Increased fasting small-bowel water content in untreated coeliac disease and scleroderma as assessed by magnetic resonance imaging.

Background and aims: The regular overnight migrating motor complex (MMC) ensures that the normal fasting small-bowel water content (SBWC) is minimised. We have applied our recently validated non-invasive magnetic resonance technique to assess SBWC in newly diagnosed coeliac disease (CD), scleroderma (SCD) and irritable bowel syndrome (IBS), conditions possibly associated with small intestinal bacterial overgrowth (SIBO). Methods: A total of 20 CD and 15 SCD patients with gastrointestinal symptoms were compared to 20 healthy volunteers (HV) and 26 IBS with diarrhoea (IBS-D) patients, as previously reported. All underwent a fasting magnetic resonance imaging (MRI) scan on a 1.5 T Philips Achieva MRI scanner to assess fasting SBWC and colonic volumes. Stool and symptom diaries were completed for one week. Results: Compared to HV, all patients had significantly increased stool frequency and Bristol stool form score. SBWC was significantly increased in CD (median 109 mL; interquartile range (IQR) 53-224 mL) compared to HV (median 53 mL; IQR 31-98 mL; p < 0.01) and IBS-D (median 42 mL; IQR 28-67 mL; p < 0.01). A variable increase in SBWC was also found in SCD (median 77 mL; IQR 39-158 mL), but this was not significant (p = 0.2). Colonic volumes were similar for all groups, being a median of 547 mL (IQR 442-786 mL) for CD, 511 mL (453-789 mL) for SCD, 612 mL (445-746 mL) for HV and 521 mL (428-757 mL) for IBS-D. When CD patients were subdivided according to the Marsh classification, the higher grades had larger colonic volumes. Conclusion: Fasting SBWC as assessed by MRI is significantly increased in newly diagnosed CD and SCD but decreased in IBS-D. Future studies should test whether increased resting fluid predisposes to SIBO.

Abnormalities of mucosal serotonin metabolism and 5-HT3 receptor subunit 3C polymorphism in irritable bowel syndrome with diarrhoea predict responsiveness to ondansetron.

BACKGROUND: Irritable bowel syndrome with diarrhoea (IBS-D) is a common condition, greatly reducing the quality of life with few effective treatment options available. AIM: To report the beneficial response shown in our trial with the 5-hydroyxtryptamine (5-HT) receptor 3 antagonist, ondansetron in IBS-D METHODS: A randomised, placebo-controlled, cross-over trial of 5 weeks of ondansetron versus placebo in 125 patients meeting modified Rome III criteria for IBS-D as previously described. Patients were compared to 21 healthy controls. 5-HT and 5-HIAA were measured in rectal biopsies. Whole gut transit time was assessed using a radio-opaque marker technique. Whole blood DNA was genotyped for an insertion polymorphism in the promoter region of the serotonin transporter gene SLC6A4, as well as single nucleotide polymorphisms (SNPs) of the tryptophan hydroxylase gene TPH1 and 5-HT3 receptor genes HTR3A, C and E. RESULTS: Patients' biopsies showed significantly higher 5-HIAA levels (2.1 (1.2-4.2) pmol/mg protein vs 1.1 (0.4-1.5) in controls, P < .0001). 39 patients used < 4 mg/d ("super-responders") while 55 required ≥ 4 mg/d. 5-HT concentrations in rectal biopsies were significantly lower in super-responders (21.3 (17.0-31.8) vs 37.7 (21.4-61.4), P = .0357) and the increase in transit time on ondansetron was significantly greater (15.6 (1.8-31) hours vs 3.9 (-5.1-17.9) hours). Stool consistency responders were more likely to carry the CC genotype of the SNP p.N163K rs6766410 of the HTR3C gene (33% vs 14%, P = .0066). CONCLUSION: IBS-D patients have significant abnormalities in mucosal 5-HT metabolism. Those with the lowest concentration of 5-HT in rectal biopsies showed the greatest responsiveness to ondansetron.

Effects of bowel cleansing on the intestinal microbiota.

