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).

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.

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.

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).

Alterations in mucosal neuropeptides in patients with irritable bowel syndrome and ulcerative colitis in remission: a role in pain symptom generation?

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal pain. The transient receptor potential vanilloid 1 (TRPV1) channel, which is involved in visceral pain signalling, has been shown to be up-regulated in IBS. Activation of TRPV1 leads to the release of neuropeptides, such as somatostatin and substance P (SP). We hypothesized that increased pain perception in IBS could be explained by increased transcription in TRPV1 and/or altered levels of neuropeptides. We therefore assessed the transcription of TRPV1 and the mucosal concentration of somatostatin and SP in IBS in comparison to healthy volunteers and patients with ulcerative colitis (UC) in remission as disease controls, and to ascertain their relationship to pain symptoms. METHOD: Sigmoid colonic mucosal samples were collected from 12 patients with IBS, 34 patients with UC in remission and 9 healthy volunteers, in which groups TRPV1 mRNA levels were determined using quantitative polymerase chain reaction and neuropeptide concentrations by radioimmunoassay. Pain symptom intensity was determined by questionnaires. RESULTS: Transcription of TRPV1 as well as the concentration of neuropeptides were significantly higher in IBS, but only the former correlated with pain symptom severity. CONCLUSION: Increased transcription of TRPV1 may provide a possible explanation for pain generation in IBS. While the neuropeptides SP and somatostatin were both found to be increased in IBS, these changes are not sufficient to explain pain generation. Pain generation in IBS is probably explained by a complex redundancy in the regulation of local nociceptive mechanisms, which remains a subject of intensive investigation.

Effect of cholecystokinin on rectal motor and sensory function in patients with irritable bowel syndrome and healthy controls.

AIM: Ingestion of a meal frequently induces an urge to defaecate, the so-called gastro-colonic or gastro-rectal reflex. In patients with irritable bowel syndrome (IBS), symptoms are often provoked by meals. Cholecystokinin (CCK), a proximal gut peptide released after ingestion of a meal, may mediate these postprandial changes. The potential role of CCK in rectal sensory and motor function was evaluated by a rectal barostat study in healthy controls and patients with IBS. METHOD ; The sensory effects on serosal and mucosal receptors were studied. Twelve healthy controls and 12 patients with IBS underwent a ramp distension procedure of the rectum during infusion of CCK and placebo in random order. In 10 other healthy controls and 10 IBS patients an intermittent distension procedure was performed during infusion of CCK and placebo in random order. RESULTS: No differences were found in rectal compliance during ramp distensions between IBS patients and controls. CCK did not affect perception of urge and pain in controls or in IBS patients. Similar results were obtained during the intermittent distensions, but at higher distension pressures CCK significantly increased rectal sensitivity in IBS patients. CONCLUSION: Infusion of exogenous CCK to plasma levels normally seen in the postprandial state did not influence rectal motor function or sensations during ramp distension but it did significantly increase pain sensation in IBS patients during rapid intermittent distension.

Rectal hypersensitivity as hallmark for irritable bowel syndrome: defining the optimal cutoff.

BACKGROUND: Visceral hypersensitivity is a frequently observed hallmark of irritable bowel syndrome (IBS). Studies have reported differently about the presence of visceral hypersensitivity in IBS resulting from lack of standardization of the barostat procedure and due to different criteria used to assess hypersensitivity. We aimed to calculate the optimal cutoff to detect visceral hypersensitivity in IBS. METHODS: A total of 126 IBS patients and 30 healthy controls (HC) were included for assessment of visceroperception by barostat. Pain perception was assessed on a visual analogue scale (VAS). ROC-curves were used to calculate optimal discriminative cutoff (pressure and VAS-score) between IBS patients and HC to define hypersensitivity. Furthermore, pain perception to distension sequences below the pressure threshold for hypersensitivity was defined as allodynia. KEY RESULTS: Irritable bowel syndrome patients showed increased visceroperception compared to HC. Thresholds for first sensation and first pain were lower in IBS patients VS HC (P < 0.01). ROC-curves showed optimal discrimination between IBS patients and HC at 26 mmHg with a VAS cutoff ≥20 mm. Using this criterion, hypersensitivity percentages were 63.5% and 6.6% in IBS patients and HC, respectively. No significant differences were observed between IBS subtypes. Allodynia was found in a small number of patients (11%). CONCLUSIONS & INFERENCES: Optimal cutoff for visceral hypersensitivity was found at pressure 26 mmHg with a VAS ≥20 mm, resulting in 63.5% of IBS patients being hypersensitive and 11% being allodynic. Standardization of barostat procedures and defining optimal cutoff values for hypersensitivity is warranted when employing rectal barostat measurements for research or clinical purposes.

Revisiting concepts of visceral nociception in irritable bowel syndrome.

BACKGROUND AND OBJECTIVE: Irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain related to defecation with a change in bowel habit. Patients with IBS often exhibit increased visceral sensitivity, which can be tested clinically by rectal balloon distension procedures. This paper aims to give an overview of mechanisms involved in visceral hypersensitivity in IBS by reviewing recent literature. DATABASES AND DATA TREATMENT: A literature search in the electronic databases Pubmed and MEDLINE was executed using the search terms 'visceral pain' or 'visceral nociception' or 'visceral hypersensitivity' and 'irritable bowel syndrome.' Both original articles and review articles were considered for data extraction. RESULTS: Recent advances in molecular neurophysiology provide knowledge to better understand the underlying mechanism in pain generation in the human gut, in particular, in IBS patients. Sensitization of peripheral nociceptive afferents, more specifically high-threshold afferents, has been proposed as one of the principle mechanism in the development of visceral hypersensitivity. On the other hand, central mechanisms also play an important role. In terms of clinical testing of visceral perception, considerable discrepancies remain, however, across different centres. CONCLUSION: Alterations in the modulatory balance of pro- and antinociceptive central processing of noxious peripheral input may serve as in integrative hypothesis for explaining visceral hypersensitivity in IBS. Nevertheless, it remains troublesome to estimate the contribution of central and peripheral factors in visceral hypersensitivity, posing a challenge in determining effective therapeutic entities.

Does meal ingestion enhance sensitivity of visceroperception assessment in irritable bowel syndrome?

BACKGROUND: Visceral hypersensitivity is frequently observed in irritable bowel syndrome (IBS). Previous studies have shown that administration of a meal can aggravate symptoms or increase visceroperception in IBS patients. We investigated whether meal ingestion could increase the sensitivity of the barostat procedure for the detection of visceral hypersensitivity in IBS patients. METHODS: Seventy-one IBS patients and 30 healthy controls (HC) were included in the study. All subjects underwent a barostat procedure under fasted and postprandial conditions to measure visceroperception. Urge, discomfort, and pain were scored on a visual analog scale. Furthermore, percentages of hypersensitive IBS patients and HC were calculated and dynamic rectal compliance was assessed. KEY RESULTS: In IBS patients, urge, discomfort, and pain scores were significantly increased postprandially vs the fasted state. The HC showed increased scores for urge and pain only. Rectal dynamic compliance remained unaltered in both groups. Postprandial hypersensitivity percentages did not significantly differ vs the fasted state in IBS patients, nor in HC. CONCLUSIONS & INFERENCES: Postprandial barostat measurement enhances visceroperception in IBS but has no added value to detect visceral hypersensitivity in individual IBS patients.