Abdominal pain in patients with inflammatory bowel disease in remission: A prospective study on contributing factors.

BACKGROUND: Abdominal pain is highly prevalent in patients with inflammatory bowel disease (IBD) in remission, but the aetiology is incompletely understood. AIM: To investigate the association of clinical, lifestyle and psychosocial factors with abdominal pain in patients with IBD in remission. METHODS: We performed a prospective multicentre study enrolling consecutive patients with IBD. Data were collected between 1 January 2020 and 1 July 2021, using myIBDcoach, an established remote monitoring platform for IBD. Chronic abdominal pain in IBD in remission (IBDremissionPain+) was defined as abdominal pain score ≥3 (0-10 NRS) on ≥1/3 of all assessments, combined with faecal calprotectin <150 µg/g in 90 days around periodic assessments. Disease activity, lifestyle and psychosocial factors were assessed every 1-3 months during 18 months. Using linear mixed models, the association of these factors with abdominal pain over time was analysed. RESULTS: We included 559 patients, of whom 429 (76.7%) remained in biochemical remission. Of these, 198 (46.2%) fulfilled the criteria for chronic abdominal pain. IBDremissionPain+ patients were characterised by female sex, younger age, higher BMI, and shorter disease duration. They reported more often or higher levels of stress, fatigue, depressive and anxiety symptoms, and life events (all p < 0.001). In the multivariable analysis, sex, disease entity, fatigue, depressive symptoms and life events were associated with abdominal pain over time (all p < 0.05). CONCLUSION: In this cohort of patients with IBD in remission, abdominal pain was common and associated with psychosocial factors. A more holistic treatment approach for patients with IBD suffering from abdominal pain may improve quality of care and subjective wellbeing.

A combination of fecal calprotectin and human beta-defensin 2 facilitates diagnosis and monitoring of inflammatory bowel disease.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies.We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing.Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing-based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC ≈ 0.7).HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data.

Control Crohn Safe with episodic adalimumab monotherapy as first-line treatment study (CoCroS): study protocol for a randomised controlled trial.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease with a heterogeneous clinical presentation, relapse rate and treatment response. At present, no markers are available to adequately predict disease course at diagnosis. To prevent overtreatment of patients with a relative mild disease course, a step-up approach starting with corticosteroids is usually applied. Timely introduction of potentially disease modifying drugs and tight control of mucosal inflammation are crucial to prevent disease-related complications in patients with a complex disease course. We hypothesise that episodic treatment with adalimumab monotherapy in combination with close monitoring after drug discontinuation improves long-term outcome and reduces drug-related side effects, while preventing overtreatment. METHODS AND ANALYSIS: In this pragmatic multicentre randomised controlled trial, newly diagnosed CD patients or CD patients with a flare, naïve to thiopurines and biologicals, will be included and randomised 1:1 to open-label episodic (ie, 24 weeks) adalimumab monotherapy or step-up care starting with corticosteroids. The primary outcome is the number of yearly quarters of corticosteroid free clinical (Monitor Inflammatory Bowel Disease At Home score ≤3) and biochemical (C reactive protein within normal range and faecal calprotectin ≤200 µg/g) remission at week 96. Secondary outcomes are total healthcare costs, cumulative corticosteroid dose, proportion of patients with endoscopic remission at week 24, corticosteroid-free clinical remission, time to remission and patient-reported outcome measures on quality of life, (work) disability and treatment adherence. Safety outcomes are drug-related and disease-related adverse events and disease progression on MRI-enterography at week 96. ETHICS AND DISSEMINATION: This study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 21 August 2019 (METC18-076) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT03917303.

Rome III vs Rome IV criteria for irritable bowel syndrome: A comparison of clinical characteristics in a large cohort study.

