Klara Garsed

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.

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 patients 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.

Narrow-band imaging with magnification in Barrett's esophagus: validation of a simplified grading system of mucosal morphology patterns against histology.

BACKGROUND AND STUDY AIMS Validation of a simplified classification of mucosal morphology in prediction of histology in Barretts esophagus using narrow-band imaging with magnification (NBI-Z) and assessing its reproducibility by endoscopists experienced in the use of NBI (NBI-experts) and by endoscopists who were new to NBI (non-NBI-experts). PATIENTS AND METHODS In a prospective cohort study of 109 patients with Barretts esophagus at a single tertiary referral center, mucosal patterns visualized in Barretts esophagus on NBI-Z were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI-Z grading was compared with the final histopathological diagnosis, and positive (PPV) and negative predictive values (NPV) were calculated. The reproducibility of the grading was then assessed by NBI-expert and non-NBI-expert endoscopists, and interobserver and intraobserver agreement were calculated using kappa statistics. RESULTS Per-biopsy analysis: In 903 out of 1021 distinct areas (87.9%) the NBI-Z grading corresponded to the histological diagnosis. Per-patient analysis: The PPV and NPV for type A pattern (columnar mucosa without intestinal metaplasia) were 100% and 97% respectively; for types B and C (intestinal metaplasia) they were 88% and 91% respectively, and for type D (high-grade dysplasia) 81% and 99% respectively. Inter- and intraobserver agreement: The mean kappa values in assessing the various patterns were 0.71 and 0.87 in the non-expert group; 0.78 and 0.91 in the expert group. CONCLUSIONS This study has validated a simplified classification of the various morphologic patterns visualized in Barretts esophagus and confirmed its reproducibility when used by NBI-expert and non-NBI-expert endoscopists.

Infection, inflammation, and the irritable bowel syndrome

Gastrointestinal infection is ubiquitous worldwide though the pattern of infection varies widely. Poor hygiene and lack of piped water is associated with a high incidence of childhood infection, both viral and bacterial. However in developed countries bacterial infection is commoner in young adults. Studies of bacterial infections in developed countries suggest 75% of adults fully recover, however around 25% have long lasting changes in bowel habit and a smaller number develop the irritable bowel syndrome (IBS). Whether the incidence is similar in developing countries is unknown. Post-infective IBS (PI-IBS) shares many features with unselected IBS but by having a defined onset allows better definition of risk factors. These are in order of importance: severity of initial illness, smoking, female gender and adverse psychological factors. Symptoms may last many years for reasons which are unclear. They are likely to include genetic factors controlling the immune response, alterations in serotonin signaling, low grade mucosal inflammation maintained by psychological stressors and alterations in gut microbiota. As yet there are no proven specific treatments, though 5HT(3) receptor antagonists, anti-inflammatory agents and probiotics are all logical treatments which should be examined in large well-designed randomised placebo controlled trials.

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.

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.

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.

Fasting and postprandial volumes of the undisturbed colon: normal values and changes in diarrhea-predominant irritable bowel syndrome measured using serial MRI.

Previous assessments of colon morphology have relied on tests which were either invasive or used ionizing radiation. We aimed to measure regional volumes of the undisturbed colon in healthy volunteers (HV) and patients with diarrhea‐predominant irritable bowel syndrome (IBS‐D).

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. ClinicalTrials.gov NCT00745004.

Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose

Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo‐colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing.