Gareth Parkes

Review article: lactose intolerance in clinical practice – myths and realities

Background  Approximately 70% of the world population has hypolactasia, which often remains undiagnosed and has the potential to cause some morbidity. However, not everyone has lactose intolerance, as several nutritional and genetic factors influence tolerance.

Gastrointestinal microbiota in irritable bowel syndrome: Their role in its pathogenesis and treatment

Irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain, change in bowel habit, and bloating. It has traditionally been viewed as a disorder of visceral hypersensitivity heavily influenced by stress, and therefore therapeutic strategies to date have largely reflected this. However, more recently, there is good evidence for a role of the gastrointestinal (GI) microbiota in its pathogenesis. Changes in fecal microbiota, the use of probiotics, the phenomenon of postinfectious IBS, and the recognition of an upregulated host immune system response suggest that an interaction between the host and GI microbiota may be important in the pathogenesis of IBS. This article explores the role of the GI microbiota in IBS and how their modification might lead to therapeutic benefit.

Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome

Background  There is increasing evidence to support a role for the gastrointestinal microbiota in the etiology of irritable bowel syndrome (IBS). Given the evidence of an inflammatory component to IBS, the mucosa‐associated microbiota potentially play a key role in its pathogenesis. The objectives were to compare the mucosa‐associated microbiota between patients with diarrhea predominant IBS (IBS‐D), constipation predominant IBS (IBS‐C) and controls using fluorescent in situ hybridization and to correlate specific bacteria groups with individual IBS symptoms.

The mechanisms and efficacy of probiotics in the prevention of Clostridium difficile-associated diarrhoea

The proportion and severity of Clostridium difficile-associated diarrhoea (CDAD) is increasing in health-care settings. Antibiotics remain the most important risk factor for CDAD, due to their limiting the ability of the gastrointestinal flora to inhibit C difficile colonisation. Probiotics have therefore been investigated for primary and secondary prophylaxis against CDAD, with varying success. This Review looks at the current literature for in-vitro and clinical evidence for probiotic use in the prevention of CDAD. Its aim is to examine the mechanisms through which probiotics interact with C difficile and its toxin, and the association of these mechanisms with the clinical evidence for probiotics in the prevention of this disease. The Review briefly describes the recent epidemiological changes in C difficile disease, and our current understanding of its pathophysiology. It looks at the safety profile of probiotics, highlighting patients groups in which their use is inappropriate, and attempts to synthesise guidance for clinicians interested in using probiotics to prevent CDAD within health-care institutions.

Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease

DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohns disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10−5 to 1.40 × 10−9), and that the CNV and the 5′-untranslated region variant −308(GTTT)5 contribute independently to CD susceptibility (P = 2.6 × 10−7 and P = 2 × 10−5, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10−12) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case–control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene–gene or gene–environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European–Asian split.

Quantification and characterization of mucosa-associated and intracellular Escherichia coli in inflammatory bowel disease.

Background:Mucosa-associated Escherichia coli are abundant in inflammatory bowel disease (IBD), but whether these bacteria gain intracellular access within the mucosa is uncertain. If E. coli does gain intracellular access, the contribution of bacterial pathogenicity to this requires further elucidation. This study aimed to quantify and characterize mucosa-associated and intracellular E. coli in patients with IBD and in healthy control subjects (HC). Methods:Mucosal biopsies from 30 patients with Crohns disease (CD), 15 with ulcerative colitis (UC), and 14 HC were cultured with or without gentamicin protection to recover intracellular or mucosa-associated E. coli, respectively. Overall, 40 strains (CD: n = 24, UC: n = 9, and HC: n = 7) were characterized by phylogenetic typing, adhesion and invasion assays, detection of virulence factors, antimicrobial resistance genes, and proteomic analysis. Results:Mucosa-associated E. coli were more abundant in CD and UC than in HC (2750 versus 1350 versus 230 median colony-forming units per biopsy; P = 0.01). Intracellular E. coli were more prevalent in CD (90%) than in UC (47%) or HC mucosal biopsies (0%) (P < 0.001). Of 24 CD strains, 2 were adherent and invasive, but there were no unifying pathogenicity determinants that could distinguish most CD strains from UC or HC strains, or intracellular isolates from mucosa-associated isolates. Conclusions:Intracellular E. coli are more common in CD than in UC and not identified in HC. Most intracellular E. coli did not have characterizing pathogenic features, suggesting a significant role for defects in mucosal immunity or barrier dysfunction in their ability to gain intracellular access.

