Showing papers in "Alimentary Pharmacology & Therapeutics in 2015"

Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection.

Abstract: SummaryBackground Faecal microbiota transplantation (FMT) from healthy donors is considered an effective treatment against recurrent Clostridium difficile infection. Aim To study the effect of FMT via colonoscopy in patients with recurrent C. difficile infection compared to the standard vancomycin regimen. Methods In an open-label, randomised clinical trial, we assigned subjects with recurrent C. difficile infection to receive: FMT, short regimen of vancomycin (125 mg four times a day for 3 days), followed by one or more infusions of faeces via colonoscopy; or vancomycin, vancomycin 125 mg four times daily for 10 days, followed by 125–500 mg/day every 2–3 days for at least 3 weeks. The latter treatment did not include performing colonoscopy. The primary end point was the resolution of diarrhoea related to C. difficile infection 10 weeks after the end of treatments. Results The study was stopped after a 1-year interim analysis. Eighteen of the 20 patients (90%) treated by FMT exhibited resolution of C. difficile-associated diarrhoea. In FMT, five of the seven patients with pseudomembranous colitis reported a resolution of diarrhoea. Resolution of C. difficile infection occurred in 5 of the 19 (26%) patients in vancomycin (P < 0.0001). No significant adverse events were observed in either of the study groups. Conclusions Faecal microbiota transplantation using colonoscopy to infuse faeces was significantly more effective than vancomycin regimen for the treatment of recurrent C. difficile infection. The delivery of donor faeces via colonoscopy has the potential to optimise the treatment strategy in patients with pseudomembranous colitis.

Review Article: Dietary Fibre-Microbiota Interactions

Abstract: Background Application of modern rapid DNA sequencing technology has transformed our understanding of the gut microbiota. Diet, in particular plant‐based fibre, appears critical in influencing the composition and metabolic activity of the microbiome, determining levels of short‐chain fatty acids (SCFAs) important for intestinal health.

Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome

Abstract: SummaryBackground A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h. Aim To determine the efficacy of a low FODMAP diet in childhood IBS and whether gut microbial composition and/or metabolic capacity are associated with its efficacy. Methods In a double-blind, crossover trial, children with Rome III IBS completed a 1-week baseline period. They then were randomised to a low FODMAP diet or typical American childhood diet (TACD), followed by a 5-day washout period before crossing over to the other diet. GI symptoms were assessed with abdominal pain frequency being the primary outcome. Baseline gut microbial composition (16S rRNA sequencing) and metabolic capacity (PICRUSt) were determined. Metagenomic biomarker discovery (LEfSe) compared Responders (≥50% decrease in abdominal pain frequency on low FODMAP diet only) vs. Nonresponders (no improvement during either intervention). Results Thirty-three children completed the study. Less abdominal pain occurred during the low FODMAP diet vs. TACD [1.1 ± 0.2 (SEM) episodes/day vs. 1.7 ± 0.4, P < 0.05]. Compared to baseline (1.4 ± 0.2), children had fewer daily abdominal pain episodes during the low FODMAP diet (P < 0.01) but more episodes during the TACD (P < 0.01). Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity (e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii) and three Kyoto Encyclopedia of Genes and Genomes orthologues, of which two relate to carbohydrate metabolism. Conclusions In childhood IBS, a low FODMAP diet decreases abdominal pain frequency. Gut microbiome biomarkers may be associated with low FODMAP diet efficacy. ClinicalTrials.gov identifier: NCT01339117.

Chemotherapy‐driven dysbiosis in the intestinal microbiome

Abstract: Summary Background Chemotherapy is commonly used as myeloablative conditioning treatment to prepare patients for haematopoietic stem cell transplantation (HSCT). Chemotherapy leads to several side effects, with gastrointestinal (GI) mucositis being one of the most frequent. Current models of GI mucositis pathophysiology are generally silent on the role of the intestinal microbiome. Aim To identify functional mechanisms by which the intestinal microbiome may play a key role in the pathophysiology of GI mucositis, we applied high-throughput DNA-sequencing analysis to identify microbes and microbial functions that are modulated following chemotherapy. Methods We amplified and sequenced 16S rRNA genes from faecal samples before and after chemotherapy in 28 patients with non-Hodgkin's lymphoma who received the same myeloablative conditioning regimen and no other concomitant therapy such as antibiotics. Results We found that faecal samples collected after chemotherapy exhibited significant decreases in abundances of Firmicutes (P = 0.0002) and Actinobacteria (P = 0.002) and significant increases in abundances of Proteobacteria (P = 0.0002) compared to samples collected before chemotherapy. Following chemotherapy, patients had reduced capacity for nucleotide metabolism (P = 0.0001), energy metabolism (P = 0.001), metabolism of cofactors and vitamins (P = 0.006), and increased capacity for glycan metabolism (P = 0.0002), signal transduction (P = 0.0002) and xenobiotics biodegradation (P = 0.002). Conclusions Our study identifies a severe compositional and functional imbalance in the gut microbial community associated with chemotherapy-induced GI mucositis. The functional pathways implicated in our analysis suggest potential directions for the development of intestinal microbiome-targeted interventions in cancer patients.

