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  • Gastric microbes associated with gastric inflammation, atrophy and intestinal metaplasia 1 year after Helicobacter pylori eradication
    Gut (IF 17.943) Pub Date : 2020-01-23
    Joseph J Y Sung; Olabisi Oluwabukola Coker; Eagle Chu; Chun Ho Szeto; Simson Tsz Yat Luk; Harry Cheuk Hay Lau; Jun Yu

    Objective Helicobacter pylori is associated with gastric inflammation, precancerous gastric atrophy (GA) and intestinal metaplasia (IM). We aimed to identify microbes that are associated with progressive inflammation, GA and IM 1 year after H. pylori eradication. Design A total of 587 H . pylori –positive patients were randomised to receive H. pylori eradication therapy (295 patients) or placebo (292 patients). Bacterial taxonomy was analysed on 404 gastric biopsy samples comprising 102 pairs before and after 1 year H. pylori eradication and 100 pairs before and after 1 year placebo by 16S rRNA sequencing. Results Analysis of microbial sequences confirmed the eradication of H. pylori in treated group after 1 year. Principal component analysis revealed distinct microbial clusters reflected by increase in bacterial diversity (p<0.00001) after H. pylori eradication. While microbial interactions remained largely unchanged after placebo treatment, microbial co-occurrence was less in treated group. Acinetobacter lwoffii , Streptococcus anginosus and Ralstonia were enriched while Roseburia and Sphingomonas were depleted in patients with persistent inflammation 1 year after H. pylori eradication. A distinct cluster of oral bacteria comprising Peptostreptococcus , Streptococcus , Parvimonas , Prevotella, Rothia and Granulicatella were associated with emergence and persistence of GA and IM. Probiotic Faecalibacterium praustznii was depleted in subjects who developed GA following H. pylori eradication. Functional pathways including amino acid metabolism and inositol phosphate metabolism were enriched while folate biosynthesis and NOD-like receptor signalling decreased in atrophy/IM-associated gastric microbiota. Conclusion This study identified that gastric microbes contribute to the progression of gastric carcinogenesis after H. pylori eradication.

    更新日期:2020-01-23
  • Transgenic expression of human PRSS2 exacerbates pancreatitis in mice
    Gut (IF 17.943) Pub Date : 2020-01-23
    Jianhua Wan; Ashley Haddock; Brandy Edenfield; Baoan Ji; Yan Bi

    We read with great interest the study by Hegyi et al 1 which reported that a commonly occurring haplotype spanning the PRSS1-PRSS2 locus (encoding human cationic and anionic trypsinogens) is associated with chronic pancreatitis. While PRSS1 is the major focus in many studies,2 3 PRSS2 is also a major trypsinogen isoform synthesised in human pancreas. In normal human, the PRSS1/PRSS2 ratio is approximately 2:1.4 Chronic alcoholism increases the risk of pancreatitis. Strikingly, in these patients, total trypsinogen secretion was increased with selective upregulation of PRSS2, reversing the PRSS1/PRSS2 ratio.5 In vitro studies have shown human PRSS2 more sensitive to autocatalytic degradation and with lower autoactivation than PRSS1.6 In test tube assays under conditions of intracellular pathological trypsinogen activation, mixtures of PRSS1 and PRSS2 with increasing ratios of PRSS2 had markedly decreased rates of trypsinogen activation and yields of active trypsin.6 These observations led to a hypothesis that upregulation of PRSS2 may play a protective role against pancreatitis.6 …

    更新日期:2020-01-23
  • The complicated dialogue between Helicobacter pylori and p53
    Gut (IF 17.943) Pub Date : 2020-01-23
    Zhi-Hang Tao; Jing-Yuan Fang

    We recently read the interesting paper published in GUT elucidating the role of upstream stimulatory factor 1 (USF1) in Helicobacter pylori (Hp )-induced p53 degradation.1 The work greatly broadens our knowledge of the interplay between Hp and p53 during gastric carcinogenesis. Here we propose some additional exploration, if incorporated in study design, can further deepen our understanding. The significance of USF1 in gastric carcinogenesis should be acknowledged as the study showed that loss of USF1, on its own, exacerbated the severity of …

    更新日期:2020-01-23
  • Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery
    Gut (IF 17.943) Pub Date : 2020-01-21
    Kiana Ashley West; Chidimma Kanu; Tanya Maric; Julie Anne Kathryn McDonald; Jeremy K Nicholson; Jia V Li; Mark R Johnson; Elaine Holmes; Makrina D Savvidou

    Objective Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development. Design A parallel metabonomic (molecular phenotyping based on proton nuclear magnetic resonance spectroscopy) and gut bacterial (16S ribosomal RNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared with women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed. Results Previous malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p- cresol sulfate, indoxyl sulfate and p- hydroxyphenylacetate), and a shift in the gut microbiota. The urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (p=0.001) and was also elevated in urine of neonates born from these mothers (p=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight. Conclusion Metabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.

    更新日期:2020-01-22
  • Intravenous supplementation type and volume are associated with 1-year outcome and major complications in patients with chronic intestinal failure
    Gut (IF 17.943) Pub Date : 2020-01-21
    Loris Pironi; Ezra Steiger; Francisca Joly; Geert J A Wanten; Cecile Chambrier; Umberto Aimasso; Anna Simona Sasdelli; Kinga Szczepanek; Amelia Jukes; Miriam Theilla; Marek Kunecki; Joanne Daniels; Mireille J Serlie; Sheldon C Cooper; Florian Poullenot; Henrik Højgaard Rasmussen; Charlene W Compher; Adriana Crivelli; Sarah-Jane Hughes; Lidia Santarpia; Francesco William Guglielmi; Nada Rotovnik Kozjek; Lars Ellegard; Stéphane M Schneider; Przemysław Matras; Alastair Forbes; Nicola Wyer; Anna Zmarzly; Marina Taus; Margie O'Callaghan; Emma Osland; Ronan Thibault; Cristina Cuerda; Lynn Jones; Brooke Chapman; Peter Sahin; Núria M Virgili; Andre Dong Won Lee; Paolo Orlandoni; Konrad Matysiak; Simona Di Caro; Maryana Doitchinova-Simeonova; Luisa Masconale; Corrado Spaggiari; Carmen Garde; Aurora E Serralde-Zúñiga; Gabriel Olveira; Zeljko Krznaric; Estrella Petrina Jáuregui; Ana Zugasti Murillo; José P Suárez-Llanos; Elena Nardi; André Van Gossum; Simon Lal

    Background and aim No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. Methods At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as <1, 1–2, 2–3 and >3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). Results Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN <1 L/day than for FE and all PN >1 L/day), patients’ death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2–3 and PN >3 L/day). Conclusions The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.

