Symptom classification in irritable bowel syndrome as a guide to treatment.

OBJECTIVE: The treatment of irritable bowel syndrome (IBS) remains unsatisfactory. There are no objective markers for diagnosis, and classification (currently based on symptoms) provides little insight into potential causes or optimal therapy. The aim of this study was to determine whether a Swedish classification of IBS based on cluster analysis of patients' symptoms might provide a guide to successful treatment. MATERIAL AND METHODS: Patients in a research clinic for IBS were classified according to criteria published by Ragnarsson & Bodemar (R&B) and also assessed independently by a clinician. Patients fulfilling the R&B criteria for subgroups 1 and 2 received specific treatments, either bulk laxatives or dietary treatment to reduce colonic fermentation, respectively. Patients who did not fit into these categories were given "best treatment" targeted at their predominant symptoms, but not limited in any way. Results before and after follow-up were assessed using a validated symptom-scoring scale. RESULTS: Seventy-one successive patients were recruited, and the numbers falling into R&B subgroups 1 and 2 were 15 (21%), and 28 (39%), respectively, leaving 28 (39%) unclassified. Receiver operating characteristic plots showed that the criteria for separation into subgroups 1 and 2 correlated well with the clinician's assessment. After treatment, symptom scores for the whole group showed a significant improvement (p<0.0001), but results were significantly better in subgroups 1 and 2 than in those unclassified, even when allowance was made for a potential therapeutic placebo effect of 40%. CONCLUSION: The R&B classification provides a helpful guide to treatment in many cases of IBS.

Interferon beta-1a for the maintenance of remission in patients with Crohn's disease: results of a phase II dose-finding study.

BACKGROUND: Crohn's disease (CD) and multiple sclerosis (MS) share common pathogenic processes. Interferon (IFN) beta-1a is effective and generally well tolerated in patients with MS and has been shown to down-regulate the expression of interleukin-12, a cytokine that is thought to be involved in mucosal degeneration in CD. IFN beta-1a therefore offers promise as a treatment for CD. METHODS: In this multicentre, double-blind, placebo-controlled, phase II, dose-finding study, patients with steroid-induced clinical remissions of CD were randomized 1:1:1:1 to subcutaneous IFN beta-1a: 66 mcg three times weekly (tiw), 44 mcg tiw, 44 mcg twice weekly (biw), or matching placebo tiw with steroid tapering. The primary endpoint was the proportion of patients relapse-free at Week 26. Safety was also assessed. RESULTS: This study was terminated early following a planned interim analysis at 26 weeks. Of the planned 192 patients, 67 were randomized to treatment: placebo (n = 16), or IFN beta-1a 44 mcg biw (n = 17), 44 mcg tiw (n = 16) or 66 mcg tiw (n = 18). In total, 20/67 patients (29.9%) completed 26 weeks and 7 patients (10.4%) completed 52 weeks. The proportion of patients who remained relapse-free at Week 26 did not differ significantly between the placebo group (5/16, 31%) and the IFN beta-1a 44 mcg biw (6/17, 35%; p = 0.497), 44 mcg tiw (7/16, 44%; p = 0.280) or 66 mcg tiw (2/18, 11%; p = 0.333) groups. There was little difference between treatment groups in secondary efficacy endpoints. IFN beta-1a was generally well tolerated at all doses. Adverse events (AEs) were generally mild or moderate in IFN beta-1a-treated patients, with the most common AEs (influenza-like symptoms, headache, injection-site reactions) being similar to those reported with IFN beta-1a in MS. CONCLUSION: There was no difference in efficacy between patients with CD receiving IFN beta-1a or placebo. However, these results should be considered in the context of the low patient numbers and high dropout rate. Overall, IFN beta-1a was generally well tolerated, with a safety profile that was consistent with previous experience in MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT00304252.

Effect of probiotics on preventing disruption of the intestinal microflora following antibiotic therapy: a double-blind, placebo-controlled pilot study.