Systematic review: dietary fibre and FODMAP‐restricted diet in the management of constipation and irritable bowel syndrome

Abstract: SummaryBackground Dietary fibre supplements have been advocated for the management of chronic constipation (CC) and irritable bowel syndrome (IBS). Recently, a fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) restricted diet has been recommended for IBS. Aim To systematically examine recent evidence for dietary interventions with fibre in CC and IBS and FODMAP-restricted diet in IBS, and provide recommendations. Methods We searched PUBMED, MEDLINE, OVID and COCHRANE databases from 2004 to 2014. Published studies in adults with CC and IBS and constipation-predominant IBS (IBS-C) that compared fibre with placebo/alternative and FODMAP-restricted diet with alternative were included. Results Of 550 potentially eligible clinical trials on fibre, 11 studies were found and of 23 potentially eligible studies on FODMAPs, six were found. A meta-analysis was not performed due to heterogeneity and methodological quality. Fibre was beneficial in 5/7 studies in CC and 3/3 studies in IBS-C. FODMAP-restricted diet improved overall IBS symptoms in 4/4 and IBS-C symptoms in 1/3 studies and three studies did not meet inclusion criteria. There were significant disparities in subject selection, interventions and outcome assessments in both fibre and FODMAPs studies. Conclusions Fibre supplementation is beneficial in mild to moderate CC and IBS-C, although larger, more rigorous and long-term RCTs are needed (Fair evidence–Level II, Grade B). Although the FODMAP-restricted diet may be effective in short-term management of selected patients with IBS (Fair evidence–Level II, Grade C) and IBS-C (Poor evidence–Level III, Grade C), more rigorous trials are needed to establish long-term efficacy and safety, particularly on colonic health and microbiome.

Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects--a randomised open-label cross-over study.

Abstract: SummaryBackground Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. Vonoprazan is a member of a new class of acid suppressants; potassium-competitive acid blockers. Vonoprazan may thus be an alternative to PPIs. Aim To evaluate efficacy, rapidity and duration of acid-inhibitory effects of vonoprazan vs. two control PPIs, esomeprazole and rabeprazole, in 20 healthy Japanese adult male volunteers with CYP2C19 extensive metaboliser genotype. Methods In this randomised, open-label, two-period cross-over study, vonoprazan 20 mg and esomeprazole 20 mg (Study V vs. E) or rabeprazole 10 mg (Study V vs. R) were orally administered daily for 7 days. Primary pharmacodynamic endpoint was gastric pH over 24 h measured as percentage of time pH ≥3, ≥4 and ≥5 (pH holding time ratios; HTRs) and mean gastric pH. Results Acid-inhibitory effect (pH4 HTR) of vonoprazan was significantly greater than that of esomeprazole or rabeprazole on both Days 1 and 7; Day 7 difference in pH4 HTR for vonoprazan vs. esomeprazole was 24.6% [95% confidence interval (CI): 16.2–33.1] and for vonoprazan vs. rabeprazole 28.8% [95% CI: 17.2–40.4]. The Day 1 to Day 7 ratio of 24-h pH4 HTRs was >0.8 for vonoprazan, compared with 0.370 for esomeprazole and 0.393 for rabeprazole. Vonoprazan was generally well tolerated. One vonoprazan subject withdrew due to a rash which resolved after discontinuation. Conclusions This study demonstrated a more rapid and sustained acid-inhibitory effect of vonoprazan 20 mg vs. esomeprazole 20 mg or rabeprazole 10 mg. Therefore, vonoprazan may be a potentially new treatment for acid-related diseases.

Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed

Abstract: SummaryBackground One-third of patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving anti-TNFs do not respond to treatment, and a relevant proportion experience loss of response or intolerance. Aim To investigate the efficacy and safety of a second anti-TNF agent after primary/secondary failure or intolerance to a first drug. Methods Inclusion criteria: studies evaluating the efficacy of infliximab (IFX), adalimumab (ADA) and certolizumab-pegol (CZP) as the second anti-TNF in CD or UC. Search strategy: Bibliographical searches (PubMed/Embase). Data synthesis: percentage of response/remission; the meta-analysis was performed using the inverse variance method. Results We included 46 studies (37 CD, 8 UC, 1 pouchitis). The CD studies comprised 32 switching IFX→ADA, 4 IFX→CZP and 1 ADA→IFX. Overall, the second anti-TNF after the failure of IFX in CD induced remission in 43% and response in 63% of patients. The remission rate was higher when the reason to withdraw the first anti-TNF was intolerance (61%) than after secondary (45%) or primary failure (30%); response rates were, respectively, 72%, 62% and 53%. All UC studies switched IFX→ADA, six of them reporting remission rates ranging from 0% to 50%. Adverse events rate ranged from 0% to 81% in CD, most of them mild (serious adverse event 0–21%, discontinuation rate <20%). Conclusions The efficacy of a second anti-TNF in CD patients largely depends on the cause for switching. The remission rate is higher when the reason to withdraw the first anti-TNF is intolerance (61%), compared with secondary (45%) or primary failure (30%). Further studies of switch ADA→IFX are needed to evaluate this strategy. PROSPERO-registry-number: CRD42014012943.

Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey.

Abstract: SummaryBackground Validated non-invasive measures of fatty liver are needed that can be applied across populations and over time. A fatty liver index (FLI) including body mass index, waist circumference, triglycerides and gamma glutamyltransferase (GGT) activity was developed in an Italian municipality, but has not been validated widely or examined in a multiethnic population. Aims We evaluated this FLI in the multiethnic U.S. National Health and Nutrition Examination Survey (NHANES) and also to explore whether an improved index for the U.S. population (US FLI) could be derived. The US FLI would then used to examine U.S. time trends in fatty liver prevalence. Methods We studied 5869 fasted, viral hepatitis negative adult participants with abdominal ultrasound data on fatty liver in the 1988–1994 NHANES. Time trend analyses included 21 712 NHANES 1988–1994 and 1999–2012 participants. Results The prevalence of fatty liver was 20%. For the FLI, the area under the receiver operating characteristic curve [AUC; 95% confidence interval (CI)] was 0.78 (0.74–0.81). The US FLI included age, race-ethnicity, waist circumference, GGT activity, fasting insulin and fasting glucose and had an AUC (95% CI) of 0.80 (0.77–0.83). Defining fatty liver as a US FLI ≥ 30, the prevalence increased from 18% in 1988–1991 to 29% in 1999–2000 to 31% in 2011–2012. Conclusions For predicting fatty liver, the US FLI was a modest improvement over the FLI in the multiethnic U.S. population. Using this measure, the fatty liver prevalence in the U.S. population increased substantially over two decades.

Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD

Abstract: SummaryBackground Dysbiosis is associated with many diseases, including irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD), obesity and diabetes. Potential clinical impact of imbalance in the intestinal microbiota suggests need for new standardised diagnostic methods to facilitate microbiome profiling. Aim To develop and validate a novel diagnostic test using faecal samples to profile the intestinal microbiota and identify and characterise dysbiosis. Methods Fifty-four DNA probes targeting ≥300 bacteria on different taxonomic levels were selected based on ability to distinguish between healthy controls and IBS patients in faecal samples. Overall, 165 healthy controls (normobiotic reference collection) were used to develop a dysbiosis model with a bacterial profile and Dysbiosis Index score output. The model algorithmically assesses faecal bacterial abundance and profile, and potential clinically relevant deviation in the microbiome from normobiosis. This model was tested in different samples from healthy volunteers and IBS and IBD patients (n = 330) to determine the ability to detect dysbiosis. Results Validation confirms dysbiosis was detected in 73% of IBS patients, 70% of treatment-naive IBD patients and 80% of IBD patients in remission, vs. 16% of healthy individuals. Comparison of deep sequencing and the GA-map Dysbiosis Test, (Genetic Analysis AS, Oslo, Norway) illustrated good agreement in bacterial capture; the latter showing higher resolution by targeting pre-determined highly relevant bacteria. Conclusions The GA-map Dysbiosis Test identifies and characterises dysbiosis in IBS and IBD patients, and provides insight into a patient's intestinal microbiota. Evaluating microbiota as a diagnostic strategy may allow monitoring of prescribed treatment regimens and improvement in new therapeutic approaches.

Systematic review: colitis associated with anti‐CTLA‐4 therapy

Abstract: SummaryBackground Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) has an important role in T-cell regulation, proliferation and tolerance. Anti-CTLA-4 agents, such as ipilimumab and tremelimumab, have been shown to prolong overall survival in patients with metastatic melanoma, and their use is being investigated in the treatment of other malignancies. Their novel immunostimulatory mechanism, however, predisposes patients to immune-related adverse effects, of which gastrointestinal effects such as diarrhoea and colitis are the most common. Aims To discuss the existing literature and summarise the epidemiology, pathogenesis and clinical features of anti-CTLA-4-associated colitis, and to present a management algorithm for it. Methods We searched PubMed for studies published through October 2014 using the terms ‘anti-CTLA,’ ‘ipilimumab,’ ‘tremelimumab,’ ‘colitis,’ ‘gastrointestinal,’ ‘immune-related adverse effect,’ ‘immunotherapy,’ ‘melanoma,’ and ‘diarrhoea.’ Results Watery diarrhoea is commonly associated with anti-CTLA-4 therapy (27–54%), and symptoms occur within a few days to weeks of therapy. Diffuse acute and chronic colitis are the most common findings on endoscopy (8–22%). Concomitant infectious causes of diarrhoea must be evaluated. Most cases may be successfully managed with discontinuation of anti-CTLA-4 and conservative therapy. Those with persistent grade 2 and grade 3/4 diarrhoea should undergo endoscopic evaluation and require corticosteroid therapy. Corticosteroid-resistant cases may respond to anti-tumour necrosis factor-alpha therapy such as infliximab. Surgery is reserved for patients with bowel perforation or failure of medical therapy. Conclusion Given the increasing use of anti-CTLA-4 therapy, clinicians must be aware of related adverse events and their management.

