in beta diversity of the MaM according to IEL count in the terminal ileal (TI) (P = 0.079). High TI IEL counts associated with a significant expansion of the genus Blautia (P = 0.024) and unclassified Clostridiales (P = 0.036) in colon MaM.DISCUSSION: A modest but significant increase in IELs was observed in IBS vs. controls in a population-based setting. Subtle TI and cecal inflammation may play a pathogenic role in IBS but needs confirmation. Modest but discernible differences in the colonic MaM were seen according to TI IEL count but not IBS status.
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| 8. |
- Talley, Nicholas J., et al.
(författare)
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Role of smoking in functional dyspepsia and irritable bowel syndrome : three random population-based studies
- 2021
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Ingår i: Alimentary Pharmacology and Therapeutics. - : John Wiley & Sons. - 0269-2813 .- 1365-2036. ; 54:1, s. 32-42
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is uncertain if functional dyspepsia (FD) or irritable bowel syndrome (IBS) are linked to smoking, and smoking cessation is not part of the routine advice provided to these patients.Aim: To assess if smoking is an independent risk factor for FD and IBS.Methods: Three population-based endoscopy studies in Sweden with 2560 community individuals in total (mean age 51.5 years, 46% male). IBS (14.9%), FD (33.5%), and associated symptoms were assessed using the validated abdominal symptom questionnaire, and smoking (17.9%) was obtained from standardised questions during a clinic visit. The effect of smoking on symptom status was analysed in an individual person data meta-analysis using mixed effect logistic regression, adjusted for snuffing, age and sex.Results: Individuals smoking cigarettes reported significantly higher odds of postprandial distress syndrome (FD-PDS) (OR 10-19 cig/day = 1.42, 95% CI 1.04-1.98 P = 0.027, OR ≥20 cig/day = 2.16, 95% CI 1.38-3.38, P = 0.001) but not epigastric pain. Individuals smoking 20 or more cigarettes per day reported significantly higher odds of IBS-diarrhoea (OR = 2.40, 95% CI 1.12-5.16, P = 0.025), diarrhoea (OR = 2.01, 95%CI 1.28-3.16, P = 0.003), urgency (OR = 2.21, 95%CI 1.41-3.47, P = 0.001) and flatus (OR = 1.77, 95%CI 1.14-2.76, P = 0.012) than non-smokers. Smoking was not associated with IBS-constipation or IBS-mixed.Conclusion: Smoking is an important environmental risk factor for postprandial distress syndrome, the most common FD subgroup, with over a twofold increased odds of PDS in heavy smokers. The role of smoking in IBS-diarrhoea, but not constipation, is also likely important.
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| 9. |
- Agah, Shahram, et al.
(författare)
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Systematic review with meta-analysis: Effects of probiotic supplementation on symptoms in functional dyspepsia
- 2020
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Ingår i: Journal of Functional Foods. - : Elsevier BV. - 1756-4646. ; 68
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Forskningsöversikt (refereegranskat)abstract
- The pathophysiology of functional dyspepsia (FD) remains poorly understood, but alterations of the small intestinal microbiome have been observed. The place of probiotics in treatment is uncertain. We performed a systematic review and meta-analysis of the currently available randomized, controlled trials (RCTs) to evaluate the potential beneficial effects and risks of probiotics in FD. Pubmed, EMBASE, Scopus, Web of Science and the Cochrane Controlled Trials Register were searched (up to May 2019) for RCTs evaluating the effects of probiotic supplementation compared to placebo in adults with FD. Two reviewers independently assessed eligibility, trial quality and extracted information from identified articles. To compare the effects of probiotics with placebo, risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random effects models. Six trials, including 422 participants were included but only three RCTs could be included in the meta-analysis. Lactobacillus strains showed potential positive effects in terms of improving upper gastrointestinal (GI) symptoms in patients with FD. Probiotic supplementation tended to improve global dyspepsia score (n = 3 RCTs, risk ratio [RR]: 1.35, 95% CI 0.99 to 1.84; P = 0.061) and bacterial composition in the GI tract. Probiotics were well tolerated without any serious adverse events. While the available data suggest that supplementation with probiotics may improve GI symptoms in patients with FD, the evidence is insufficient to draw clear conclusions regarding efficacy. Thus, high-quality RCTs are needed to establish the beneficial effects of probiotic supplementation on FD outcomes.
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| 10. |
- Agréus, Lars, et al.
(författare)
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Predictors and non-predictors of symptom relief in dyspepsia consultations in primary care
- 2008
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Ingår i: Digestive Diseases. - : S. Karger AG. - 0257-2753 .- 1421-9875. ; 26:3, s. 248-255
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We aimed to evaluate if the course of dyspepsia is influenced by medical consultation in primary care. DESIGN, SETTING AND PATIENTS: Australian general practitioners (n = 27) recruited 157 dyspeptic patients, of whom 94 were eligible for follow-up. Dyspepsia, comorbidity, quality of life, emotional status, locus of control and consultation satisfaction were measured at baseline and follow-up (mean 3 months). MAIN OUTCOME MEASURE: Response was defined as improvement of dyspepsia over time on the Nepean Dyspepsia Index score. RESULTS: Dyspepsia improved in 82% (n = 77). There was no significant change in non-gastrointestinal symptoms. Half were worried or stressed by their symptoms, and 85% wanted reassurance, a need that (univariately) differentiated responders from non-responders (p = 0.02). Most patients seen in primary care with dyspepsia improved. If the doctor believed it was likely that the patient would follow their recommendations, the patient was nearly five times as likely to be a responder (OR 4.9, 95% CI 1.2-19.0). The only other significant predictor was acid suppression therapy (OR 3.5, 95% CI 1.1-10.9). CONCLUSION: Most primary care visits for dyspepsia are followed by improvement, which may be predicted in part by indicators of patient compliance. Prescription of acid suppression therapy may also improve outcome in dyspepsia
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