BACKGROUND: The Rome criteria for irritable bowel syndrome (IBS) have been revised and are expected to apply only to the subset of Rome III IBS subjects with abdominal pain as predominant symptom, occurring at least once a week. The aim of this study was to determine the percentage of Rome III IBS subjects that fulfills Rome IV criteria and to evaluate differences between Rome IV-positive and Rome IV-negative subjects. METHODS: Four hundred and four Rome III IBS subjects completed a 14-day end-of-day symptom diary, the Gastrointestinal Symptom Rating Scale (GSRS), Hospital Anxiety and Depression Scale, and RAND 36-item Short-Form Health Survey (SF-36). Diary-based surrogate Rome IV criteria were defined as occurrence of abdominal pain at least 1 day each week with a severity of ≥2 (mild; definition 1) or ≥3 (considerable; definition 2). KEY RESULTS: Using surrogate Rome IV criteria, 353 (87.4%, definition 1) and 249 (61.6%, definition 2) subjects were defined as Rome IV positive. These patients were more often female, younger, and recruited from secondary/tertiary care compared with Rome IV-negative subjects. They also presented with higher abdominal pain scores and gastrointestinal (GI) symptom severity on both end-of-day diary and GSRS, higher psychological symptom scores, and lower quality of life compared with Rome IV-negative subjects. CONCLUSIONS AND INFERENCES: The Rome IV IBS population likely reflects a subgroup of Rome III IBS patients with more severe GI symptomatology, psychological comorbidities, and lower quality of life. This implies that results from Rome III IBS studies may not be directly comparable to those from Rome IV IBS populations.

[Changes in the treatment of Crohn's disease: fewer hospitalizations, less surgery, and reduced glucocorticoid use]. / Veranderingen in de behandeling van ziekte van Crohn.

OBJECTIVE: To study changes in treatment and disease course in patients with Crohn's disease (CD) in the South Limburg region of the Netherlands between 1991 and 2014. DESIGN: Population-based cohort study. METHODS: All 1162 CD patients in the 'IBD South Limburg cohort' were divided across three subcohorts on the basis of year of diagnosis: 1991-1998 (N = 316), 1999-2005 (N = 387) and 2006-2011 (N = 459). We compared the risk of hospitalization, bowel resection and the development of strictures and/or fistulas across the subcohorts. We also compared cumulative corticosteroid use and the relationship between the outcome measures and maintenance medication. RESULTS: In the period 1991-2014 there was an increase in the number of patients treated within 5 years with immunomodulators from 30.6% to 70.8%. For treatment with biologicals there was an increase from 3.1% to 41.2%. In parallel, the risk of hospitalization decreased from 65.9% to 44.2% and the risk of bowel resection decreased from 42.9% to 17.4%. The risk of developing strictures or fistulas remained stable (21.2%). There was no significant association between the outcome measures and the use of immunomodulators or biologicals. Furthermore, corticosteroid use decreased over time; this was linked to use of immunomodulators and biologicals. CONCLUSION: Treatment of Crohn's disease has changed over the past two decades, and the disease course has improved. We found no association between changes in maintenance medication and disease course.

Habitual diet and diet quality in Irritable Bowel Syndrome: A case-control study.

BACKGROUND: Diet is considered to be a key factor in symptom generation in Irritable Bowel Syndrome (IBS) and patients tend to exclude food products from their diet in pursue of symptom relief, which may impair diet quality. METHODS: We evaluated habitual dietary intake in IBS patients with regard to nutrients and food products using an extensive food frequency questionnaire. One hundred ninety-four IBS patients were compared to 186 healthy controls using multiple logistic regression analysis. An overall diet quality score was calculated for each participant based on the criteria of the Dutch Healthy Diet (DHD) index. KEY RESULTS: A lower DHD-score was found for IBS (mean [SD]: 52.9 [9.6]) vs controls (55.1 [9.2], P=.02). The diet of patients was lower in fibers (21 g vs 25 g per day, P=.002) and fructose (14 g vs 16 g, P=.033), while higher in total fat (37% vs 36% of total energy intake, P=.010) and added sugars (46 g vs 44 g, P=.029). Differences in daily intake of food products included lower consumption of apples (40 g vs 69 g, P<.001), pasta (28 vs 37 g, P=.029) and alcoholic beverages (130 g vs 193 g, P=.024) and higher consumption of processed meat (38 g vs 29 g, P<.001). Some of these findings correlated with gastrointestinal symptoms, showing differences between IBS subtypes. CONCLUSIONS AND INFERENCES: Differences in habitual diet were described, showing lower diet quality in IBS patients compared to controls, with increased consumption of fat and lower intake of fibers and fructose. Our data support the importance of personalized and professional nutritional guidance of IBS patients.