    更新日期:2020-01-22
  • Harnessing liver progenitors in the treatment of liver fibrosis: a step in the right direction?
    Gut (IF 17.943) Pub Date : 2020-01-20
    Katja Breitkopf-Heinlein; Wing-Kin Syn

    Liver fibrosis is a leading cause of morbidity and mortality worldwide, and the prevalence of chronic liver disease is expected to increase in parallel with obesity and type 2 diabetes mellitus epidemics.1 As there is currently no Food and Drug Administration (FDA)-approved drug treatment for liver fibrosis, a liver transplant is the only curative treatment for a minority of individuals who develop cirrhosis-associated complications such as liver cancer and liver failure. In the face of an acute organ shortage, there is a growing impetus to better understand the precise cellular and molecular mechanisms of adult liver repair and regeneration, so that clinically relevant therapeutic targets can be identified. In adults, after an acute liver injury, ‘normal’ regeneration occurs through the proliferation and expansion of remaining healthy hepatocytes and cholangiocytes, and there is minimal involvement of liver progenitors. By contrast, repair during chronic liver injury involves the proliferation of progenitor cells and cells with certain stem-like properties to differentiate into both hepatocytes and cholangiocytes, and thus support the restoration of liver function.2 3 What are the identity and/or origin of these liver progenitors? Multiple progenitor markers have been proposed, but none are completely specific as recent studies demonstrate that liver progenitors are actually a heterogeneous population that contains a variety of cell types, ranging from more primitive progenitors to more differentiated cells (eg, hepatocyte-like). Indeed, in adult mice, progenitors include biliary-like cells (also known as ‘oval cells’ in rodents) which arise in the ductal region, as well as progenitors around the central vein, de-differentiated hepatocytes or cholangiocytes, as well as multipotent mesenchymal stem cells (MSC) which also exhibit immunomodulatory properties.3 4 Similar …

    更新日期:2020-01-21
  • DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia
    Gut (IF 17.943) Pub Date : 2020-01-20
    Vaidehi Krishnan; Debbie Xiu En Lim; Phuong Mai Hoang; Supriya Srivastava; Junichi Matsuo; Kie Kyon Huang; Feng Zhu; Khek Yu Ho; Jimmy Bok Yan So; Christopher Khor; Stephen Tsao; Ming Teh; Kwong Ming Fock; Tiing Leong Ang; Anand D Jeyasekharan; Patrick Tan; Khay-Guan Yeoh; Yoshiaki Ito

    Objective Intestinal metaplasia (IM) is a premalignant stage that poses a greater risk for subsequent gastric cancer (GC). However, factors regulating IM to GC progression remain unclear. Previously, activated DNA damage response (DDR) signalling factors were shown to engage tumour-suppressive networks in premalignant lesions. Here, we interrogate the relationship of DDR signalling to mutational accumulation in IM lesions. Design IM biopsies were procured from the gastric cancer epidemiology programme, an endoscopic surveillance programme where biopsies have been subjected to (epi)genomic characterisation. IM samples were classified as genome-stable or genome-unstable based on their mutational burden/somatic copy-number alteration (CNA) profiles. Samples were probed for DDR signalling and cell proliferation, using the markers γH2AX and MCM2, respectively. The expression of the gastric stem cell marker, CD44v9, was also assessed. Tissue microarrays representing the GC progression spectrum were included. Results MCM2-positivity increased during GC progression, while γH2AX-positivity showed modest increase from normal to gastritis and IM stages, with further increase in GC. γH2AX levels correlated with the extent of chronic inflammation. Interestingly, genome-stable IM lesions had higher γH2AX levels underscoring a protective anti-cancer role for DDR signalling. In contrast, genome-unstable IM lesions with higher mutational burden/CNAs had lower γH2AX levels, elevated CD44v9 expression and modest promoter hypermethylation of DNA repair genes WRN, MLH1 and RAD52 . Conclusions Our data suggest that IM lesions with active DDR will likely experience a longer latency at the premalignant state until additional hits that override DDR signalling clonally expand and promote progression. These observations provide insights on the factors governing IM progression.

    更新日期:2020-01-21
  • Long-term colorectal cancer incidence after adenoma removal and the effects of surveillance on incidence: a multicentre, retrospective, cohort study
    Gut (IF 17.943) Pub Date : 2020-01-17
    Amanda J Cross; Emma C Robbins; Kevin Pack; Iain Stenson; Paula L Kirby; Bhavita Patel; Matthew D Rutter; Andrew M Veitch; Brian P Saunders; Stephen W Duffy; Kate Wooldrage

    Objective Postpolypectomy colonoscopy surveillance aims to prevent colorectal cancer (CRC). The 2002 UK surveillance guidelines define low-risk, intermediate-risk and high-risk groups, recommending different strategies for each. Evidence supporting the guidelines is limited. We examined CRC incidence and effects of surveillance on incidence among each risk group. Design Retrospective study of 33 011 patients who underwent colonoscopy with adenoma removal at 17 UK hospitals, mostly (87%) from 2000 to 2010. Patients were followed up through 2016. Cox regression with time-varying covariates was used to estimate effects of surveillance on CRC incidence adjusted for patient, procedural and polyp characteristics. Standardised incidence ratios (SIRs) compared incidence with that in the general population. Results After exclusions, 28 972 patients were available for analysis; 14 401 (50%) were classed as low-risk, 11 852 (41%) as intermediate-risk and 2719 (9%) as high-risk. Median follow-up was 9.3 years. In the low-risk, intermediate-risk and high-risk groups, CRC incidence per 100 000 person-years was 140 (95% CI 122 to 162), 221 (195 to 251) and 366 (295 to 453), respectively. CRC incidence was 40%–50% lower with a single surveillance visit than with none: hazard ratios (HRs) were 0.56 (95% CI 0.39 to 0.80), 0.59 (0.43 to 0.81) and 0.49 (0.29 to 0.82) in the low-risk, intermediate-risk and high-risk groups, respectively. Compared with the general population, CRC incidence without surveillance was similar among low-risk (SIR 0.86, 95% CI 0.73 to 1.02) and intermediate-risk (1.16, 0.97 to 1.37) patients, but higher among high-risk patients (1.91, 1.39 to 2.56). Conclusion Postpolypectomy surveillance reduces CRC risk. However, even without surveillance, CRC risk in some low-risk and intermediate-risk patients is no higher than in the general population. These patients could be managed by screening rather than surveillance.