Review article: the diagnosis and management of food allergy and food intolerances.

Abstract: SummaryBackground Adverse reactions to food include immune mediated food allergies and non-immune mediated food intolerances. Food allergies and intolerances are often confused by health professionals, patients and the public. Aim To critically review the data relating to diagnosis and management of food allergy and food intolerance in adults and children. Methods MEDLINE, EMBASE and the Cochrane Database were searched up until May 2014, using search terms related to food allergy and intolerance. Results An estimated one-fifth of the population believe that they have adverse reactions to food. Estimates of true IgE-mediated food allergy vary, but in some countries it may be as prevalent as 4–7% of preschool children. The most common food allergens are cow's milk, egg, peanut, tree nuts, soy, shellfish and finned fish. Reactions vary from urticaria to anaphylaxis and death. Tolerance for many foods including milk and egg develops with age, but is far less likely with peanut allergy. Estimates of IgE-mediated food allergy in adults are closer to 1–2%. Non-IgE-mediated food allergies such as Food Protein-Induced Enterocolitis Syndrome are rarer and predominantly recognised in childhood. Eosinophilic gastrointestinal disorders including eosinophilic oesophagitis are mixed IgE- and non-IgE-mediated food allergic conditions, and are improved by dietary exclusions. By contrast food intolerances are nonspecific, and the resultant symptoms resemble other common medically unexplained complaints, often overlapping with symptoms found in functional disorders such as irritable bowel syndrome. Improved dietary treatments for the irritable bowel syndrome have recently been described. Conclusions Food allergies are more common in children, can be life-threatening and are distinct from food intolerances. Food intolerances may pose little risk but since functional disorders are so prevalent, greater efforts to understand adverse effects of foods in functional disorders are warranted.

Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease

Abstract: SummaryBackground Vedolizumab, an anti-α4β7 integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. Aims To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic–pharmacodynamic relationship using population modelling. Methods Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. Results Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CLL) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (Vc) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for Vc; residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CLL. Conclusions Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK‐438 (vonoprazan), a novel potassium‐competitive acid blocker, in healthy male subjects

Abstract: Background TAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H+, K+-ATPase.

Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults

Abstract: SummaryBackground The effects of probiotics are strain specific. The clinical effects of each strain need to be evaluated separately. Aim To evaluate the efficacy of Lactobacillus rhamnosus GG (LGG) in the prevention of antibiotic-associated diarrhoea (AAD) in children and adults. Methods The Cochrane Library, MEDLINE, and EMBASE databases were searched up to July 2015, with no language restrictions, for randomised controlled trials (RCTs). Reference lists of reviews and included studies were examined. The quality of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. Results Twelve RCTs (1499 participants) were included. Treatment with LGG compared with placebo or no additional treatment reduced the risk of AAD in patients treated with antibiotics from 22.4% to 12.3% (11 RCTs, n = 1308, relative risk, RR: 0.49, 95% confidence interval, CI: 0.29–0.83, low QoE). However, when children and adults were evaluated separately, the difference was significant in children only (five RCTs, n = 445, RR 0.48, 95% CI 0.26–0.89; moderate QoE). In adults, the difference was not significant (six RCTs, n = 863, RR 0.48, 95% CI 0.20–1.15; low QoE), except for in a subset of patients receiving antibiotics as part of Helicobacter pylori eradication therapy (four RCTs, n = 280, RR 0.26, 95% CI 0.11–0.59; low QoE). Conclusions This meta-analysis shows that Lactobacillus rhamnosus GG is effective in preventing antibiotic-associated diarrhoea in children and adults treated with antibiotics for any reason. However, the quality of evidence is moderate to low.