OBJECTIVE: An adequate bowel cleansing is essential for a successful colonoscopy. Although purgative consumption is safe for the patient, there is little consensus on how the intestinal microbiota is affected by the procedure, especially regarding the potential long-term consequences. DESIGN: 23 healthy subjects were randomised into two study groups consuming a bowel preparation (Moviprep), either in two separate doses of 1 L or as a single 2-L dose. Participants donated faecal samples at the baseline, after bowel cleansing, 14 and 28 days after the treatment. The intestinal microbiota composition was determined with phylogenetic microarray as well as quantitative PCR analysis and correlated with the previously quantified faecal serine proteases. RESULTS: The lavage introduced an instant and substantial change to the intestinal microbiota. The total microbial load was decreased by 31-fold and 22% of the participants lost the subject-specificity of their microbiota. While the bacterial levels and community composition were essentially restored within 14 days, the rate of recovery was dose dependent: consumption of the purgative in a single dose had a more severe effect on the microbiota composition than that of a double dose, and notably increased the levels of Proteobacteria, Fusobacteria and bacteria related to Dorea formicigenerans. The abundance of the latter also correlated with the amount of faecal serine proteases that were increased after purging. CONCLUSIONS: Our results suggest that the bowel cleansing using two separate dosages introduces fewer alterations to the intestinal microbiota than a single dose and hence may be preferred in clinical practice.

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea.

BACKGROUND: Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D. METHODS: 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment. RESULTS: Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo -0.9, 95% CI -1.1 to -0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001. CONCLUSIONS: Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.

Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome.

BACKGROUND: About 10% of patients with IBS report the start of the syndrome after infectious enteritis. The clinical features of postinfectious IBS (PI-IBS) resemble those of diarrhoea-predominant IBS (IBS-D). While altered faecal microbiota has been identified in other IBS subtypes, composition of the microbiota in patients with PI-IBS remains uncharacterised. OBJECTIVE: To characterise the microbial composition of patients with PI-IBS, and to examine the associations between the faecal microbiota and a patient's clinical features. DESIGN: Using a phylogenetic microarray and selected qPCR assays, we analysed differences in the faecal microbiota of 57 subjects from five study groups: patients with diagnosed PI-IBS, patients who 6 months after gastroenteritis had either persisting bowel dysfunction or no IBS symptoms, benchmarked against patients with IBS-D and healthy controls. In addition, the associations between the faecal microbiota and health were investigated by correlating the microbial profiles to immunological markers, quality of life indicators and host gene expression in rectal biopsies. RESULTS: Microbiota analysis revealed a bacterial profile of 27 genus-like groups, providing an Index of Microbial Dysbiosis (IMD), which significantly separated patient groups and controls. Within this profile, several members of Bacteroidetes phylum were increased 12-fold in patients, while healthy controls had 35-fold more uncultured Clostridia. We showed correlations between the IMD and expression of several host gene pathways, including amino acid synthesis, cell junction integrity and inflammatory response, suggesting an impaired epithelial barrier function in IBS. CONCLUSIONS: The faecal microbiota of patients with PI-IBS differs from that of healthy controls and resembles that of patients with IBS-D, suggesting a common pathophysiology. Moreover, our analysis suggests a variety of host-microbe associations that may underlie intestinal symptoms, initiated by gastroenteritis.

Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit.

OBJECTIVES: Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing and transit time. DESIGN: Faecal samples were obtained from 30 healthy volunteers (HV) and 79 patients with IBS-D participating in a trial of ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Samples were also obtained from 24 HV before and after colonic cleansing with the osmotic laxative MoviPrep. FSPs were purified from faecal extracts using benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem mass spectrometry. Functional protease activity in faecal extracts was measured using a colorimetric assay based on the proteolysis of azo-casein. RESULTS: Protein analysis identified the most abundant FSPs as being of human origin and probably derived from pancreatic juice. Functional assays showed increased faecal protease (FP) and amylase in patients with IBS-D compared with HV. Those with higher amylase had significantly higher FP and greater anxiety. FP activity correlated negatively with whole gut transit in patients with IBS-D (Spearman r=-0.32, p=0.005) and HV (r=-0.55, p=0.014). Colon cleansing caused a significant rise in FP activity in HV from a baseline of median (IQR) 253 (140-426) to 1031 (435-2296), levels similar to those seen in patients with IBS-D. FSP activity correlated positively with days/week with urgency. CONCLUSIONS: The most abundant FSPs are of human origin. Rapid transit through the colon and/or decreased (possibly bacterial) proteolytic degradation increases their faecal concentration and could contribute to visceral hypersensitivity in patients with IBS-D. CLINICALTRIALSGOV: NCT00745004.

Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation.

BACKGROUND & AIMS: Patients with irritable bowel syndrome with diarrhea (IBS-D) have increased mucosal serotonin (5-hydroxytryptamine [5-HT]) availability, possibly because immune activation reduces activity of the 5-HT transporter (SERT). We investigated the relationship between mucosal and platelet SERT and immune activation of the duodenal mucosa in patients with IBS-D. METHODS: We quantified mucosal intraepithelial lymphocytes (IELs), mast cells, and enterochromaffin cells in blood samples, measured levels of SERT messenger RNA (mRNA) in mucosal samples, and assessed platelet uptake of 5-HT and platelet membrane binding of (3)H-paroxetine in samples from 29 healthy volunteers (HVs), 20 patients with IBS-D, and 20 untreated patients with celiac disease. RESULTS: Patients with IBS-D or celiac disease had increased numbers of IELs and mast cells compared with HVs (both P < .001). Levels of SERT mRNA were reduced in the mucosa of patients with IBS-D or celiac disease and were inversely correlated with numbers of IELs (r = -0.72, P < .0001). Uptake of 5-HT by platelets from patients with IBS-D or celiac disease was reduced (mean, 17.1 ± 3.5 and 28.3 ± 4.1 nmol·min(-1)·mg(-1), respectively) compared with HVs (50.8 ± 8.0 nmol·min(-1)·mg(-1), P < .01 and P = .05, respectively). Binding of paroxetine to membranes of platelets from patients with IBS-D (median [interquartile range], 226 [92-405] fmol/mg protein) was significantly greater than that from HVs (109 [69-175] fmol/mg protein) and correlated inversely with platelet uptake of 5-HT (r = -0.62, P = .03). Tryptase release from incubated biopsy samples was significantly increased in patients with IBS-D (2.2 [0.42-3.5] vs 0.50 [0.25-0.86] ng·mL(-1)·mg(-1) for HVs; P = .03). CONCLUSIONS: Platelet SERT is reduced in IBS-D and associated with reduced levels of SERT mRNA and duodenal immune activation.

Postinfectious irritable bowel syndrome.

Approximately 1 in ten patients with irritable bowel syndrome (IBS) believe their IBS began with an infectious illness. Prospective studies have shown that 3% to 36% of enteric infections lead to persistent new IBS symptoms; the precise incidence depends on the infecting organism. Whereas viral gastroenteritis seems to have only short-term effects, bacterial enteritis and protozoan and helminth infections are followed by prolonged postinfective IBS (PI-IBS). Risk factors for developing PI-IBS include, in order of importance, prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse life events in the preceding 3 months. Age older than 60 years might protect against PI-IBS, whereas treatment with antibiotics has been associated with increased risk. The mechanisms that cause PI-IBS are unknown but could include residual inflammation or persistent changes in mucosal immunocytes, enterochromaffin and mast cells, enteric nerves, and the gastrointestinal microbiota. Adverse psychological factors contribute to persistent low-grade inflammation. The prognosis for patients with PI-IBS is somewhat better than for those with unselected IBS, but PI-IBS can still take years to resolve. There are no specific treatments for PI-IBS; these should be tailored to the predominant bowel disturbance, which is most frequently diarrhea.

Comparison of high-resolution magnification narrow-band imaging and white-light endoscopy in the prediction of histology in Barrett's oesophagus.

