Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet.

OBJECTIVE: Reducing FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can be clinically beneficial in IBS but the mechanism is incompletely understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action. DESIGN: We used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet. RESULTS: Unsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet, IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalisation of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared with IBSH (p=0.02). CONCLUSION: 50% of IBS cases manifested a 'pathogenic' gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP reduction in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms.

Prevalence and outcome of portal thrombosis in a cohort of cirrhotic patients undergoing liver transplantation.

INTRODUCTION: The prevalence of portal vein thrombosis (PVT) in patients that have undergone liver transplantation (LT) is 9.7% (SD 4.5). The aim of our study was to determine the prevalence, assess the factors that are associated with PVT and clarify their association with prognosis in patients with liver cirrhosis (LC) and LT. AIMS AND METHODS: From 2005 to 2014, laboratory, radiological and surgical data were collected from patients with LC in our center who had undergone LT for the first time. RESULTS: One hundred and ninety-one patients were included. The mean age was 55 (SD 9), 75.4% of patients were male and 48.7% had HCV. The Child-Pugh scores were A/B/C 41.9%/35.9%/25.5% and the MELD score was 15 (SD 6). Previous decompensations were: ascites (61.4%), hepatic encephalopathy (34.4%), variceal bleeding (25.4%), hepatocellular carcinoma (48.9%) and spontaneous bacterial peritonitis (SPB) (14.3%). The mean post-transplant follow-up was 42 months (0-113). PVT was diagnosed at LT in 18 patients (9.4%). Six patients were previously diagnosed using imaging tests (33.3%): 2 patients (11.1%) by DU and 4 patients (22.2%) by CT scan. All patients with PVT had DU in a mean time of 6 months before LT (0-44) and 90 patients (47.1%) had a CT scan in a median time of 6 months before LT (0-45). PVT was significantly related to the presence of SBP (33.3% vs 12.6%; p = 0.02) and lower levels of albumin (3.1g/dl vs 3.4g/dl; p = 0.05). MELD was higher in patients with PVT (16.6 vs 14.9; p = 0.3). There were no significant differences with regard to the need for transfusion of blood components. Moreover, the surgery time was similar in both groups. PVT correlated with a higher mortality in the first 30 days (8.8% vs 16.7%; p = 0.2). CONCLUSION: Prior history of SBP and lower levels of albumin were identified as factors associated with PVT. The pre-transplant diagnosis rate is very low and the presence of PVT may have implications for short-term mortality.

Appendicular bleeding: an excepcional cause of lower hemorrhage.

Chronic complications of acute appendicitis managed in a conservative manner are not frequent. We present a case of acute lower gastrointestinal hemorrhage in a young patient with a previous acute appendicitis without surgical intervention. The colonoscopy detected an appendicular bleeding which was surgically treated. The anatomopathological diagnosis was granulomatous appendicitis. The clinical evolution of the patient was favorable without bleeding recurrence. Appendicular hemorrhage can be an unusual complication-however potentially severe-of acute appendicitis not treated surgically.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Prevalence of viral hepatitis (B and C) serological markers in healthy working population.

INTRODUCTION AND OBJECTIVES: prevalence of viral hepatitis (B and C) changes geographically. Our aim was to determinate the prevalence of hepatitis B (HBV) and hepatitis C virus (HCV) serological markers in healthy working population and to describe the epidemiological characteristics associated to its presence. METHODS: blood samples and epidemiological data of 5,017 healthy workers from Murcia and Madrid were recorded prospectively. RESULTS: a total of 5,017 healthy volunteers participated. Mean age 39 ± 11 years, men predominance (73 %). Prevalence of serological markers of HCV and HBV was 0.6 % and 0.7 %. Age of patients with HCV antibody was significantly higher (43 + or - 9 years vs. 39 + or - 11 years; p = 0.03). We observed significant differences in liver test values (alanine aminotransferase [ALT] 64 ± 56 IU/L vs. 28 ± 20 IU/L; p < 0.001; aspartate aminotransferase [AST] (51 + or - 45 IU/L vs. 23 + or - 12 IU/L; p < 0.001) and in gamma-glutamyltransferase(GGT) value (104 + or - 122 IU/L vs. 37 + or - 46 IU/L; p < 0.001. The presence of HCV antibody was related significantly to previous transfusion (13 % vs. 5 %; p = 0.03), tattoos (29 % vs. 13 %; p < 0.01), intravenous drug addiction (13 % vs. 0.2 %; p < 0.001) and coexistence with people with positive HCV antibody (16 % vs. 4 %; p < 0.001). In HBV no differences in basal characteristics were observed with exception in AST values (29 + or - 15 IU/L vs. 23 + or - 12 IU/L; p < 0.01). Hepatitis B surface antigen (HBsAg) was related significantly to previous transfusion (15 % vs. 5 %; p < 0.01), tattoos (26 % vs. 14 %; p = 0.04) and coexistence with people with positive HBsAg (17 % vs. 4 %; p < 0.001). CONCLUSIONS: Prevalence of serological markers in healthy working population is low. Risk factors for infection were previous transfusion and tattoos. Intravenous drug addiction was only a risk factor in HCV.