In this pilot-scale, double-blind, placebo-controlled trial, 30 patients with Helicobacter pylori infection were randomised into three groups prior to their 7 days eradication therapy, to study the effects of probiotic supplement comprising Lactobacillus acidophilus and Bifidobacterium bifidum on the intestinal microflora in response to antibiotic therapy. Group I received the placebo product from day 1 to day 15, Group II received placebo from day 1 to day 7 and probiotics from day 8 to day 15 and Group III received probiotics from day 1 to day 15. Patients provided stool samples for analysis on days 1, 7, 12, 17 and 27. For patients in Groups I and II, significant increases in the facultative anaerobe component of the microflora occurred between days 1 and 7. In Group I, the numbers remained elevated to day 27 but in Group II, the numbers decreased significantly between days 7 and 27 back to the starting levels. In Group III, the facultative anaerobe population remained stable throughout. The total anaerobe numbers increased significantly at day 27 than at day 1 for Group I, were unchanged throughout for Group II and decreased significantly for the patients in Group III between days 1 and 7 before reverting to the starting levels by day 27. From these results, it can be seen that probiotic supplementation modulates the response of the intestinal microflora to the effects of antibiotic therapy.

Use of the Analysis of the Volatile Faecal Metabolome in Screening for Colorectal Cancer.

Diagnosis of colorectal cancer is an invasive and expensive colonoscopy, which is usually carried out after a positive screening test. Unfortunately, existing screening tests lack specificity and sensitivity, hence many unnecessary colonoscopies are performed. Here we report on a potential new screening test for colorectal cancer based on the analysis of volatile organic compounds (VOCs) in the headspace of faecal samples. Faecal samples were obtained from subjects who had a positive faecal occult blood sample (FOBT). Subjects subsequently had colonoscopies performed to classify them into low risk (non-cancer) and high risk (colorectal cancer) groups. Volatile organic compounds were analysed by selected ion flow tube mass spectrometry (SIFT-MS) and then data were analysed using both univariate and multivariate statistical methods. Ions most likely from hydrogen sulphide, dimethyl sulphide and dimethyl disulphide are statistically significantly higher in samples from high risk rather than low risk subjects. Results using multivariate methods show that the test gives a correct classification of 75% with 78% specificity and 72% sensitivity on FOBT positive samples, offering a potentially effective alternative to FOBT.

Derivation and identification of questions that act as predictors of abdominal pain of musculoskeletal origin.

OBJECTIVE: Although most causes of abdominal pain have a visceral origin, the musculoskeletal system must be considered when the cause is not obvious. This prospective study aimed to identify questions that would aid the diagnosis of patients with abdominal pain of musculoskeletal origin. DESIGN: Assessment of consecutive patients with abdominal pain recruited from gastroenterological outpatient clinics to develop diagnostic pointers to identify abdominal pain arising from musculoskeletal disorders. PARTICIPANTS: Subjects with benign abdominal pain, with or without a change in bowel habit, were recruited from gastroenterological clinics. Patients with inflammatory or neoplastic disease were excluded. SETTING: The study was conducted in the Physiotherapy Department, Addenbrooke's NHS Trust Hospital, Cambridge. MAIN OUTCOME MEASURES: A set of questions developed to indicate a musculoskeletal cause of a patient's abdominal symptoms. RESULTS The questions 'Does taking a deep breath aggravate your symptoms?' and 'Does twisting your back aggravate your symptoms?' had a significant positive indication of abdominal symptoms of musculoskeletal origin. The questions 'Has there been any change in bowel habit since onset of your symptoms?', 'Does eating foods aggravate your symptoms?' and 'Has there been any weight change since onset of symptoms?' had a significant negative indication for abdominal symptoms not of musculoskeletal origin. A combination of these questions gave 96% specificity and 67% sensitivity. CONCLUSION: These questions may help with the early identification of patients with abdominal pain of musculoskeletal origin and will be tested in further studies.

Evaluation of hydrogen excretion after lactulose administration as a screening test for causes of irritable bowel syndrome.