Biomarkers for visceral hypersensitivity in patients with irritable bowel syndrome.

BACKGROUND: Increased visceral sensitivity is observed in up to 60% of patients with Irritable Bowel Syndrome (IBS). Mucosal inflammation, altered neuroendocrine activity and intraluminal metabolic processes may contribute to the development of visceral hypersensitivity. Previously, we demonstrated that biomarkers, indicative for these biological processes, were altered in IBS patients compared to healthy controls. However, how these processes relate to visceral hypersensitivity is unknown. AIM: The aim of this study was to provide insight in biological processes associated with visceral hypersensitivity. Fecal and plasma biomarkers were measured in normosensitive and hypersensitive IBS patients. METHODS: A total of 167 IBS patients underwent a rectal barostat procedure to assess visceral sensitivity to pain. Based on the outcome, patients were classified into a normosensitive or hypersensitive group. Calprotectin, human ß-defensin 2 (HBD2), chromogranin A (CgA), and short chain fatty acids (SCFAs) were measured in feces, citrulline in plasma, and serotonin and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) in platelet-poor plasma. KEY RESULTS: Fecal markers and plasma citrulline were measured in 83 hypersensitive and 84 normosensitive patients, while platelet-poor plasma for the assessment of serotonin and 5-HIAA was available for a subgroup, i.e. 53 hypersensitive and 42 normosensitive patients. No statistically significant differences were found in concentrations of biomarkers between groups. Adjustment of the analyses for potential confounders, such as medication use, did not alter this conclusion. CONCLUSIONS & INFERENCES: Our findings do not support a role for the biological processes as ascertained by biomarkers in visceral hypersensitivity in IBS patients. This study is registered in the US National Library of Medicine (clinicaltrials.gov, NCT00775060).

The potential of volatile organic compounds for the detection of active disease in patients with ulcerative colitis.

BACKGROUND: To optimise treatment of ulcerative colitis (UC), patients need repeated assessment of mucosal inflammation. Current non-invasive biomarkers and clinical activity indices do not accurately reflect disease activity in all patients and cannot discriminate UC from non-UC colitis. Volatile organic compounds (VOCs) in exhaled air could be predictive of active disease or remission in Crohn's disease. AIM: To investigate whether VOCs are able to differentiate between active UC, UC in remission and non-UC colitis. METHODS: UC patients participated in a 1-year study. Clinical activity index, blood, faecal and breath samples were collected at each out-patient visit. Patients with clear defined active faecal calprotectin >250 µg/g and inactive disease (Simple Clinical Colitis Activity Index <3, C-reactive protein <5 mg/L and faecal calprotectin <100 µg/g) were included for cross-sectional analysis. Non-UC colitis was confirmed by stool culture or radiological evaluation. Breath samples were analysed by gas chromatography time-of-flight mass spectrometry and kernel-based method to identify discriminating VOCs. RESULTS: In total, 72 UC (132 breath samples; 62 active; 70 remission) and 22 non-UC-colitis patients (22 samples) were included. Eleven VOCs predicted active vs. inactive UC in an independent internal validation set with 92% sensitivity and 77% specificity (AUC 0.94). Non-UC colitis patients could be clearly separated from active and inactive UC patients with principal component analysis. CONCLUSIONS: Volatile organic compounds can accurately distinguish active disease from remission in UC and profiles in UC are clearly different from profiles in non-UC colitis patients. VOCs have demonstrated potential as new non-invasive biomarker to monitor inflammation in UC.