    更新日期:2020-01-21
  • Influence of gastrectomy for gastric cancer treatment on faecal microbiome and metabolome profiles
    Gut (IF 17.943) Pub Date : 2020-01-16
    Pande Putu Erawijantari; Sayaka Mizutani; Hirotsugu Shiroma; Satoshi Shiba; Takeshi Nakajima; Taku Sakamoto; Yutaka Saito; Shinji Fukuda; Shinichi Yachida; Takuji Yamada

    Objective Recent evidence points to the gut microbiome’s involvement in postoperative outcomes, including after gastrectomy. Here, we investigated the influence of gastrectomy for gastric cancer on the gut microbiome and metabolome, and how it related to postgastrectomy conditions. Design We performed shotgun metagenomics sequencing and capillary electrophoresis time-of-flight mass spectrometry-based metabolomics analyses on faecal samples collected from participants with a history of gastrectomy for gastric cancer (n=50) and compared them with control participants (n=56). Results The gut microbiota in the gastrectomy group showed higher species diversity and richness (p<0.05), together with greater abundance of aerobes, facultative anaerobes and oral microbes. Moreover, bile acids such as genotoxic deoxycholic acid and branched-chain amino acids were differentially abundant between the two groups (linear discriminant analysis (LDA) effect size (LEfSe): p<0.05, q<0.1, LDA>2.0), as were also Kyoto Encyclopedia of Genes and Genomes modules involved in nutrient transport and organic compounds biosynthesis (LEfSe: p<0.05, q<0.1, LDA>2.0). Conclusion Our results reveal alterations of gut microbiota after gastrectomy, suggesting its association with postoperative comorbidities. The multi-omic approach applied in this study could complement the follow-up of patients after gastrectomy.

    更新日期:2020-01-17
  • Optical diagnosis of T1 CRCs and treatment consequences in the Dutch CRC screening programme
    Gut (IF 17.943) Pub Date : 2020-01-14
    Lonne W T Meulen; Alouisa J P van de Wetering; Marie-Eline P H Debeuf; Zlatan Mujagic; Ad A M Masclee

    With great interest, we have read the article by Backes et al ,1 on the pre-resection accuracy of the real-time optical diagnosis of T1 colorectal cancer (T1CRC) in large non-pedunculated colorectal polyps. In this multicentre, prospective study, the authors developed and validated the OPTICAL model, in which a sensitivity of 78.7% (95% CI: 64.3 to 89.3) for optical diagnosis of T1CRC was obtained. With the implementation of the Dutch bowel cancer screening programme (BCSP) in 2014, a shift has occurred towards the more frequent diagnoses of early AJCC (American Joint Committee on Cancer) stage I cancers.2 Estimating the risk of a T1CRC is crucial to determine the optimal treatment strategy, and to select cases for more elaborative and expensive endoscopic en bloc resection techniques such as endoscopic submucosal dissection, transanal minimally invasive surgery or endoscopic full-thickness resection. Current studies mainly report on the outcomes of advanced imaging by expert centres with dedicated endoscopists,3 4 whereas …

    更新日期:2020-01-15
  • Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities: joint APAGE/APLAR/APSDE/APSH/APSN/PoA recommendations
    Gut (IF 17.943) Pub Date : 2020-01-14
    Cheuk-Chun Szeto; Kentaro Sugano; Ji-Guang Wang; Kazuma Fujimoto; Samuel Whittle; Gopesh K Modi; Chen-Huen Chen; Jeong-Bae Park; Lai-Shan Tam; Kriengsak Vareesangthip; Kelvin K F Tsoi; Francis K L Chan

    Background Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications, but they are associated with a number of serious adverse effects, including hypertension, cardiovascular disease, kidney injury and GI complications. Objective To develop a set of multidisciplinary recommendations for the safe prescription of NSAIDs. Methods Randomised control trials and observational studies published before January 2018 were reviewed, with 329 papers included for the synthesis of evidence-based recommendations. Results Whenever possible, a NSAID should be avoided in patients with treatment-resistant hypertension, high risk of cardiovascular disease and severe chronic kidney disease (CKD). Before treatment with a NSAID is started, blood pressure should be measured, unrecognised CKD should be screened in high risk cases, and unexplained iron-deficiency anaemia should be investigated. For patients with high cardiovascular risk, and if NSAID treatment cannot be avoided, naproxen or celecoxib are preferred. For patients with a moderate risk of peptic ulcer disease, monotherapy with a non-selective NSAID plus a proton pump inhibitor (PPI), or a selective cyclo-oxygenase-2 (COX-2) inhibitor should be used; for those with a high risk of peptic ulcer disease, a selective COX-2 inhibitor plus PPI are needed. For patients with pre-existing hypertension receiving renin-angiotensin system blockers, empirical addition (or increase in the dose) of an antihypertensive agent of a different class should be considered. Blood pressure and renal function should be monitored in most cases. Conclusion NSAIDs are a valuable armamentarium in clinical medicine, but appropriate recognition of high-risk cases, selection of a specific agent, choice of ulcer prophylaxis and monitoring after therapy are necessary to minimise the risk of adverse events.

    更新日期:2020-01-15
  • The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis
    Gut (IF 17.943) Pub Date : 2020-01-10
    Abdul K Siraj; Tariq Masoodi; Rong Bu; Sandeep Kumar Parvathareddy; Sarah Siraj; Ali Alassiri; Fouad Al-Dayel; Fowzan S Alkuraya; Khawla S Al-Kuraya

    We read with interest the study by Møller and colleagues.1 The isolation and relative homogeneity of the Saudi population enhance the potential to discover founder mutations, while its high rates of consanguinity enhances homozygosity even for typically dominant disease genes.2 3 We have previously explored the contribution of Lynch syndrome (LS) to colorectal cancer (CRC) based on ~800 Saudi patients.4 We have since expanded our cohort to 1207 CRC patients. Of the 112 mismatch repair deficient (dMMR) cases, MMR gene mutations were identified in 26 cases and these varied in their cancer risk by age 50 years (figure 1). Three founder mutations were observed, accounting for 42.3% (n=11) of LS cases, and none is listed in gnomAD. The PMS2 :c.1376C>G;p.S459X variant was the most commonly encountered LS variant (n=6), and we calculated its minor allele frequency at 0.0001. ​ Importantly, we were able to identify a homozygous individual for PMS2 :c.1376C>G;p.S459X through a large scale whole-exome sequencing (WES) study.2 This individual presented at age 8 years with haematochezia and a typical picture of familial adenomatous …

    更新日期:2020-01-10
  • S100A11/ANXA2 belongs to a tumour suppressor/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development
    Gut (IF 17.943) Pub Date : 2020-01-09
    Cyril Sobolewski; Daniel Abegg; Flavien Berthou; Dobrochna Dolicka; Nicolas Calo; Christine Sempoux; Margot Fournier; Christine Maeder; Anne-Sophie Ay; Pierre-Alain Clavien; Bostjan Humar; Jean-François Dufour; Alexander Adibekian; Michelangelo Foti

    Objective Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. Design The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. Results A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. Conclusion Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis.