Systematic review: patient‐reported outcomes in chronic hepatitis C ‐ the impact of liver disease and new treatment regimens

Abstract: SummaryBackground Treatment for chronic hepatitis C (CH-C) is rapidly changing and moving away from an interferon and ribavirin-based therapy to interferon-free ribavirin-free all oral regimens. These regimens are simpler and shorter to administer with very high efficacy rates and better side effect profiles. As advances in the treatment of CH-C occur, it is imperative to capture both clinical outcomes (efficacy and safety) as well as patient-reported outcomes (PROs). In fact, PROs assesses and quantifies the impact of these regimens on patient experience. PROs assess patients' health-related quality of life (HRQOL) especially in the realms of fatigue and neuropsychiatric issues such as depression which can affect treatment adherence and work productivity. Aim To review the literature related to PRO's in HCV patients and summarise the impact of CH-C and its treatment on PROs. Methods Databases Ovid MEDLINE and PubMed were searched from 1990 to October 2014 using a combination of MEsh, thesaurus terms and relevant text words: hepatitis C, CH-C, treatment, quality of life, health-related quality of life, fatigue, work productivity, adherence, patient-reported outcomes, direct acting anti-viral agents and second generation direct acting anti-viral agents. Each manuscript was assessed for pertinence to the issue of PROs in CH-C as well as the quality of study design and publications. Results From the literature, it is evident that CH-C patients have baseline PRO impairment. Furthermore, treatment with interferon with or without ribavirin and first generation DAAs causes additional PRO burden which can negatively impact treatment adherence and indirectly, treatment efficacy and work productivity. The new treatment regimens with interferon- and ribavirin-free regimens not only have very high efficacy, but also result in the improvement of PRO scores as early as 2 weeks into treatment as well as possibly better adherence to treatment regimens. Conclusions CH-C and its treatment have been associated with patient-reported outcome impairment. The new IF-free and RBV-free regimens are associated with high efficacy and substantial improvement of patient-reported outcomes in clinical trial setting. Although very encouraging, more data are needed to assess patient-reported outcomes, adherence and work productivity of CH-C patients in the real world setting of clinical practice.

Systematic review: the effects of long‐term proton pump inhibitor use on serum gastrin levels and gastric histology

Abstract: SummaryBackground Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy. Aim To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology. Methods A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology. Results A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8–52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47–4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25–20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found. Conclusions Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.

Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea.

Abstract: SummaryBackground Antibiotic-associated diarrhoea is a common complication of antibiotic use, but it can be prevented with administration of probiotics. Aim To update our 2005 meta-analysis on the effectiveness of Saccharomyces boulardii in preventing antibiotic-associated diarrhoea in children and adults. Methods The Cochrane Library, MEDLINE, and EMBASE databases were searched up until May 2015, with no language restrictions, for randomised controlled trials; additional references were obtained from reviewed articles. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. Results Twenty-one randomised controlled trials (4780 participants), among which 16 were new trials, met the inclusion criteria for this updated systematic review. Administration of S. boulardii compared with placebo or no treatment reduced the risk of antibiotic-associated diarrhoea (as defined by the study investigators) in patients treated with antibiotics from 18.7% to 8.5% (risk ratio, RR: 0.47; 95% CI: 0.38–0.57, number needed to treat, NNT: 10; 95% CI: 9–13). In children, S. boulardii reduced the risk from 20.9% to 8.8% (6 randomised controlled trials, n=1653, RR: 0.43, 95% CI: 0.3–0.6); in adults, from 17.4% to 8.2% (15 randomised controlled trials, n=3114, RR: 0.49, 95% CI: 0.38–0.63). Moreover, S. boulardii reduced the risk of Clostridium difficile-associated diarrhoea; however, this reduction was significant only in children (2 randomised controlled trials, n = 579, RR: 0.25; 95% CI: 0.08–0.73) and not in adults (9 randomised controlled trials, n = 1441, RR: 0.8, 95% CI: 0.47–1.34). Conclusions This meta-analysis confirms that S. boulardii is effective in reducing the risk of antibiotic-associated diarrhoea in children and adults.

Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease.

Abstract: SummaryBackground The human intestinal microbiota is a key regulator of host metabolic and immune functions and alterations in the microbiome (‘dysbiosis’) have been implicated in several human diseases. Because of the anatomical links between the intestines and the liver, dysbiosis may also disrupt hepatic function and thereby contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Aim To perform a comprehensive review of the medical literature investigating associations between intestinal dysbiosis and NAFLD, with a particular emphasis on studies that characterise the microbiome in NAFLD. Methods We conducted a search of PubMed, Embase, and Web of Science using multiple search terms including: ‘NAFLD, NASH, fatty liver, steatohepatitis’ combined with ‘metagenome, microbiom*, microbiota*, fecal flora, intestinal flora, gut bacteria’. Results were manually reviewed and studies selected based on relevance to intestinal microbiota and NAFLD. We also included studies that addressed potential mechanistic models of pathways linking the dysbiosis to NAFLD. Results Nine studies (five human and four animal models) were identified in our search that assessed associations between specific intestinal microbiota composition and NAFLD. We reviewed and summarised the results of additional investigations that more broadly addressed the mechanisms by which the microbiome may impact NAFLD pathogenesis. Conclusions Investigations in humans and animals demonstrate associations between intestinal dysbiosis and NAFLD; however, causality has not been proven and mechanistic links require further delineation. As the field of microbiome research matures in techniques and study design, more detailed insights into NAFLD pathogenesis and its associations with the intestinal microbiota will be elucidated.