Volatile organic compounds in breath as markers for irritable bowel syndrome: a metabolomic approach.

BACKGROUND: The diagnosis of irritable bowel syndrome (IBS) is challenging because of its heterogeneity and multifactorial pathophysiology. No reliable biomarkers of IBS have been identified so far. AIMS: In a case-control study, using a novel application of breath analysis to distinguish IBS patients from healthy controls based on the analysis of volatile organic compounds (VOCs). Subsequently, the diagnostic VOC-biomarker set was correlated with self-reported gastrointestinal (GI) symptoms of subjects of the Maastricht IBS clinical cohort and of a general population cohort, LifeLines DEEP. METHODS: Breath samples were collected from 170 IBS patients and 153 healthy controls in the clinical cohort and from 1307 participants in general population cohort. Multivariate statistics were used to identify the most discriminatory set of VOCs in the clinical cohort, and to find associations between VOCs and GI symptoms in both cohorts. RESULTS: A set of 16 VOCs correctly predicted 89.4% of the IBS patients and 73.3% of the healthy controls (AUC = 0.83). The VOC-biomarker set correlated moderately with a set of GI symptoms in the clinical (r = 0.55, P = 0.0003) and general population cohorts (r = 0.54, P = 0.0004). A Kruskal-Wallis test showed no influence from possible confounding factors in distinguishing IBS patients from healthy controls. CONCLUSIONS: A set of 16 breath-based biomarkers that distinguishes IBS patients from healthy controls was identified. The VOC-biomarker set correlated significantly with GI symptoms in two independent cohorts. We demonstrate the potential use of breath analysis in the diagnosis and monitoring of IBS, and a possible application of VOC analyses in a general population cohort.

High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors.

BACKGROUND: Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms remain unclear. AIM: To study the association between exposure to these drugs and MC, with attention to time of exposure, duration, dosage and combined exposure, and to test hypotheses on underlying pharmacological mechanisms. METHODS: A case-control study was conducted using the British Clinical Practice Research Datalink. MC cases (1992-2013) were matched to MC-naive controls on age, sex and GP practice. Drug exposure was stratified according to time of exposure, duration of exposure or dosage. Conditional logistic regression analysis was applied to calculate adjusted odds ratios (AORs). RESULTS: In total, 1211 cases with MC were matched to 6041 controls. Mean age was 63.4 years, with 73.2% being female. Current use of NSAIDs (AOR 1.86, 95% CI 1.39-2.49), PPIs (AOR 3.37, 95% CI 2.77-4.09) or SSRIs (AOR 2.03, 95% CI 1.58-2.61) was associated with MC compared to never or past use. Continuous use for 4-12 months further increased the risk of MC. Strongest associations (fivefold increased risk) were observed for concomitant use of PPIs and NSAIDs. Statins were not associated with MC. CONCLUSIONS: Current exposure to NSAIDs, PPIs or SSRIs and prolonged use for 4-12 months increased the risk of MC. Concomitant use of NSAIDs and PPIs showed the highest risk of MC. Acid suppression related dysbiosis may contribute to the PPI effect, which may be exacerbated by NSAID-related side-effects.

Alterations in serotonin metabolism in the irritable bowel syndrome.