    更新日期:2020-01-10
  • Histopathologist features predictive of diagnostic concordance at expert level among a large international sample of pathologists diagnosing Barrett’s dysplasia using digital pathology
    Gut (IF 17.943) Pub Date : 2020-01-09
    Myrtle J van der Wel; Helen G Coleman; Jacques J G H M Bergman; Marnix Jansen; Sybren L Meijer

    Objective Guidelines mandate expert pathology review of Barrett’s oesophagus (BO) biopsies that reveal dysplasia, but there are no evidence-based standards to corroborate expert reviewer status. We investigated BO concordance rates and pathologist features predictive of diagnostic discordance. Design Pathologists (n=51) from over 20 countries assessed 55 digitised BO biopsies from across the diagnostic spectrum, before and after viewing matched p53 labelling. Extensive demographic and clinical experience data were obtained via online questionnaire. Reference diagnoses were obtained from a review panel (n=4) of experienced Barrett’s pathologists. Results We recorded over 6000 case diagnoses with matched demographic data. Of 2805 H&E diagnoses, we found excellent concordance (>70%) for non-dysplastic BO and high-grade dysplasia, and intermediate concordance for low-grade dysplasia (42%) and indefinite for dysplasia (23%). Major diagnostic errors were found in 248 diagnoses (8.8%), which reduced to 232 (8.3%) after viewing p53 labelled slides. Demographic variables correlating with diagnostic proficiency were analysed in multivariate analysis, which revealed that at least 5 years of professional experience was protective against major diagnostic error for H&E slide review (OR 0.48, 95% CI 0.31 to 0.74). Working in a non-teaching hospital was associated with increased odds of major diagnostic error (OR 1.76, 95% CI 1.15 to 2.69); however, this was neutralised when pathologists viewed p53 labelled slides. Notably, neither case volume nor self-identifying as an expert predicted diagnostic proficiency. Extrapolating our data to real-world case prevalence suggests that 92.3% of major diagnostic errors are due to overinterpreting non-dysplastic BO. Conclusion Our data provide evidence-based criteria for diagnostic proficiency in Barrett’s histopathology.

    更新日期:2020-01-10
  • Hepatitis E virus finds its path through the gut
    Gut (IF 17.943) Pub Date : 2020-01-08
    Noémie Oechslin; Darius Moradpour; Jérôme Gouttenoire

    Hepatitis E virus (HEV) infection is a major cause of acute hepatitis and jaundice worldwide.1 HEV genotypes (gt) 1 and 2 are transmitted through the faecal-oral route and cause primarily waterborne epidemics, whereas the zoonotic gt 3 and 4 are transmitted via the consumption of undercooked or raw pork or game meat. Infection of immunocompromised patients with HEV gt 3 may result in chronic hepatitis E and the development of cirrhosis. Beyond liver disease, HEV can cause a number of extrahepatic manifestations, including neurological complications such as neuralgic amyotrophy and Guillain-Barré syndrome. Very similar to hepatitis A virus (HAV), HEV harbours a positive-strand RNA genome, and both are found as so-called quasi-enveloped virions in blood and as naked virions in bile and faeces.2 Although HEV is known to be enterically transmitted, there was limited evidence for infection of the gastrointestinal tract. In a study published in this journal, Marion et al addressed this question by the development of different cell culture systems, including primary human small intestinal epithelial cells, polarised primary enterocytes and intestinal tissue specimens obtained from small bowel resections.3 Using primary HEV gt 1 and 3 isolates from stool samples of patients with hepatitis E as well as virus derived from the gt 3 Kernow-C1 p6 clone, the …

    更新日期:2020-01-09
  • Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: a multicentre randomised trial in Japan
    Gut (IF 17.943) Pub Date : 2020-01-08
    Sho Suzuki; Takuji Gotoda; Chika Kusano; Hisatomo Ikehara; Ryoji Ichijima; Motoki Ohyauchi; Hirotaka Ito; Masashi Kawamura; Yohei Ogata; Masahiko Ohtaka; Moriyasu Nakahara; Koichi Kawabe

    Objective To date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for Helicobacter pylori treatment. This study aimed to investigate the efficacy of the 7-day vonoprazan and low-dose amoxicillin dual therapy as a first-line H. pylori treatment, and compared this with vonoprazan-based triple therapy. Design This prospective, randomised clinical trial was performed at seven Japanese institutions. Patients with H. pylori –positive culture test and naive to treatment were randomly assigned in a 1:1 ratio to either VA-dual therapy (vonoprazan 20 mg+amoxicillin 750 mg twice/day) or VAC-triple therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day) for 7 days, with stratification by age, sex, H. pylori antimicrobial resistance and institution. Eradication success was evaluated by 13C-urea breath test at least 4 weeks after treatment. Results Between October 2018 and June 2019, 629 subjects were screened and 335 were randomised. The eradication rates of VA-dual and VAC-triple therapies were 84.5% and 89.2% (p=0.203) by intention-to-treat analysis, respectively, and 87.1% and 90.2% (p=0.372) by per-protocol analysis, respectively. VA-dual was non-inferior to VAC-triple in the per-protocol analysis. The eradication rates in strains resistant to clarithromycin for VA-dual were significantly higher than those for VAC-triple (92.3% vs 76.2%; p=0.048). The incidence of adverse events was equal between groups. Conclusion The 7-day vonoprazan and low-dose amoxicillin dual therapy provided acceptable H. pylori eradication rates and a similar effect to vonoprazan-based triple therapy in regions with high clarithromycin resistance. Trial registration number UMIN000034140.

    更新日期:2020-01-09
  • Automatic, computer-aided determination of endoscopic and histological inflammation in patients with mild to moderate ulcerative colitis based on red density
    Gut (IF 17.943) Pub Date : 2020-01-08
    Peter Bossuyt; Hiroshi Nakase; Séverine Vermeire; Gert de Hertogh; Tom Eelbode; Marc Ferrante; Tadashi Hasegawa; Hilde Willekens; Yousuke Ikemoto; Takao Makino; Raf Bisschops

    Background The objective evaluation of endoscopic disease activity is key in ulcerative colitis (UC). A composite of endoscopic and histological factors is the goal in UC treatment. We aimed to develop an operator-independent computer-based tool to determine UC activity based on endoscopic images. Methods First, we built a computer algorithm using data from 29 consecutive patients with UC and 6 healthy controls (construction cohort). The algorithm (red density: RD) was based on the red channel of the red-green-blue pixel values and pattern recognition from endoscopic images. The algorithm was refined in sequential steps to optimise correlation with endoscopic and histological disease activity. In a second phase, the operating properties were tested in patients with UC flares requiring treatment escalation. To validate the algorithm, we tested the correlation between RD score and clinical, endoscopic and histological features in a validation cohort. Results We constructed the algorithm based on the integration of pixel colour data from the redness colour map along with vascular pattern detection. These data were linked with Robarts histological index (RHI) in a multiple regression analysis. In the construction cohort, RD correlated with RHI (r=0.74, p<0.0001), Mayo endoscopic subscores (r=0.76, p<0.0001) and UC Endoscopic Index of Severity scores (r=0.74, p<0.0001). The RD sensitivity to change had a standardised effect size of 1.16. In the validation set, RD correlated with RHI (r=0.65, p=0.00002). Conclusions RD provides an objective computer-based score that accurately assesses disease activity in UC. In a validation study, RD correlated with endoscopic and histological disease activity.