Randomised clinical trial: deep remission in biologic and immunomodulator naïve patients with Crohn's disease – a SONIC post hoc analysis

Abstract: Summary Background As treatment goals in Crohn's disease (CD) evolve, targets now include clinical remission (CR), mucosal healing (MH) and biological remission [C-reactive protein normalisation (CRPnorm)]. Aims To evaluate the association of baseline factors and treatment with the achievement of different composite remission parameters at week 26. Methods This post hoc analysis of the SONIC trial evaluated different composite remission measures at week 26 in a subgroup of patients with Crohn's disease activity index (CDAI) scores, CRP, and endoscopic data available at baseline and week 26 (N = 188). Assessed composite remission measures were: CR (CDAI < 150) and MH (absence of any mucosal ulcerations), previously referred to as ‘deep remission;’ and alternative composite endpoints: CR + CRPnorm (CRP < 0.8 mg/dL); CRPnorm + MH; and CR + CRPnorm + MH. Results Among analysed patients, 136/188 (72.3%) achieved CR and 90/188 (47.9%) achieved MH at week 26. All composite outcomes were significantly greater (Bonferroni significance level, P ≤ 0.016) with combination therapy (i.e. infliximab and azathioprine; 52.3–63.6%) vs. azathioprine monotherapy (12.9–29.0%; p ≤ 0.005 for all comparisons). Composite remission rates including MH were significantly greater with combination therapy (52.3–56.9%) vs. infliximab (25.6–32.3%; P ≤ 0.015 for all comparisons except CRPnorm + MH, P = 0.017) and vs. azathioprine monotherapy (12.9–20.4%; P ≤ 0.002 for all comparisons). Median serum trough infliximab concentrations among patients who achieved MH or CR + MH were greater when compared with those among patients who did not achieve MH (P = 0.018) or CR + MH (P = 0.053). Among the subgroup of patients with early Crohn's disease, MH alone or in combination with composite remission criteria significantly improved clinical outcomes of patients who received combination therapy. Conclusions Combination therapy was more effective in achieving various composite remission measures vs. azathioprine or infliximab monotherapy. These data illustrate that ‘deep remission’ is achievable with combination therapy in a high percentage of patients with early Crohn's disease. ClinicalTrials.gov number: NCT00094458.

Systematic review with meta-analysis: the prevalence of bile acid malabsorption in the irritable bowel syndrome with diarrhoea.

Abstract: Background: Irritable bowel syndrome is a widespread disorder with a marked socioeconomic burden. Previous studies support the proposal that a subset of patients with features compatible with diarrhoea-predominant IBS (IBS-D) have bile acid malabsorption (BAM). Aims: To perform a systematic review and meta-analysis to assess the prevalence of BAM in patients meeting the accepted criteria for IBS-D. Methods: MEDLINE and EMBASE were searched up to March 2015. Studies recruiting adults with IBS-D, defined by the Manning, Kruis, Rome I, II or III criteria and which used 23-seleno-25-homotaurocholic acid (SeHCAT) testing for the assessment of BAM were included. BAM was defined as 7 day SeHCAT retention of <10%. We calculated the rate of BAM and 95% confidence intervals (CI) using a random effects model. The methodological quality of included studies was evaluated using the Quality Assessment for Diagnostic Accuracy Studies (QUADAS-2). Results: The search strategy identified six relevant studies comprising 908 individuals. The rate of BAM ranged from 16.9% to 35.3%. The pooled rate was 28.1% (95% CI: 22.6-34%). There was significant heterogeneity in effect sizes (Q-test χ2 = 17.9, P < 0.004; I2 = 72.1%). The type of diagnostic criteria used or study country did not significantly modify the effect. Conclusions: These data provide evidence that in excess of one quarter of patients meeting accepted criteria for IBS-D have bile acid malabsorption. This distinction has implications for the interpretation of previous studies, as well as contemporaneous clinical practice and future guideline development.

A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity

Abstract: SummaryBackground The Crohn's Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohn's disease (CD). Aim As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. Methods Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI <150 as criterion. The operating properties of 2- and 3-item PRO were evaluated using data from a trial of methotrexate in CD. Regression analysis determined PRO2 and PRO3 scores that correspond to CDAI-defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. Results Optimum cut-points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2- and 3-item PROs or CDAI. PRO2 and PRO3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PROs. Conclusion Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD.