BACKGROUND: Alterations in serotonin (5-HT) metabolism have been postulated to play a role in the pathogenesis of irritable bowel syndrome (IBS). However, previous reports regarding 5-HT metabolism in IBS are contradicting. AIM: To compare platelet poor plasma (PPP) 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels and their ratio in a large cohort of IBS patients and healthy controls (HC), including IBS-subgroup analysis. METHODS: Irritable bowel syndrome patients and HC were evaluated for fasting PPP 5-HT and 5-HIAA levels. Furthermore, GI-symptom diary, GSRS, quality of life, anxiety and depression scores were assessed in the 2 weeks before blood sampling. RESULTS: One hundred and fifty four IBS patients and 137 HC were included. No differences were detected in plasma 5-HT between groups. The 5-HIAA concentrations and 5-HIAA/5-HT ratio were significantly lower in IBS compared to HC: 24.6 ± 21.9 vs. 39.0 ± 29.5 µg/L (P < 0.001) and 8.4 ± 12.2 vs. 13.5 ± 16.6 (P < 0.01), respectively. Subtype analysis for 5-HIAA showed all IBS subtypes to be significantly different from HC. The 5-HIAA/5-HT ratio was significantly lower in the IBS-M subtype vs. HC. Linear regression analysis points to an influence of gender but not of GI-symptoms, psychological scores or medication use. CONCLUSIONS: We demonstrated that fasting 5-HT plasma levels are not significantly different in IBS patients compared to controls. However, decreased 5-HIAA levels and 5-HIAA/5-HT ratio in IBS patients may reflect altered serotonin metabolism in IBS. Gender affects 5-HIAA levels in IBS patients, but no effects of drugs, such as SSRIs, or higher GI-symptom or psychological scores were found.

The Experience Sampling Method--a new digital tool for momentary symptom assessment in IBS: an exploratory study.

BACKGROUND: Retrospective questionnaires are frequently used for symptom assessment in irritable bowel syndrome (IBS) patients, but are influenced by recall bias and circumstantial and psychological factors. These limitations may be overcome by random, repeated, momentary assessment during the day, using electronic Experience Sampling Methodology (ESM). Therefore, we compared symptom assessment by ESM to retrospective paper questionnaires in IBS patients. METHODS: Twenty-six IBS patients (Rome III) were included, of which 16 were diagnosed with panic disorder (DSM-IV-TR). Patients scored symptoms using end-of-day diaries during 14 days and the gastrointestinal symptom rating scale (GSRS) once. ESM was used on seven consecutive days during the same time period. KEY RESULTS: End-of-day diary abdominal pain scores were 0.4 (SE 0.1, p < 0.001) point higher (on a 1-to-5-point scale) compared to corresponding ESM mean-scores in IBS patients. The difference was even more pronounced for upper abdominal pain scores assessed by the GSRS (4.77 ± 1.50) compared to ESM mean-scores (2.44 ± 1.30, p < 0.001), both on 1-to-7-point scale. For flatulence, comparable results were found. Nausea and belching scores showed small, but significant differences between end-of-day diary and ESM. All tested symptoms were scored higher on GSRS compared to ESM mean-scores (p < 0.01). Affective comorbidity did not influence differences in pain reporting between methods. CONCLUSIONS & INFERENCES: IBS patients report higher scores for abdominal pain in retrospective questionnaires compared to ESM, with a tendency to report peak rather than average pain scores. ESM can provide more insight in symptom course and potential triggers, and may lead to a better understanding of IBS symptomatology.

Visceral hypersensitivity in irritable bowel syndrome: evidence for involvement of serotonin metabolism--a preliminary study.

BACKGROUND: Altered serotonergic (5-HT) metabolism and visceral perception have been associated with the pathogenesis of irritable bowel syndrome (IBS). Aim of this preliminary study was to assess the effect of the direct precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on systemic 5-HT metabolites and visceral perception and to assess potential differential responses between IBS and controls. METHODS: 15 IBS patients and 15 healthy volunteers participated in this randomized double-blind placebo controlled study. Visceroperception was measured by rectal barostat. The 100 mg 5-HTP or placebo was ingested orally. Serotonergic metabolites were assessed in platelet poor plasma. KEY RESULTS: 5-HTP induces rectal allodynia in a significant number of healthy controls; IBS patients exhibit lowered pain thresholds in both placebo and 5-HTP conditions. 5-HTP induces rectal hyperalgesia in hypersensitive but not in non-hypersensitive IBS patients. Administration of 5-HTP significantly increased plasma 5-HTP levels (p < 0.001), did not affect 5-HT levels (p > 0.05), while levels of the main metabolite of 5-HT, 5-hydroxyindoleacetic acid, increased significantly (p < 0.05) in both groups. The magnitude of these changes observed in 5-HT metabolites was significantly greater in IBS patients. CONCLUSIONS & INFERENCES: Oral administration of 5-HTP induced significant alterations in systemic 5-HT metabolites that were accompanied by increased visceroperception of pain in controls and hypersensitive IBS patients. Changes in 5-HT metabolism appear to be important factors involved in visceral hypersensitivity as the 5-HTP-induced pro-nociceptive response was observed in all hypersensitive IBS patients and to a lesser magnitude in a significant number of healthy controls but in none of the non-hypersensitive IBS patients.