OBJECTIVE: To evaluate whether there is any appreciable difference in imaging characteristics between high-resolution magnification white-light endoscopy (WLE-Z) and narrow-band imaging (NBI-Z) in Barrett's oesophagus (BE) and if this translates into superior prediction of histology. MATERIAL AND METHODS: This was a prospective single-centre study involving 21 patients (75 areas, corresponding NBI-Z and WLE-Z images) with BE. Mucosal patterns (pit pattern and microvascular morphology) were evaluated for their image quality on a visual analogue scale (VAS) of 1-10 by five expert endoscopists. The endoscopists then predicted mucosal morphology based on four subtypes which can be visualized in BE. Type A: round pits, regular microvasculature; type B: villous/ridge pits, regular microvasculature; type C: absent pits, regular microvasculature; type D: distorted pits, irregular microvasculature. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were then compared with the final histopathological analysis and the interobserver variability calculated. RESULTS: The overall pit and microvasculature quality was significantly higher for NBI-Z, pit: NBI-Z=6, WLE-Z=4.5, p < 0.001; microvasculature: NBI-Z=7.3, WLE-Z=4.9, p < 0.001. This translated into a superior prediction of histology (Sn: NBI-Z: 88.9, WLE-Z: 71.9, p < 0.001). For the prediction of dysplasia, NBI-Z was superior to WLE-Z (chi(2)=10.3, p < 0.05). The overall kappa agreement among the five endoscopists for NBI-Z and WLE-Z, respectively, was 0.59 and 0.31 (p < 0.001). CONCLUSIONS: NBI-Z is superior to WLE-Z in the prediction of histology in BE, with good reproducibility. This novel imaging modality could be an important tool for surveillance of patients with BE.

The clinical utility and diagnostic yield of routine gastric biopsies in the investigation of iron deficiency anemia: a case-control study.

AIMS: To audit our experience with gastrointestinal investigation of iron deficiency anemia (IDA) and assess whether gastric atrophy associates with and likely causes it. METHODS: This is a case-control study in a large U.K. teaching hospital. In total, 161 unselected patients undergoing routine investigation for iron deficiency anemia were submitted for the study, of which 5 were excluded for lack of appropriate biopsies. In total, 169 patients identified retrospectively from pathology records who had appropriate biopsies with a normal hemoglobin and no evidence of iron deficiency constituted the control group. In the group with anemia, a further internal case-control study compared cases where no definite cause for anemia was detected with controls who had a definite accepted cause for anemia. The gastric pathology, especially the presence and degree of body atrophy, was assessed by a single pathologist in both groups. Other factors including age, sex, and Helicobacter pylori infection were also evaluated. RESULTS: The mean age of the cases was 68 yr (95% confidence interval [CI] 34-102), and for the controls, it was 53 yr (95% CI 19-87). In the patients with anemia, 40 of 156 (25.6%) had significant body atrophy compared with just 7 of 169 (4.6%) of controls (P < 0.001). In a multivariate analysis, only significant body atrophy, odds ratio (OR) of 7.6 (3.1-18.6), and age, OR 1.048/yr (1.032-1.064), emerged as significant factors predicting anemia. In the cases, 35 of 156 (22%) patients had another definite cause of anemia. Of these, only 3 of 35 (9%) had significant atrophy, significantly less than the 37 of 121 (31%) without another definite cause (P = 0.008). In this anemic group, there was no difference in age between those with and without atrophy. CONCLUSIONS: Gastric atrophy is strongly associated with IDA, and this is likely to be causative in some patients and contributory in others. Gastric biopsies, especially from the corpus, may provide valuable information in the investigation of IDA.

Can oats be taken in a gluten-free diet? A systematic review.

OBJECTIVE: There has long been doubt about the need to exclude oats from a gluten-free diet (GFD). The objective of this study was to review the literature in order to arrive at a firm recommendation. MATERIAL AND METHODS: Electronic databases were searched up to February 2006 using the terms "oats" and "coeliac disease". RESULTS: Twenty relevant studies were found and presented. Early studies were small and uncontrolled and mostly indirect. In 10 studies involving 165 patients, only 1 patient was shown to have histological damage as a result of consuming oats. CONCLUSIONS: Coeliac patients can, to some advantage, include oats in a GFD although there may be the occasional patient who is also oats sensitive. Previous conflicting results may have been partly due to contamination of oats by wheat. Lest contamination is present and exceeds the safe threshold, we recommend that coeliac patients should only add oats to their GFD when they are established on a conventional GFD, and stop eating oats if they develop any symptoms.