Biologic therapy for inflammatory bowel disease: Real-world comparative effectiveness and impact of drug sequencing in 13,222 patients within the UK IBD BioResource.

BACKGROUND AND AIMS: To compare effectiveness of different biologic therapies and sequences in patients with Inflammatory Bowel Disease (IBD) using real-world data from a large cohort with long exposure. METHODS: Demographic, disease, treatment and outcome data were retrieved for patients in the UK IBD BioResource. Effectiveness of treatment was based on persistence free of discontinuation or failure, analysed by Kaplan-Meier survival analysis with inverse probability of treatment weighting to adjust for differences between groups. RESULTS: 13,222 evaluable patients received at least one biologic. In ulcerative colitis (UC) first line vedolizumab (VDZ) demonstrated superior effectiveness over five years compared to anti-TNF agents (p=0.006). VDZ was superior to both infliximab (IFX) and adalimumab (ADA) after ADA and IFX failure respectively (p<0.001 and p<0.001). Anti-TNF therapy showed similar effectiveness when used first-line, or after failure of VDZ. In Crohn's disease (CD) we found significant differences between first line treatments over ten years (p=0.045), with superior effectiveness of IFX compared to ADA in perianal CD. Non-anti-TNF biologics were superior to a second anti-TNF after first line anti-TNF failure in CD (p=0.035). Patients with UC or CD experiencing TNF-failure due to delayed loss of response or intolerance had superior outcomes when switching to a non-anti-TNF biologic, rather than a second anti-TNF. CONCLUSIONS: We provide real-world evidence to guide biologic selection and sequencing in a range of common scenarios. Our findings challenge current guidelines regarding drug selection after loss of response to first anti-TNF.

Effect of season and sunlight on viral kinetics during hepatitis C virus therapy.

BACKGROUND AND AIMS: Rapid viral response (RVR) during antiviral treatment for hepatitis C virus (HCV) predicts sustained viral response (SVR). Recently, vitamin D levels have been associated with SVR. As sunlight is the most important source of vitamin D and shows seasonal variation, we evaluated the effect of season on viral kinetics during peginterferon/ribavirin-based therapy for HCV. METHODS: Consecutive HCV patients treated with peginterferon/ribavirin and boceprevir/ telaprevir (June 2011-July 2014) were included. Patients were grouped according to season when therapy was initiated (Season A: May-October and Season B: November-April) depending on hours of daily sunlight. Multiple logistic regression analysis included factors known to influence SVR to treatment. The dependent variables were undetectable viral load (VL) or VL ≤15 UI/mL (VL ≤15) at weeks 4, 8 and 12, end of treatment and SVR. RESULTS: The study included 930 patients (66.8% men; median 54 years) treated with telaprevir (n=537) or boceprevir, without (n=481) or with lead-in therapy of peginterferon/ribavirin. Baseline characteristics of patients in Season A (45.3%, n=421) and Season B groups were similar. Overall, a higher rate of RVR (23.5% vs 16.1%, p=0.005) and VL ≤15 (51.0% vs 38.6%, p≤0.001) was observed in patients starting treatment during Season A versus Season B. By logistic regression analysis, initiating treatment in Season A proved to be an independent predictor of RVR and VL ≤15. CONCLUSIONS: In our setting, seasonality affects viral kinetics in HCV genotype 1 patients treated with peginterferon/ribavirin-based therapy. Our findings support the hypothesis that vitamin D influences viral response to peginterferon/ribavirin-based therapy.