Chapter 30 – The Role of Probiotics in the Treatment of Irritable Bowel Syndrome

Publisher Summary This chapter aims to explore a mechanistic framework behind how probiotics might be of benefit in irritable bowel syndrome (IBS). It reviews current clinical trials of probiotics in the treatment of IBS with a view to synthesizing guidance for the healthcare professional. IBS is a gastroenterological condition characterized by a triad of abdominal pain, bloating and change in bowel habit with an absence of any overt mucosal abnormality. There is an increasing interest in the role of probiotics in IBS. Because of the widespread prevalence of the disorder, there has also been a corresponding growth in advertising of probiotic products, aimed at the general public, and targeting common IBS symptoms such as slow transit and bloating. There is now sufficient evidence to suggest the use of certain, species-specific probiotics in the treatment of IBS. B. infantis 35624 and E. coli DSM 17252 have shown, in more than one trial, to significantly reduce symptom burden in IBS. In addition, there is limited evidence for the use of the combination probiotic containing L. rhamnosus GG, L. rhamnosus LC705, B. breve, Propionibacterium freudenreichii spp., and Shermanii JS. Probiotics offer a safe, sustainable method of manipulating the GI microbiota in IBS and producing symptomatic relief.

Increases in ileal mast cells in patients with diarrhoea predominant irritable bowel syndrome may be due to a relative reduction in mucosa-associated lactobacilli

Introduction There is substantial evidence for gastrointestinal (GI) immune upregulation and altered GI microbiota in patients with irritable bowel syndrome (IBS). The aim was to compare the immune cell populations in patients with IBS and controls and to correlate differences with the adjacent microbiota in small and large intestine. Methods Patients with IBS (Rome III) and healthy controls were recruited. Patients underwent ileocolonoscopy at which paired ileal and rectal biopsies were snap frozen. Rectal microbiota analysis was performed using FISH.1 Ileal microbiota analysis was performed on an adjacent biopsy using qPCR.2 Immunohistochemistry on sections cut from the same biopsy was used to enumerate mast cells, intra-epithelial and lamina-propria lymphocytes and macrophages. Symptom data was recorded using a validated questionnaire. Results 37 patients with IBS (27 diarrhoea predominant (IBS-D) and 10 constipation predominant (IBS-C)) and 23 healthy controls were recruited. There were significantly more mast cells in the rectum and ileum in the IBS-D group than in IBS-C and controls median; see figure 1. There was a inverse correlation between the number of ileal mast cells and the number of mucosa-associated lactobacilli (p = 0.005). The severity of diarrhoea positively correlated with the number of rectal macrophages (p = 0.001), mast cells (p = 0.02) and IELs (p = 0.01). Figure 1 OC-077 The median number of mast cells per high powered fields in the ileum and rectum of patients with IBS and controls Conclusion This is the first data to correlate alterations in the mucosa-associated microbiota with the adjacent immune cells in IBS. Increases in ileal mast cells in patients with IBS-D maybe due to reductions in adjacent lactobacilli. Increasing severity of diarrhoea positively correlated with increases in rectal mucosal immune cell populations

OC-026 Prebiotic b-galacto-oligosaccharides in conjunction with the low fodmap diet improves symptoms of irritable bowel syndrome but does not prevent decline of bifidobacteria: a randomised controlled trial