OBJECTIVE: To determine whether it is possible to separate cases of irritable bowel syndrome associated with excess total hydrogen production (as a surrogate of colonic fermentation; these patients may be offered an exclusion diet as treatment) from other causes of irritable bowel syndrome by determining the amount of hydrogen excreted on patients' breath after oral administration of lactulose. DESIGN: Comparison of 24-hour hydrogen excretion and breath hydrogen following lactulose in untreated patients fulfilling the Rome criteria for irritable bowel syndrome, normal controls and irritable bowel syndrome patients who had previously failed to improve on an exclusion diet. METHODS: Colonic fermentation was measured by indirect calorimetry over 24 h. Immediately after calorimetry, the patients who were fasting received 20 g lactulose; end-expiratory breath samples were then collected every 30 min for 3 h. Hydrogen concentrations were determined by an electro-chemical cell. RESULTS: The total 24-hour excretion of hydrogen was significantly greater in the irritable bowel syndrome group (median 333.7 ml/24 h, interquartile range 234.7-445.67) compared to the normal volunteers (median 203.1 ml/24 h, interquartile range 131.4-256; P = 0.002) or the failed-diet group (median 204.5 ml/24 h, interquartile range 111.35-289.13; P = 0.015). No difference was detected in breath excretion of hydrogen following lactulose in any group. CONCLUSION: Total hydrogen production over 24 h is increased in some patients with irritable bowel syndrome who may respond to exclusion diets. However, this sub-group of patients cannot be identified by measuring breath-hydrogen excretion after lactulose.

Immunoglobulin coating of faecal bacteria in inflammatory bowel disease.

OBJECTIVE: An inappropriate mucosal immune response to the commensal bacterial flora may play a role in the pathogenesis of inflammatory bowel disease (IBD). In this study we determined the percentage of immunoglobulin-coated bacteria in the stools of patients and controls. METHODS: Faecal samples were obtained from 18 patients with IBD (one sample during exacerbation and one shortly after remission was achieved), 15 healthy volunteers, eight infectious colitis patients, and 13 IBD patients in long-term remission. Bacterial immunoglobulin coating was determined by flow-cytometry analysis. Faecal alpha-1-antitrypsin concentrations were determined by radial immune diffusion. RESULTS: IBD patients had 69 +/- 19% immunoglobulin A (IgA)-, 56 +/- 32% immunoglobulin G (IgG)- and 56 +/- 29% immunoglobulin M (IgM)-coated bacteria in their faeces. Healthy controls had less immunoglobulin coating, respectively 36 +/- 12%, 11 +/- 4% and 11 +/- 7%. Infectious colitis patients had 57 +/- 14% IgA, 31 +/- 13% IgG, and 42 +/-16% IgM; however, they had higher faecal alpha-1-antitrypsin concentrations than IBD patients. Shortly after remission, IBD patients had 65 +/- 20% IgA, 32 +/- 18% IgG and 40 +/- 21% IgM. Long-term-remission IBD patients had normal IgG and IgM but increased IgA (50 +/- 16%) coating. CONCLUSIONS: Compared with healthy controls, patients with IBD had an increased percentage of immunoglobulin-coated faecal anaerobic bacteria, both in active disease and shortly after remission. These results support the concept that there may be a breakdown of mucosal tolerance to the commensal gut flora in IBD.

Analysis of volatile organic compounds of bacterial origin in chronic gastrointestinal diseases.

BACKGROUND: The aim of this study was to determine whether volatile organic compounds (VOCs) present in the headspace of feces could be used to diagnose or distinguish between chronic diseases of the gastrointestinal tract and apparently healthy volunteers. METHODS: A total of 87 people were recruited, divided between 4 categories: healthy volunteers (n = 19), Crohn's disease (n = 22), ulcerative colitis (n = 20), and irritable bowel syndrome (n = 26). They each supplied fecal samples before, and except for the healthy volunteers, after treatment. Fecal samples were incubated in a sample bag with added purified air at 40°C and headspace samples were taken and concentrated on thermal sorption tubes. Gas chromatography-mass spectrometry then desorbed and analyzed these. The concentrations of a selection of high-abundance compounds were determined and assessed for differences in concentration between the groups. RESULTS: Crohn's disease samples showed significant elevations in the concentrations of ester and alcohol derivates of short-chain fatty acids and indole compared with the other groups; indole and phenol were elevated in ulcerative colitis and irritable bowel syndrome but not at a statistically significant level. After treatment, the levels of many of the VOCs were significantly reduced and were more similar to those concentrations in healthy controls. CONCLUSIONS: The abundance of a number of VOCs in feces differs markedly between Crohn's disease and other gastrointestinal conditions. Following treatment, the VOC profile is altered to more closely resemble that of healthy volunteers.