    更新日期:2020-01-09
  • Are we ready for targeted therapy combinations in HCC?
    Gut (IF 17.943) Pub Date : 2020-01-08
    Einat Cinnamon; Eli Pikarsky

    Treatment options for advanced hepatocellular carcinoma (HCC) are limited. Although some multikinase inhibitors such as sorafenib show some benefit, this does not significantly alter the course of disease for most patients. Currently, several multikinase inhibitors were shown to work in first-line or second-line treatments, but the overall benefit is quite small. Thus, we urgently need to find ways to increase response rates and perhaps more important, to be able to sustain responses for longer periods.1 Chemotherapy combinations changed the history of cancer therapy when first introduced in childhood malignancies and such combinations remain the main treatment option for many cancer patients. Some kinase inhibitors were also shown to work better in combination—for example, the combination of B-RAF and MEK inhibitors in advanced melanoma showed significantly improved rates of progression-free and overall survival versus B-RAF inhibition alone.2 The choice of the combination in this case was made based on preclinical data suggesting that MEK activation is a major determinant of progression in vemurafenib (a B-RAF-inhibitor) treated melanomas. In the absence of clear cut mechanisms of acquired resistance to sorafenib (which is a multikinase inhibitor), how can we find drug combinations which will increase its efficacy? One way to search for therapeutic targets is the loss of function …

    更新日期:2020-01-09
  • Of FACT complex and oxidative stress response: a KEAP1/NRF2-dependent novel mechanism sustaining hepatocellular carcinoma progression
    Gut (IF 17.943) Pub Date : 2020-02-01
    Beatrice Foglia; Maurizio Parola

    Hepatocellular carcinoma (HCC) is the most common primary liver cancer that usually develops in cirrhotic patients, except for progressive non-alcoholic fatty liver disease (where the tumour may develop also in non-cirrhotic liver).1 HCC is currently the leading cause of mortality in cirrhotic patients, representing the fifth most common cancer and the second leading cause of cancer mortality worldwide.1 Although screening programmes can allow to identify HCC at an earlier stage in patients at risks, still a minority of patients can survive at 5 years from diagnosis, despite treatment. Current treatment options have limitations and first-line drugs approved for systemic therapy, like sorafenib and lenvatinib, can at best offer additional 3 months of survival to HCC patients, emphasising the urgent need to identify novel molecular targets to develop more effective therapies.1 Chronic liver disease progression towards HCC development as well as HCC progression are highly affected by microenvironmental cues in a very complex scenario involving inter-relationships between cells (cancer cells, tumour-associated macrophages or fibroblasts and cancer stem cells) as well as processes or events like inflammatory response, fibrogenic progression, autophagy, hypoxic conditions and oxidative stress.2 In particular, an increase in intracellular levels of reactive oxygen species (ROS) represents a common feature of cancer cells which is usually counterbalanced by an upregulation of antioxidant defenses, particularly through the relevant Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) pathway.3 In this pathway, KEAP1, a E2-ligase which is normally negatively regulating NRF2 protein stability via ubiquitin–proteasome degradation, is inactivated under oxidative stress; this preserves NRF2 from degradation and allows its nuclear translocation and binding to antioxidant response element (ARE) sequences in the promoter of antioxidant genes, displacing BTB domain and CNC homolog 1 (BACH1, the selective …

    更新日期:2020-01-07
  • The hidden cost of colonoscopy including cost of reprocessing and infection rate: the implications for disposable colonoscopes
    Gut (IF 17.943) Pub Date : 2020-02-01
    Sara Larsen; Anthony Kalloo; Susan Hutfless

    Multiple studies have documented a high rate of contaminated colonoscopes after reprocessing. Contaminated reusable colonoscopes may increase the risk of device-related patient infections. As disposable colonoscopes enter the market, they may play a role in infection prevention and may be cost-effective at some facilities or in high-risk patients. Using a micro-costing approach, this study found that the cost per colonoscopy including purchase, maintenance and reprocessing ranges from US$188.64 at high volume centres (3000 annual procedures) to US$501.16 at low volume centres (1000 annual procedures). Accordingly, per-procedure capital costs range from US$87.48 to US$262.45; repair costs range from US$68.77 to US$206.32; cleaning supplies and labour costs US$32.39 and infections requiring hospitalisation cost US$20.12 to US$46.52. As disposable colonoscopes enter the market, low volume centres are most likely to achieve cost savings. Determining if post-procedural infection rates differ with reusable vs disposable colonoscopes is needed. ### In more detail Each year more than 15 million colonoscopy procedures are performed in the USA and the number is increasing.1 Colonoscopy is generally thought to be safe; however, patients are sometimes hospitalised afterwards, due to infections that may have been transmitted via contaminated colonoscopes (MAUDE Adverse Event Report).2 3 Colonoscopy-related infections and complications have been reported in multiple studies, although at lower rates compared with endoscopic retrograde cholangiopancreatography (ERCP).1 4 5 Guideline revisions in response to endoscope-associated infections require healthcare institutions to invest more resources in the high-level disinfection process or conversion to sterilisation (Ofstead et al ).5 ,6 Despite colonoscopy being the highest volume GI procedure, the true cost and time associated with reusable colonoscopes are unknown. The purpose of this study was to explore real-world costs associated with …

    更新日期:2020-01-07
  • British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland/Public Health England post-polypectomy and post-colorectal cancer resection surveillance guidelines
    Gut (IF 17.943) Pub Date : 2020-02-01
    Matthew D Rutter; James East; Colin J Rees; Neil Cripps; James Docherty; Sunil Dolwani; Philip V Kaye; Kevin J Monahan; Marco R Novelli; Andrew Plumb; Brian P Saunders; Siwan Thomas-Gibson; Damian J M Tolan; Sophie Whyte; Stewart Bonnington; Alison Scope; Ruth Wong; Barbara Hibbert; John Marsh; Billie Moores; Amanda Cross; Linda Sharp

    These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address: 1. Which patients should commence surveillance post-polypectomy and post-cancer resection? 2. What is the appropriate surveillance interval? 3. When can surveillance be stopped? The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG’s guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant. The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either : This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1 year clearance colonoscopy, then a surveillance colonoscopy after 3 more years.