Introduction Dietary restriction of fermentable oligo-, di-, mono -saccharides and polyols (low FODMAP diet, LFD) is widely used for the management of irritable bowel syndrome (IBS), however it reduces gastrointestinal (GI) bifidobacteria. B-galacto-oligosaccharide (B-GOS; HOST-G904) are prebiotics that reduce symptoms and increase bifidobacteria in IBS however the combination of the two therapies has not previously been investigated. Method This randomised controlled trial aimed to investigate whether: 1) IBS symptoms improved on LFD supplemented with B-GOS compared to control; and 2) B-GOS could prevent the reduction of GI bifidobacteria seen in patients following the LFD. Adults fulfilling Rome criteria for IBS were screened (n=130). Sixty-nine patients were recruited to a multicentre 3-arm parallel RCT and were randomised to: control (sham diet/placebo), LFD only (LFD/placebo) or LFD plus B-GOS (LFD/B-GOS) for four weeks. Validated questionnaires were used to assess GI symptoms at week 0 and week 4 and a stool sample collected for analysis at week 0, week 1 and week 4. Stool were analysed for bifidobacteria using fluorescent in situ hybridisation, and short-chain fatty acids (SCFA) and pH were measured using gas chromatography and pH probe respectively. Logistic regression, and ANOVA/ANCOVA (with post-hoc correction) were used to determine differences across the three groups. Results At week 4 adequate relief of IBS symptoms differed significantly between control (30.4%), LFD (50%) and LFD/B-GOS (66.7%) (p=0.046), with post-hoc differences specifically between control and LFD/B-GOS (p=0.015). Individual IBS symptoms were more markedly improved in the LFD/B-GOS group compared to control. Bifidobacteria (log10/g dry weight) also differed across the groups (control 9.8, LFD 9.6, LFD/B-GOS 9.5; p=0.009), with post-hoc differences between the LFD/B-GOS and control at week 4 (p=0.009) Higher stool pH, and lower butyrate at week 1 and week 4 were observed in the LFD vs control diet group. Similar differences were observed in the LFD/B-GOS vs control diet group although pH was not higher than control until week 4. Conclusion Symptoms of IBS markedly improved during LFD supplemented with B-GOS prebiotic, suggesting a synergy between the two therapies. The LFD significantly impacts the GI luminal environment within the first seven days and these changes persist with diet restriction, however addition of a low dose prebiotic does not overcome the effect of diet on bifidobacteria. Disclosure of Interest B. Wilson Conflict with: BW is the recipient of a PhD fellowship awarded by Clasado BioSciences., M. Rossi: None Declared, G. Parkes: None Declared, Q. Aziz: None Declared, S. Anderson: None Declared, P. Irving: None Declared, M. Lomer: None Declared, K. Whelan: None Declared

Mo1842 Excess Steroid Use in IBD: Too Much, How Much and Why? Results From a UK Nationwide Audit

Introduction Corticosteroids are the cornerstone of inducing remission in IBD but are limited in their ability to maintain remission, and associated with significant side effects. This is the first nationwide outpatient study of steroid use in IBD and factors affecting their use. Methods We audited consecutive IBD patients attending clinics at 11 centres over 3 months using a web-based assessment tool. Cases meeting criteria for steroid excess (SE) as defined by ECCO guidelines were blind peer reviewed and classified as non-IBD use, unavoidable and inappropriate steroid excess (ISE). Associations between steroid use and patient and institutional factors were analysed. Results Of 1177 patients [48% CD, 49% UC, 3% IBD-U] 79% were in remission/mild disease, 18.5% had moderate and 2.5% severe disease. In the previous 12 months, 30% had received steroids, 13.8% had SE. Peer review revealed that SE was inappropriate in 51.2% of these (8% non-IBD use; 40.7% unavoidable). Excess steroid exposure was more common in patients with active UC compared to active CD (41.6% vs 26.6%; p = 0.02). In multivariate analysis, disease activity was a significant predictor of SE/ISE. In addition, being established on anti-TNF agents protected against SE and ISE in CD. Exposure to thiopurine (SE + ISE) and starting anti-TNF therapy (ISE) were associated with excess steroid use in UC. CD patients from centres with an IBD MDT were less likely to have SE, similarly CD patients in centres with combined surgical clinics were less likely to experience SE and ISE. Care in centres with dedicated IBD clinics was associated with less SE and ISE in patients with UC. Centres with large numbers of GI trainees showed higher rates of SE in UC and SE and ISE in CD. (All of above independent predictors on multi-variate with significance p Conclusion We identified inappropriate excess steroid use in 7% of UK IBD patients. Risk factors for steroid exposure differed between UC and CD, likely reflecting inter alia , differences in access to biologic drugs. Our study is the first to demonstrate positive effects of service configurations (IBD MDT, dedicated IBD clinics, combined surgical clinics) on treatment outcomes even after correction for differences in disease severity. There was an association between ISE in Crohn’s and the number of GI trainees per centre suggesting possible gaps in training. Routine recording of excess steroid exposure is feasible and should be considered as a quality marker for outcomes of IBD services. Disclosure of Interest None Declared