Abnormalities of serotonin metabolism and their relation to symptoms in untreated celiac disease.

BACKGROUND AND AIMS: Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut function that in excess causes nausea, vomiting, and diarrhea. We recently showed that patients with post-infective irritable bowel syndrome have increased postprandial release of 5-HT associated with low-grade T-cell mediated inflammation. Celiac disease is another common disease in which a T-cell enteropathy is associated with increased mucosal 5-HT levels. Our aim was to determine how this inflammatory lesion influenced 5-HT bioavailability and how changes in 5-HT related to the symptoms of nausea, vomiting, and diarrhea seen in untreated celiac patients. METHODS: Fasting plasma and platelet 5-HT and postprandial plasma 5-HT levels were measured after a high-carbohydrate meal in celiac patients (n = 18) and healthy controls (n = 18) using high-pressure liquid chromatography. Dyspepsia was assessed during the postprandial period using a questionnaire. Finally, we compared the histology and mucosal 5-HT levels in duodenal biopsy specimens from celiac patients and controls. RESULTS: Celiac patients had increased 5-HT-containing enterochromaffin cell numbers and significantly higher peak plasma 5-HT levels (P = .0002), postprandial area under the curve (P = .0006), and platelet 5-HT stores (P = .031) than controls. Peak 5-HT levels correlated significantly with postprandial dyspepsia scores (P = .005). Celiac patients had higher duodenal 5-HT levels (P = .007) than controls. CONCLUSIONS: Celiac disease is associated with increased mucosal 5-HT content and enhanced 5-HT release from the upper small bowel, which correlates with postprandial dyspepsia. Serotonin excess may mediate dyspeptic symptoms in untreated celiac disease.

Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes.

OBJECTIVES: Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls. METHODS: Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12). RESULTS: Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and controls (0.07 [0.035-0.19]) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious IBS (0.43 [0.29-0.63], p=0.028) or controls (0.27 [0.2-0.39]), p=0.001). CONCLUSIONS: Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.

Gallbladder contraction, gastric emptying and antral motility: single visit assessment of upper GI function in untreated celiac disease using echo-planar MRI.

PURPOSE: To assess gallbladder contraction, gastric emptying, and antral motility in untreated celiac patients and healthy controls using a single MRI examination. MATERIALS AND METHODS: Gallbladder emptying, gastric emptying, and antral motility were measured in 15 celiac patients and 15 age/sex-matched healthy controls following a 323-kcal test meal using EPI techniques. Postprandial dyspepsia scores were recorded on a questionnaire. RESULTS: Fasting gallbladder volume (P=0.01) and the volume of bile ejected postprandially (P=0.014) were increased in celiacs. Gastric emptying tended to be slower in celiacs (P=0.142). Three celiac patients with severe postprandial dyspepsia and total villous atrophy had pathologically delayed gastric emptying and increased fasting gallbladder volume. Antral contractions were absent in five out of 14 patients (36%) five minutes after the meal, but in none of 10 volunteers in whom the antrum could be visualized (P=0.128). CONCLUSION: This study shows that using MRI, multiple parameters related to upper gastrointestinal function in celiac disease can be measured in a single noninvasive study, whereas previously three separate visits would have been required. Celiacs have increased fasting gallbladder volumes and tend to have slower gastric emptying.

Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome.