    更新日期:2020-01-07
  • Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis
    Gut (IF 17.943) Pub Date : 2020-02-01
    Yinglian Xiao; Shutian Zhang; Ning Dai; Guijun Fei; Khean-Lee Goh; Hoon Jai Chun; Bor-Shyang Sheu; Chui Fung Chong; Nobuo Funao; Wen Zhou; Minhu Chen

    Objective To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). Design In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). Results In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI –3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI –1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI –4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI –5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI –8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI –9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. Conclusion Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. Trial registration number [NCT02388724][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02388724&atom=%2Fgutjnl%2F69%2F2%2F224.atom

    更新日期:2020-01-07
  • HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer
    Gut (IF 17.943) Pub Date : 2020-02-01
    Chang Xu; Wen Fong Ooi; Aditi Qamra; Jing Tan; Benjamin Yan-Jiang Chua; Shamaine Wei Ting Ho; Kakoli Das; Zul Fazreen Adam Isa; Zhimei Li; Xiaosai Yao; Tingdong Yan; Manjie Xing; Kie Kyon Huang; Joyce Suling Lin; Tannistha Nandi; Su Ting Tay; Ming Hui Lee; Angie Lay Keng Tan; Xuewen Ong; Hassan Ashktorab; Duane Smoot; Shang Li; Shyh-Chang Ng; Bin Tean Teh; Patrick Tan

    Objective Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes. Design We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. Results Gene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α -regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 ( IDH1 ) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors. Conclusions Our results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1 . Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.

    更新日期:2020-01-07
  • Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3
    Gut (IF 17.943) Pub Date : 2020-02-01
    Masahiro Maeda; Hideyuki Takeshima; Naoko Iida; Naoko Hattori; Satoshi Yamashita; Hiroshi Moro; Yoshimi Yasukawa; Kazuhiro Nishiyama; Taiki Hashimoto; Shigeki Sekine; Genichiro Ishii; Atsushi Ochiai; Takeo Fukagawa; Hitoshi Katai; Yoshiharu Sakai; Toshikazu Ushijima

    Objective Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells. Design Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database. Results CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such as WNT5A , GREM1 , NOG and IGF2 . Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration. Conclusions H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.

    更新日期:2020-01-07
  • Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing
    Gut (IF 17.943) Pub Date : 2020-02-01
    Lena Schleier; Maximilian Wiendl; Karin Heidbreder; Marie-Theres Binder; Raja Atreya; Timo Rath; Emily Becker; Anja Schulz-Kuhnt; Annette Stahl; Lisa Lou Schulze; Karen Ullrich; Simon F Merz; Lea Bornemann; Matthias Gunzer; Alastair J M Watson; Clemens Neufert; Imke Atreya; Markus F Neurath; Sebastian Zundler

    Objective To study the role of α4β7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4β7 inhibition with regard to intestinal wound healing. Design We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4β7 integrin. Results Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4β7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4β7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4β7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. Conclusion In addition to reported effects on lymphocytes, anti-α4β7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.

    更新日期:2020-01-07
  • IL23 group> IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes
    Gut (IF 17.943) Pub Date : 2020-02-01
    Rui Sun; Matija Hedl; Clara Abraham

    Objective The interleukin (IL)23 pathway contributes to IBD pathogenesis and is being actively studied as a therapeutic target in patients with IBD. Unexpected outcomes in these therapeutic trials have highlighted the importance of understanding the cell types and mechanisms through which IL23 regulates immune outcomes. How IL23 regulates macrophage outcomes and the consequences of the IL23R R381Q IBD-protective variant on macrophages are not well defined; macrophages are key players in IBD pathogenesis and inflammation. Design We analysed protein and RNA expression, signalling and localisation in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR, flow cytometry, immunoprecipitation and microscopy. Results IL23R was critical for optimal levels of pattern-recognition receptor (PRR)-induced signalling and cytokines in human MDMs. In contrast to the coreceptor IL12Rβ1, IL23 induced dynamic IL23R cell surface regulation and this required clathrin and dynamin-mediated endocytosis and endocytic recycling-dependent pathways; these pathways were essential for IL23R-mediated outcomes. The IBD-protective IL23R R381Q variant showed distinct outcomes. Relative to IL23R R381, HeLa cells expressing IL23R Q381 showed decreased IL23R recycling and reduced assembly of IL23R Q381 with Janus kinase/signal transducer and activator of transcription pathway members. In MDMs from IL23R Q381 carriers, IL23R accumulated in late endosomes and lysosomes on IL23 treatment and cells demonstrated decreased IL23R- and PRR-induced signalling and cytokines relative to IL23R R381 MDMs. Conclusion Macrophage-mediated inflammatory pathways are key contributors to IBD pathogenesis, and we identify an autocrine/paracrine IL23 requirement in PRR-initiated human macrophage outcomes and in human intestinal myeloid cells, establish that IL23R undergoes ligand-induced recycling, define mechanisms regulating IL23R-induced signalling and determine how the IBD-protective IL23R R381Q variant modulates these processes.

    更新日期:2020-01-07
  • Introduction of anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study
    Gut (IF 17.943) Pub Date : 2020-02-01
    Sanjay K Murthy; Jahanara Begum; Eric I Benchimol; Charles N Bernstein; Gilaad G Kaplan; Jeffrey D McCurdy; Harminder Singh; Laura Targownik; Monica Taljaard

    Objectives To better understand the real-world impact of biologic therapy in persons with Crohn’s disease (CD) and ulcerative colitis (UC), we evaluated the effect of marketplace introduction of infliximab on the population rates of hospitalisations and surgeries and public payer drug costs. Design We used health administrative data to study adult persons with CD and UC living in Ontario, Canada between 1995 and 2012. We used an interrupted time series design with segmented regression analysis to evaluate the impact of infliximab introduction on the rates of IBD-related hospitalisations, intestinal resections and public payer drug costs over 10 years among patients with CD and 5 years among patients with UC, allowing for a 1-year transition. Results Relative to what would have been expected in the absence of infliximab, marketplace introduction of infliximab did not produce significant declines in the rates of CD-related hospitalisations (OR at the last observation quarter 1.06, 95% CI 0.811 to 1.39) or intestinal resections (OR 1.10, 95% CI 0.810 to 1.50), or in the rates of UC-related hospitalisations (OR 1.22, 95% CI 1.07 to 1.39) or colectomies (OR 0.933, 95% CI 0.54 to 1.61). The findings were similar among infliximab users, except that hospitalisation rates declined substantially among UC patients following marketplace introduction of infliximab (OR 0.515, 95% CI 0.342 to 0.777). There was a threefold rise over expected trends in public payer drug cost among patients with CD following infliximab introduction (OR 2.98,95% CI 2.29 to 3.86), suggesting robust market penetration in this group, but no significant change among patients with UC (OR 1.06, 95% CI 0.955 to 1.18). Conclusions Marketplace introduction of infliximab has not yielded anticipated reductions in the population rates of IBD-related hospitalisations or intestinal resections, despite robust market penetration among patients with CD. Misguided use of infliximab in CD patients and underuse of infliximab in UC patients may largely explain our study findings.