Systemic review: the pathogenesis and pharmacological treatment of hiccups

Abstract: SummaryBackground Hiccups are familiar to everyone, but remain poorly understood. Acute hiccups can often be terminated by physical manoeuvres. In contrast, persistent and intractable hiccups that continue for days or months are rare, but can be distressing and difficult to treat. Aim To review the management of hiccups, including a systematic review of reported efficacy and safety of pharmacological treatments. Methods Available articles were identified using three electronic databases in addition to hand searching of published articles. Inclusion criteria were any reports of pharmaceutical therapy of ‘hiccup(s)’, ‘hiccough(s)’ or ‘singultus’ in English or German. Results Treatment of 341 patients with persistent or intractable hiccups was reported in 15 published studies. Management was most effective when directed at the underlying condition. An empirical trial of anti-reflux therapy may be appropriate. If the underlying cause is not known or not treatable, then a range of pharmacological agents may provide benefit; however, systematic review revealed no adequately powered, well-designed trials of treatment. The use of baclofen and metoclopramide are supported by small randomised, placebo-controlled trials. Observational data suggest that gabapentin and chlorpromazine are also effective. Baclofen and gabapentin are less likely than standard neuroleptic agents to cause side effects during long-term therapy. Conclusions This systematic review revealed no high quality data on which to base treatment recommendations. Based on limited efficacy and safety data, baclofen and gabapentin may be considered as first line therapy for persistent and intractable hiccups, with metoclopramide and chlorpromazine in reserve.

Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease.

Abstract: SummaryBackground The general increased life expectancy is reflected in the age of patients with inflammatory bowel disease (IBD). The knowledge about efficacy and safety of anti-tumour necrosis factor (TNF) therapy in elderly is scarce and conflicting. Aim To assess the efficacy and safety of anti-TNF therapy in elderly patients taking into account eventual comorbidity. Methods Observational and retrospective single-centred study where 66 IBD patients initiating anti-TNF treatment at age ≥65 years (cases: ≥65 anti-TNF) were compared with 112 IBD patients initiating anti-TNF <65 years (controls <65 anti-TNF) and 61 anti-TNF naive IBD patients treated with immunosuppressants (IMS) and/or corticosteroids (CS) ≥65 years (controls ≥65 IMS/CS). Controls were matched to cases for IBD type, follow-up, disease duration and anti-TNF type. Comorbidity was assessed by using the Charlson Comorbidity Index (CCI). Both efficacy and safety of treatment were adjusted for comorbidity. Results The short-term clinical response to anti-TNF at 10 weeks was significantly lower in cases: ≥65 anti-TNF (68% vs. 89%; P 0 were independent risk factors for malignancy and mortality regardless of the medication. Conclusion Elderly patients treated with anti-TNF have a lower rate of short-term clinical response and a higher rate of severe adverse events than the younger patients under the same treatment.

Faecal microbiota transplantation plus selected use of vancomycin for severe-complicated Clostridium difficile infection: description of a protocol with high success rate.

Abstract: SummaryBackground Severe and severe/complicated Clostridium difficile infection (CDI) can result in ICU admission, sepsis, toxic megacolon and death. In this setting, colectomy is the standard of care but it is associated with a 50% mortality. Aim To evaluate safety and efficacy of a sequential faecal microbiota transplantation (FMT) and antibiotic protocol in severe and severe/complicated CDI patients who are at high risk for colectomy. Methods All patients with severe and severe/complicated CDI refractory to oral vancomycin ± rectal vancomycin and intravenous metronidazole therapy were offered FMT. Treatment consisted of sequential FMTs via colonoscopy with the need for repeat FMT and continued vancomycin guided by clinical response and pseudomembranes at colonoscopy. Results A total of 29 patients underwent FMT between July 2013 and August 2014. The overall treatment response of endoscopic sequential FMT was 93% (27/29), with 100% (10/10) for severe CDI and 89% (17/19) for severe/complicated CDI. A single FMT was performed in 62%, two FMTs were performed in 31% and three FMTs in 7% of patients. The use of non-CDI antibiotics predicted repeat FMT (odds ratio = 17.5). The 30-day all-cause mortality after FMT was 7%, and the cumulative 3-month survival was 76%. Of the two patients who died within 30 days, one underwent colectomy and succumbed to sepsis; the other died from septic shock related to CDI. Conclusion The success of a treatment protocol for severe and severe/complicated involving faecal microbiota transplantation and continued vancomycin in selected patients was high, and it warrants further evaluation.

Review article: spontaneous bacterial peritonitis--bacteriology, diagnosis, treatment, risk factors and prevention

Abstract: SummaryBackground Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites. Aim To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP. Methods Information was obtained from reviewing medical literature accessible on PubMed Central. The search term ‘spontaneous bacterial peritonitis’ was cross-referenced with ‘bacteria’, ‘risk factors’, ‘ascites’, ‘paracentesis’, ‘ascitic fluid analysis’, ‘diagnosis’, ‘treatment’, ‘antibiotics’, ‘prophylaxis’, ‘liver transplantation’ and ‘nutrition’. Results Gram-positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at-risk individuals. Conclusions Third-generation, broad-spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long-term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin–tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta-adrenergic antagonist therapy in patients with end-stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications.