BACKGROUND & AIMS: 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonists improve symptoms in patients with diarrhea-predominant irritable bowel syndrome (D-IBS), 5-HT 4 agonists help those with constipation-predominant IBS (C-IBS). These data suggest excess or deficiency in 5-HT in D-IBS or C-IBS, respectively. Mucosal 5-HT-containing enterochromaffin cells (EC) are increased in postinfectious IBS (PI-IBS). Our aim was to define the postprandial release of 5-HT in PI-IBS and C-IBS patients and to relate this to mucosal 5-HT turnover. METHODS: Fifteen PI-IBS patients with diarrhea-predominant symptoms, 15 C-IBS patients, and 15 healthy controls underwent serial (platelet-poor) plasma 5-HT measurement for 3 hours after a standard 520-kcal meal. Rectal biopsy specimens were assayed for 5-HT and its metabolite 5-hydroxindoleacetic acid (5-HIAA). Colonic transit was measured using radio-opaque markers. RESULTS: Colonic transit was prolonged in C-IBS patients (mean +/- SEM) (49.4 +/- 3.8 h) compared with PI-IBS (26.7 +/- 4.5) and control patients (34.1 +/- 4.5) ( P < .02). Release of 5-HT assessed by area under the curve (AUC) of platelet-poor plasma 5-HT from 0 to 180 minutes postprandially was significantly lower in C-IBS patients (2593 +/- 309 mmol/L . min) compared with P-IBS (5623 +/- 721) and control patients (4822 +/- 598) ( P < .001). PI-IBS patients showed significantly higher peak postprandial plasma 5-HT values (median, range) (71.7, 43.4-125.3) ng/L compared with C-IBS patients (31.2, 15.2-40.5) and control patients (43.6, 26.7-50.1) ( P < .01). Mucosal 5-HT turnover as assessed by mucosal 5-HIAA/5-HT ratio was decreased in both C-IBS and PI-IBS patients, .14 (.01-.6) and .21 (.02-2.5), respectively, compared with control patients 1.12 (.17-3.1) ( P < .002). CONCLUSIONS: C-IBS patients show impaired postprandial 5-HT release whereas PI-IBS patients have higher peak levels, abnormalities that may be related to their different symptoms.

Cytochrome P450 2E1 high activity polymorphism in alcohol abuse and end-organ disease.

AIM: To investigate a possible role for a recently identified polymorphism in the gene of cytochrome P450 2E1, the presence of which is associated with high activity of the enzyme. METHODS: Two hundred and thirty-nine alcohol consumers, ICD 10.1/.2 (ALC), and 208 normal controls were studied. PCR amplification of the CYP2E1 gene region was performed to assess polymorphic variation. Fisher's exact test was used to assess the data. RESULTS: Twelve normal controls (5.8%) possessed the insertion. Five ALC (2.1%) had the insertion; of these 2 of 144 with alcohol induced chronic pancreatitis, none of 28 with alcoholic liver disease and 3 of 67 without end-organ disease had the polymorphism. A significantly Lower frequency of subjects possessed the insertion than normal controls [P=0.049 (genotype analysis P=0.03)]. To further assess, if there was a relationship to alcohol problems per se or end-organ disease, we compared patients with alcohol induced end-organ disease vs alcoholic controls without end-organ disease vs normal controls which again showed a significant difference [P=0.045 (genotype analysis, P=0.011)], further sub-group analysis did not identify which group(s) accounted for these differences. CONCLUSION: We have shown the frequencies of this high-activity polymorphism in alcohol related patient groups for the first time. The frequency is significantly less in alcoholics than normal controls, as with high activity polymorphisms of alcohol dehydrogenase. The biological significance, and whether the relevance is solely for alcoholism or is there a relationship to end-organ disease, would benefit from the assessment in the populations with a greater frequency of this polymorphism.

Age-related decline in rectal mucosal lymphocytes and mast cells.

BACKGROUND: Previous studies have shown that irritable bowel syndrome declines with age and is more common in women. Recent reports suggest that some diarrhoea predominant irritable bowel syndrome patients have low-grade inflammation with increased numbers of mucosal T lymphocytes, 5-hydroxytryptamine (5-HT) containing enteroendocrine cells and mast cells. OBJECTIVE: To determine whether there are age or gender-related changes in mucosal T lymphocytes, mast cells or enteroendocrine cells which might explain these findings. METHODS: Forty healthy volunteers (20 subjects below 55 years of age and 20 above 55 years) free from gastro-intestinal symptoms or disease answered detailed bowel symptom questionnaires and underwent sigmoidoscopy, rectal biopsy and colonic transit measurement. Biopsies were immunostained and quantified for lamina propria and intra-epithelial T lymphocytes, mast cells and 5-HT and peptide YY enteroendocrine cells. RESULTS: There was a reduction in lamina propria T lymphocyte counts (P = 0.018), crypt intra-epithelial T lymphocytes (P = 0.014) and mast cells (P = 0.02) in the > 55 year group. Enteroendocrine cell numbers did not decline with age and were not related to colonic transit. There were no gender differences between any of the cells quantified. CONCLUSIONS: Lymphocyte and mast cell numbers decline with age in normal large bowel mucosa. Reduced numbers of mucosal inflammatory cells may influence the low-grade inflammatory response to luminal antigens and contribute to the reduction of irritable bowel syndrome observed in older subjects.

Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome.

OBJECTIVE: Irritable bowel syndrome after gastroenteritis is well recognized. Our aim was to determine whether postinfective IBS (PI-IBS) has histological or clinical features that are distinct from those of IBS patients with no history of preceding infection. METHODS: A total of 75 consecutive IBS outpatients and 36 healthy control subjects completed a questionnaire detailing symptoms, mode of onset, and previous psychiatric history. All underwent a full diagnostic workup including rectal biopsy, which included immunostaining and quantification for lamina propria or intraepithelial T lymphocytes, serotonin-containing enterochromaffin (EC), and mast cells. Patients were divided according to onset of symptoms into PI-IBS (n = 23) or non-PI-IBS (n = 52) patients. RESULTS: Diarrhea predominance occurred more frequently in PI-IBS (70%) than in non-PI-IBS (42%) patients (p = 0.03). A history of previous treatment for anxiety or depression was present in 26% of PI-IBS patients compared to 54% of non-PI-IBS (p = 0.02). Biopsy results for all patients were normal using conventional criteria; however, quantification revealed that PI-IBS showed increased EC cells compared to those of non-PI-IBS patients (p = 0.017) and controls (p = 0.02). Lamina propria T lymphocytes were increased in PI-IBS (p = 0.026) and non-PI-IBS (p = 0.011) patients compared to controls. Mast cells were increased in non-PI-IBS patients (p = 0.054) compared to controls. CONCLUSIONS: Individuals with PI-IBS are a clinically distinct subgroup characterized by diarrheal symptoms, less psychiatric illness, and increased serotonin-containing EC cells compared to those with non-PI-IBS.

Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.

BACKGROUND & AIMS: Both psychological and mucosal changes (increased enterochromaffin [EC] cells and T lymphocytes) have been associated with postinfectious irritable bowel syndrome (PI-IBS). However, previous studies have been underpowered to determine the relative importance of these changes in predicting the development of PI-IBS. Our aim was to prospectively determine the relative importance of both psychological and histologic factors in the development of PI-IBS after Campylobacter infection. METHODS: Questionnaires detailing psychological and bowel symptoms were sent to 1977 patients 3 months after infection. Twenty-eight patients with new-onset PI-IBS, 28 age- and sex-matched patient controls who were asymptomatic after infection, and 34 healthy volunteers underwent rectal biopsy, which was assessed for serotonin-containing EC cells, mast cells, and lamina propria T lymphocytes. RESULTS: PI-IBS, predominantly of the diarrhea-predominant subtype, occurred in 103 of 747 (13.8%) of those infected. EC cell counts per high-power field (hpf) were higher in patients with PI-IBS (35.8 +/- 1.2) compared with patient controls (30.6 +/- 1.9; P = 0.022) and volunteers (29.1 +/- 1.8; P = 0.006). Lamina propria T lymphocytes per hpf were higher in patients with PI-IBS (127.1 +/- 8.7) and patient controls (113.4 +/- 6.2) in contrast to healthy volunteers (97.1 +/- 5.7) (P = 0.006 and P = 0.058, respectively). Anxiety, depression, and fatigue were significantly increased in patients with PI-IBS compared with patient controls. Multivariate analysis indicated that increased EC cell counts and depression were equally important predictors of developing PI-IBS (relative risk, 3.8 and 3.2 for each standard deviation increase in respective values). CONCLUSIONS: Both increased EC cells and depression are important independent predictors of developing PI-IBS.