    更新日期:2020-01-07
  • Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model
    Gut (IF 17.943) Pub Date : 2020-02-01
    Min-Soo Kim; Yoonhee Kim; Hyunjung Choi; Woojin Kim; Sumyung Park; Dongjoon Lee; Dong Kyu Kim; Haeng Jun Kim; Hayoung Choi; Dong-Wook Hyun; June-Young Lee; Eun Young Choi; Dong-Sup Lee; Jin-Woo Bae; Inhee Mook-Jung

    Objective Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. Design Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. Results Composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice. Conclusion These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

    更新日期:2020-01-07
  • Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study
    Gut (IF 17.943) Pub Date : 2020-02-01
    Annieke C G van Baar; Frits Holleman; Laurent Crenier; Rehan Haidry; Cormac Magee; David Hopkins; Leonardo Rodriguez Grunert; Manoel Galvao Neto; Paulina Vignolo; Bu’Hussain Hayee; Ann Mertens; Raf Bisschops; Jan Tijssen; Max Nieuwdorp; Caterina Guidone; Guido Costamagna; Jacques Devière; Jacques J G H M Bergman

    Background The duodenum has become a metabolic treatment target through bariatric surgery learnings and the specific observation that bypassing, excluding or altering duodenal nutrient exposure elicits favourable metabolic changes. Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure that has been shown to improve glycaemic control in people with type 2 diabetes mellitus (T2D) irrespective of body mass index (BMI) changes. DMR involves catheter-based circumferential mucosal lifting followed by hydrothermal ablation of duodenal mucosa. This multicentre study evaluates safety and feasibility of DMR and its effect on glycaemia at 24 weeks and 12 months. Methods International multicentre, open-label study. Patients (BMI 24–40) with T2D (HbA1c 59–86 mmol/mol (7.5%–10.0%)) on stable oral glucose-lowering medication underwent DMR. Glucose-lowering medication was kept stable for at least 24 weeks post DMR. During follow-up, HbA1c, fasting plasma glucose (FPG), weight, hepatic transaminases, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), adverse events (AEs) and treatment satisfaction were determined and analysed using repeated measures analysis of variance with Bonferroni correction. Results Forty-six patients were included of whom 37 (80%) underwent complete DMR and 36 were finally analysed; in remaining patients, mainly technical issues were observed. Twenty-four patients had at least one AE (52%) related to DMR. Of these, 81% were mild. One SAE and no unanticipated AEs were reported. Twenty-four weeks post DMR (n=36), HbA1c (−10±2 mmol/mol (−0.9%±0.2%), p<0.001), FPG (−1.7±0.5 mmol/L, p<0.001) and HOMA-IR improved (−2.9±1.1, p<0.001), weight was modestly reduced (−2.5±0.6 kg, p<0.001) and hepatic transaminase levels decreased. Effects were sustained at 12 months. Change in HbA1c did not correlate with modest weight loss. Diabetes treatment satisfaction scores improved significantly. Conclusions In this multicentre study, DMR was found to be a feasible and safe endoscopic procedure that elicited durable glycaemic improvement in suboptimally controlled T2D patients using oral glucose-lowering medication irrespective of weight loss. Effects on the liver are examined further. Trial registration number [NCT02413567][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02413567&atom=%2Fgutjnl%2F69%2F2%2F295.atom

    更新日期:2020-01-07
  • Prospective colonoscopic study to investigate risk of colorectal neoplasms in first-degree relatives of patients with non-advanced adenomas
    Gut (IF 17.943) Pub Date : 2020-02-01
    Siew C Ng; Moe Htet Kyaw; Bing Yee Suen; Yee Kit Tse; Martin C S Wong; Aric J Hui; Hui Yee Tak; James Y W Lau; Joseph J Y Sung; Francis K L Chan

    Objective The risk associated with a family history of non-advanced adenoma (non-AA) is unknown. We determined the prevalence of colorectal neoplasms in subjects who have a first-degree relative (FDR) with non-AA compared with subjects who do not have an FDR with adenomas. Design In a blinded, cross-sectional study, consecutive subjects with newly diagnosed non-AA were identified from our colonoscopy database. 414 FDRs of subjects with non-AA (known as exposed FDRs; mean age 55.0±8.1 years) and 414 age and sex-matched FDRs of subjects with normal findings from colonoscopy (known as unexposed FDRs; mean age 55.2±7.8 years) underwent a colonoscopy from November 2015 to June 2018. One FDR per family was recruited. FDRs with a family history of colorectal cancer were excluded. The primary outcome was prevalence of advanced adenoma (AA). Secondary outcomes included prevalence of all adenomas and cancer. Results The prevalence of AA was 3.9% in exposed FDRs and 2.4% in unexposed FDRs (matched OR (mOR)=1.67; 95% CI 0.72 to 3.91; p=0.238 adjusted for proband sex and proband age). Exposed FDRs had a higher prevalence of any adenomas (29.2% vs 18.6%; mOR=1.87; 95% CI 1.32 to 2.66; p<0.001) and non-AA (25.4% vs 16.2%; mOR=1.91; 95% CI 1.32 to 2.76; p=0.001). A higher proportion of exposed FDRs than unexposed FDRs (4.3% vs 2.2%; adjusted mOR=2.44; 95% CI 1.01 to 5.86; p=0.047) had multiple adenomas. No cancer was detected in both groups. Conclusion A positive family history of non-AA does not significantly increase the risk of clinically important colorectal neoplasia. The data support current guidelines which do not advocate earlier screening in individuals with a family history of non-AA. Trial registration number [NCT0252172][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT0252172&atom=%2Fgutjnl%2F69%2F2%2F304.atom

    更新日期:2020-01-07
  • Synthetic indicator of the impact of colorectal cancer screening programmes on incidence rates
    Gut (IF 17.943) Pub Date : 2020-02-01
    Manuel Zorzi; Marco Zappa

    Objective The impact of a screening programme on colorectal cancer (CRC) incidence in its target population depends on several variables, including coverage with invitations, participation rate, positivity rate of the screening test, compliance with an invitation to second-level assessment and endoscopists’ sensitivity. We propose a synthetic indicator that may account for all the variables influencing the potential impact of a screening programme on CRC incidence. Design We defined the ‘rate of advanced adenoma on the target population’ (AA-TAP) as the rate of patients who received a diagnosis of advanced adenoma within a screening programme, divided by the programme target population. We computed the AA-TAP for the CRC Italian screening programmes (biennial faecal immunochemical test, target population 50–69 year olds) using the data of the Italian National Survey from 2003 to 2016, overall and by region, and assessed the association between AA-TAP and CRC incidence fitting a linear regression between the trend of regional CRC incidence rates in 50–74 year old subjects and the cumulative AA-TAP. Results In 2016, the AA-TAP at a national level was 105×100 000, whereas significant differences were observed between the northern and central regions (respectively 126 and 149×100 000) and the South and Islands (36×100 000). The cumulative AA-TAP from 2004 to 2012 was significantly correlated with the difference between CRC incidence rates in 2013–2014 and those in 2003–2004 (p=0.009). Conclusion The AA-TAP summarises into a single indicator the potential impact of a screening programme in reducing CRC incidence rates.