Diversity and distribution of sulphate-reducing bacteria in human faeces from healthy subjects and patients with inflammatory bowel disease.

The relative abundance of different groups of sulphate-reducing bacteria (SRB) in faecal DNA collected before and after therapy from patients suffering from Crohn's disease (CD), irritable bowel syndrome (IBS) or ulcerative colitis (UC) has been compared with that from healthy controls. Growth tests revealed that SRB were not more abundant in samples from patients with CD before treatment than in the healthy control group. For most of the 128 samples available, these preliminary results were confirmed using degenerate PCR primers that amplify the dsrAB gene. However, some samples from patients with CD before treatment contained a growth inhibitor that was absent from IBS or UC samples. In-depth sequencing of PCR-generated dsrB fragments revealed that the diversity detected was surprisingly low, with only eight strains of SRB and the sulphite-reducing bacterium, Bilophila wadsworthia, detected above the 0.1% threshold. The proportion of the two major species detected, B. wadsworthia and Desulfovibrio piger, was as high as 93.5% of the total SRB population in the healthy control group and lower in all patient groups. Four previously undescribed species were found: it is impossible to predict whether they are sulphate or sulphite-reducing bacteria.

Is the abundance of Faecalibacterium prausnitzii relevant to Crohn's disease?

Reports that bacteria within the Firmicutes phylum, especially the species Faecalibacterium prausnitzii, are less abundant in Crohn's disease (CD) patients and supernatants from cultures of this bacterium are anti-inflammatory prompted the investigation of the possible correlations between the abundance of F. prausnitzii and the response to treatment in patients with gut diseases and healthy controls. In a randomized, double-blind trial, faeces were collected from healthy volunteers, and from patients with active CD, ulcerative colitis (UC) and irritable bowel syndrome before and after treatment. The levels of F. prausnitzii DNA in faecal suspensions were determined by PCR. Treatment by an elemental diet was effective, resulting in decreases in both the Harvey and Bradshaw index (P<0.001) and the concentrations of serum C-reactive protein (P<0.05). The total levels of F. prausnitzii in faecal samples from CD patients at presentation were lower than those in the other groups both before and after the treatment. There was no correlation between F. prausnitzii abundance and the severity of CD before treatment. Clinical improvement unexpectedly correlated with a significant decrease in the abundance of F. prausnitzii, especially the A2-165 subgroup (P<0.05). Our data suggest that a paucity of F. prausnitzii in the gastrointestinal microbial communities is likely to be a minor aetiological factor in CD: recovery following elemental diet is attributed to lower levels of gut flora.

Do interventions which reduce colonic bacterial fermentation improve symptoms of irritable bowel syndrome?

Abnormal fermentation may be an important factor in irritable bowel syndrome (IBS). Gastroenteritis or antibiotic therapy may damage the colonic microflora, leading to increased fermentation and the accumulation of gas. Gas excretion may be measured by whole-body calorimetry but there has only been one such study on IBS to date. We aimed to assess the relationship between IBS symptoms and fermentation rates in IBS. A purpose-built, 1.4-m3, whole-body calorimeter was used to assess excretion of H2 and CH4 in IBS subjects while consuming a standard diet and, again, after open randomization on either the standard diet together with the antibiotic metronidazole or a fiber-free diet to reduce fermentation. Metronidazole significantly reduced the 24-hr excretion of hydrogen (median value compared to the control group, 397 vs 230 ml/24 hr) and total gas (H2 + CH4; 671 vs 422 ml/min) and the maximum rate of gas excretion (1.6 vs 0.8 ml/min), as did a no-fiber polymeric diet (hydrogen, 418 vs 176 ml/min; total gas, 564 vs 205 ml/min; maximum rate of gas excretion, 1.35 vs 0.45 ml/min), with a significant improvement in abdominal symptoms. IBS may be associated with rapid excretion of gaseous products of fermentation, whose reduction may improve symptoms.