Markers for visceral hypersensitivity in patients with irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a heterogenous disorder with visceral hypersensitivity as important hallmark. It is not known whether IBS patients with visceral hypersensitivity have different epidemiological and clinical characteristics compared with IBS patients without visceral hypersensitivity. Aim of our study was to compare in detail a large group of hyper- vs normosensitive IBS patients with respect to epidemiological and clinical characteristics. METHODS: IBS patients (Rome III criteria) have been recruited for a large-scale cohort study. All patients from this cohort who underwent a rectal barostat procedure were included and allocated based on those with and without visceral hypersensitivity. Patient demographics, and symptoms were collected using questionnaires (GSRS, HADS, SF-36) and a 14-day symptom diary for IBS-related symptoms. A multivariate logistic regression model was used to identify risk markers for having visceral hypersensitivity. KEY RESULTS: Ninety-five normosensitive and 93 hypersensitive IBS patients participated in this study. Hypersensitive patients had significantly higher scores for GSRS abdominal pain (p < 0.05), indigestion, reflux and constipation syndrome (all p < 0.01), and IBS symptom intensity, discomfort (both p < 0.05) and mean symptom composite score (p < 0.01). Age, female sex, and the use of SSRI medication were significantly different between the normo- and the hypersensitive IBS patients. However, after adjustment for other risk markers, only increasing age was found to be significantly associated with lower odds for having hypersensitivity (OR 0.97 [95% CI: 0.94; 0.99]). CONCLUSIONS & INFERENCES: Apart from more severe symptomatology, hypersensitive IBS patients are characterized by significantly younger age compared with normosensitive IBS patients. The study has been registered in the US National Library of Medicine (http://www.clinicaltrials.gov, NCT00702026).

Small intestinal permeability is increased in diarrhoea predominant IBS, while alterations in gastroduodenal permeability in all IBS subtypes are largely attributable to confounders.

BACKGROUND: Intestinal permeability has been studied in small groups of IBS patients with contrasting findings. AIMS: To assess intestinal permeability at different sites of the GI tract in different subtypes of well-characterised IBS patients and healthy controls (HC), and to assess potential confounding factors. METHODS: IBS patients and HC underwent a multi-sugar test to assess site-specific intestinal permeability. Sucrose excretion and lactulose/rhamnose ratio in 0-5 h urine indicated gastroduodenal and small intestinal permeability, respectively. Sucralose/erythritol ratio in 0-24 h and 5-24 h urine indicated whole gut and colonic permeability, respectively. Linear regression analysis was used to assess the association between IBS groups and intestinal permeability and to adjust for age, sex, BMI, anxiety or depression, smoking, alcohol intake and use of medication. RESULTS: Ninety-one IBS patients, i.e. 37% IBS-D, 23% IBS-C, 33% IBS-M and 7% IBS-U and 94 HC were enrolled. Urinary sucrose excretion was significantly increased in the total IBS group [µmol, median (Q1;Q3): 5.26 (1.82;11.03) vs. 2.44 (0.91;5.85), P < 0.05], as well as in IBS-C and IBS-D vs. HC. However, differences attenuated when adjusting for confounders. The lactulose/rhamnose ratio was increased in IBS-D vs. HC [0.023 (0.013;0.038) vs. 0.014 (0.008;0.025), P < 0.05], which remained significant after adjustment for confounders. No difference was found in 0-24 and 5-24 h sucralose/erythritol ratio between groups. CONCLUSIONS: Small intestinal permeability is increased in patients with IBS-D compared to healthy controls, irrespective of confounding factors. Adjustment for confounders is necessary when studying intestinal permeability, especially in a heterogeneous disorder such as IBS.

Serotonergic reinforcement of intestinal barrier function is impaired in irritable bowel syndrome.

BACKGROUND: Alterations in serotonergic (5-HT) metabolism and/or intestinal integrity have been associated with irritable bowel syndrome (IBS). AIMS: To assess the effects of the precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on mucosal 5-HT availability and intestinal integrity, and to assess potential differences between healthy controls and IBS patients. METHODS: Fifteen IBS patients and 15 healthy volunteers participated in this randomised double-blind placebo-controlled study. Intestinal integrity was assessed by dual-sugar test and by determining the mucosal expression of tight junction proteins after ingestion of an oral bolus of 100 mg 5-HTP or placebo. Mucosal serotonergic metabolism was assessed in duodenal biopsy samples. RESULTS: 5-HTP administration significantly increased mucosal levels of 5-HIAA, the main metabolite of 5-HT, in both healthy controls (7.1 ± 1.7 vs. 2.5 ± 0.7 pmol/mg, 5-HTP vs. placebo, P = 0.02) and IBS patients (20.0 ± 4.8 vs. 8.1 ± 1.3 pmol/mg, 5-HTP vs. placebo, P = 0.02), with the latter group showing a significantly larger increase. Lactulose/L-rhamnose ratios were significantly lower after administration of 5-HTP (P < 0.05) in healthy controls and were accompanied by redistribution of zonula occludens-1 (ZO-1), pointing to reinforcement of the barrier. In IBS, expression of the tight junction proteins was significantly lower compared to healthy controls, and 5-HTP resulted in a further decrease in occludin expression. CONCLUSIONS: Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients.

Randomized clinical trial on the effect of a multispecies probiotic on visceroperception in hypersensitive IBS patients.

BACKGROUND: Irritable bowel syndrome (IBS) is characterized by heterogeneous pathophysiology and low response to treatment. Up to 60% of IBS patients suffers from visceral hypersensitivity, which is associated with symptom severity and underlying pathophysiological mechanisms. Recently, positive effects of probiotics in IBS have been reported, but overall the response was modest. We performed a study in IBS patients, characterized by visceral hypersensitivity measured with the rectal barostat, aiming to assess the effect of 6 weeks of multispecies probiotic mix on visceral pain perception. METHODS: We conducted a randomized, placebo-controlled, double-blind trial in forty Rome III IBS patients with visceral hypersensitivity. Prior to intake, patients kept a 2-week symptom diary and underwent a rectal barostat measurement. When hypersensitivity was confirmed, participation was allowed and patients received a multispecies probiotic with in vitro proven potential beneficial effects on mechanisms contributing to visceral hypersensitivity (six different probiotic strains; 10(9)  cfu/g), or a placebo product of one sachet (5 g) per day for 6 weeks. At the end of the intervention period, visceroperception and symptoms were reassessed. KEY RESULTS: Thirty-five patients completed the trial. The percentage of patients with visceral hypersensitivity decreased significantly in the probiotic and placebo group (76.5% and 71.4%, respectively; N.S. between groups). Improvement in pain scores and mean symptom score did not differ between the probiotic and placebo group. CONCLUSIONS & INFERENCES: In this placebo-controlled trial in IBS patients with visceral hypersensitivity, no significant effect of a multispecies probiotic on viscerperception was observed. The study has been registered in the US National Library of Medicine (http://www.clinicaltrials.gov, NCT00702026).