The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.

Abstract: Summary Background Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. Aim To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. Methods After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. Results In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133–237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (−24% after 2 weeks treatment, P = 0.03), stool form (−14%, P = 0.05) and diarrhoea index (−34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. Conclusions This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025

Systematic review with meta-analysis: faecal diversion for management of perianal Crohn's disease.

Abstract: SummaryBackground Temporary faecal diversion is sometimes used for management of refractory perianal Crohn's disease (CD) with variable success. Aims To perform a systematic review with meta-analysis to evaluate the effectiveness, long-term outcomes and factors associated with success of temporary faecal diversion for perianal CD. Methods Through a systematic literature review through 15 July 2015, we identified 16 cohort studies (556 patients) reporting outcomes after temporary faecal diversion. We estimated pooled rates [with 95% confidence interval (CI)] of early clinical response, attempted and successful restoration of bowel continuity after temporary faecal diversion (without symptomatic relapse), and rates of re-diversion (in patients with attempted restoration) and proctectomy (with or without colectomy and end-ileostomy). We identified factors associated with successful restoration of bowel continuity. Results On meta-analysis, 63.8% (95% CI: 54.1–72.5) of patients had early clinical response after faecal diversion for refractory perianal CD. Restoration of bowel continuity was attempted in 34.5% (95% CI: 27.0–42.8) of patients, and was successful in only 16.6% (95% CI: 11.8–22.9). Of those in whom restoration was attempted, 26.5% (95% CI: 14.1–44.2) required re-diversion because of severe relapse. Overall, 41.6% (95% CI: 32.6–51.2) of patients required proctectomy after failure of temporary faecal diversion. There was no difference in the successful restoration of bowel continuity after temporary faecal diversion in the pre-biological or biological era (13.7% vs. 17.6%, P = 0.60), in part due to selection bias. Absence of rectal involvement was the most consistent factor associated with restoration of bowel continuity. Conclusions Temporary faecal diversion may improve symptoms in approximately two-thirds of patients with refractory perianal Crohn's disease, but bowel restoration is successful in only 17% of patients.

Impaired fasting pyloric compliance in gastroparesis and the therapeutic response to pyloric dilatation

Abstract: Summary Background Pyloric pressure and compliance have never been investigated in health nor gastroparesis. Aim We hypothesised that pyloric pressure and/or compliance may be altered in gastroparesis. Methods Fasting pyloric pressure and compliance were investigated in 21 healthy volunteers (HV), 27 gastroparetic patients (GP) and 5 patients who had undergone oesophagectomy without pyloroplasty as positive controls. Under videofluoroscopic control, pyloric compliance and pressure were measured by the EndoFLIP technique. Gastric emptying half time (T1/2) using 13C–octanoic acid breath test, as well as symptoms and quality of life (GIQLI score) were also monitored. Results Mean fasting pyloric compliance was measured at 25.2 ± 2.4 mm²/mmHg in HV, and was lower both in GP (16.9 ± 2.1 mm²/mmHg; P < 0.05) and patients with oesophagectomy (10.9 ± 2.9 mm²/mmHg; P < 0.05). By contrast, fasting pyloric pressure was not different among groups. Fasting pyloric compliance and pressure correlated with T1/2 in GP (R = −0.43; P = 0.04). Fasting pyloric compliance, but not pressure, correlated with symptoms and GIQLI score. Pyloric dilation in 10 GP with low fasting pyloric compliance (<10 mm²/mmHg) increased compliance from 7.4 ± 0.4 to 20.1 ± 4.9 mm²/mmHg (P < 0.01) and improved the GIQLI score from 72.5 ± 5.5 to 89.3 ± 6.1 (P = 0.04). Conclusion This prospective study assessed pyloric compliance for the first time, and showed that fasting pyloric compliance is decreased in gastroparetic patients and is associated with T1/2, symptoms and quality of life. This suggests that pyloric compliance may be a new relevant metric in gastroparetic patients, and may be useful to target patients for pyloric dilation or botulinum toxin injection.

Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress.

Abstract: Background: A subset of irritable bowel syndrome (IBS) patients, denoted post-infectious IBS (PI-IBS), develop symptoms after an enteric infection. Bacterial dysbiosis and mucosal inflammation have ...

Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study.

Abstract: Background Two-dimensional magnetic resonance elastography (2D-MRE) is an advanced magnetic resonance method with high diagnostic accuracy for predicting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) patients. However, no prospective, head-to-head comparisons between 2D-MRE and clinical prediction rules (CPRs) have been performed in patients with biopsy-proven NAFLD.