    更新日期:2020-01-07
  • Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome
    Gut (IF 17.943) Pub Date : 2020-02-01
    Sangeetha N Kalimuthu; Gavin W Wilson; Robert C Grant; Matthew Seto; Grainne O’Kane; Rajkumar Vajpeyi; Faiyaz Notta; Steven Gallinger; Runjan Chetty

    Introduction Transcriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC. Design We first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes. Results We identified four morphological patterns that segregated into two components (‘gland forming’ and ‘non-gland forming’) based on the presence/absence of well-formed glands. A morphological cut-off (≥40% ‘non-gland forming’) was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as ‘classical’ using RNA-Seq. Conclusion Our study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

    更新日期:2020-01-07
  • Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression
    Gut (IF 17.943) Pub Date : 2020-02-01
    Jialing Shen; Mengnuo Chen; Derek Lee; Cheuk-Ting Law; Lai Wei; Felice Ho-Ching Tsang; Don Wai-Ching Chin; Carol Lai-Hung Cheng; Joyce Man-Fong Lee; Irene Oi-Lin Ng; Carmen Chak-Lui Wong; Chun-Ming Wong

    Objective Facilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC). Design We obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models. Results We showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib. Conclusion In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.

    更新日期:2020-01-07
  • A unique B cell epitope-based particulate vaccine shows effective suppression of hepatitis B surface antigen in mice
    Gut (IF 17.943) Pub Date : 2020-02-01
    Tian-Ying Zhang; Xue-Ran Guo; Yang-Tao Wu; Xiao-Zhen Kang; Qing-Bing Zheng; Ruo-Yao Qi; Bin-Bing Chen; Ying Lan; Min Wei; Shao-Juan Wang; Hua-Long Xiong; Jia-Li Cao; Bao-Hui Zhang; Xiao-Yang Qiao; Xiao-Fen Huang; Ying-Bin Wang; Mu-Jin Fang; Ya-Li Zhang; Tong Cheng; Yi-Xin Chen; Qin-Jian Zhao; Shao-Wei Li; Sheng-Xiang Ge; Pei-Jer Chen; Jun Zhang; Quan Yuan; Ning-shao Xia

    Objective This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. Methods A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically. Results Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. Conclusions The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.

    更新日期:2020-01-07
  • Polyploidy spectrum: a new marker in HCC classification
    Gut (IF 17.943) Pub Date : 2020-02-01
    Myriam Bou-Nader; Stefano Caruso; Romain Donne; Séverine Celton-Morizur; Julien Calderaro; Géraldine Gentric; Mathilde Cadoux; Antoine L’Hermitte; Christophe Klein; Thomas Guilbert; Miguel Albuquerque; Gabrielle Couchy; Valérie Paradis; Jean-Pierre Couty; Jessica Zucman-Rossi; Chantal Desdouets

    Objectives Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC. Design Ploidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections. Results We first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis. Conclusions Our results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.

    更新日期:2020-01-07
  • Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma
    Gut (IF 17.943) Pub Date : 2020-02-01
    Man Liu; Jingying Zhou; Xiaoyu Liu; Yu Feng; Weiqin Yang; Feng Wu; Otto Ka-Wing Cheung; Hanyong Sun; Xuezhen Zeng; Wenshu Tang; Myth T S Mok; John Wong; Philip Chun Yeung; Paul Bo San Lai; Zhiwei Chen; Hongchuan Jin; Jie Chen; Stephen Lam Chan; Anthony W H Chan; Ka Fai To; Joseph J Y Sung; Minhu Chen; Alfred Sze-Lok Cheng

    Objective Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. Design Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined. Results Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model. Conclusion Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

    更新日期:2020-01-07
  • Functional microRNA screen uncovers O-linked N-acetylglucosamine transferase as a host factor modulating hepatitis C virus morphogenesis and infectivity
    Gut (IF 17.943) Pub Date : 2020-02-01
    Katharina Herzog; Simonetta Bandiera; Sophie Pernot; Catherine Fauvelle; Frank Jühling; Amélie Weiss; Anne Bull; Sarah C Durand; Béatrice Chane-Woon-Ming; Sébastien Pfeffer; Marion Mercey; Hervé Lerat; Jean-Christophe Meunier; Wolfgang Raffelsberger; Laurent Brino; Thomas F Baumert; Mirjam B Zeisel

    Objective Infection of human hepatocytes by the hepatitis C virus (HCV) is a multistep process involving both viral and host factors. microRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Given that miRNAs were indicated to regulate between 30% and 75% of all human genes, we aimed to investigate the functional and regulatory role of miRNAs for the HCV life cycle. Design To systematically reveal human miRNAs affecting the HCV life cycle, we performed a two-step functional high-throughput miRNA mimic screen in Huh7.5.1 cells infected with recombinant cell culture-derived HCV. miRNA targeting was then assessed using a combination of computational and functional approaches. Results We uncovered miR-501-3p and miR-619-3p as novel modulators of HCV assembly/release. We discovered that these miRNAs regulate O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) protein expression and identified OGT and O-GlcNAcylation as regulators of HCV morphogenesis and infectivity. Furthermore, increased OGT expression in patient-derived liver tissue was associated with HCV-induced liver disease and cancer. Conclusion miR-501-3p and miR-619-3p and their target OGT are previously undiscovered regulatory host factors for HCV assembly and infectivity. In addition to its effect on HCV morphogenesis, OGT may play a role in HCV-induced liver disease and hepatocarcinogenesis.

    更新日期:2020-01-07
  • GI highlights from the literature
    Gut (IF 17.943) Pub Date : 2020-02-01
    Mairi H McLean

    ### An in vitro model of colitis and a new colitis-associated stem cell population Wang Y, Chiang IL, Ohara TE, et al . Long-term culture captures injury-repair cycles of colonic stem cells. Cell 2019; 179:1144–59. A stem cell population that mediates regeneration in colitis is unidentified. This is in part due to the challenge of an in vitro epithelial system with the continuous process of damage and repair. The authors used a chemical induced model of colitis (dextran sulphate sodium (DSS)) to show that crypts became atrophic during injury, with reduced expression of Lgr5 and Hopx. Subsequently hypertrophic crypts appeared adjacent to ulcers, and Hopx expression re-emerged in these crypts. An inducible Hopx-labelled mouse model showed that the Hopx positive cells also expressed the foetal-like marker Tacstd2. The Hopx cells could be lineage traced and gave rise to multiple differentiated cell lines. Sorted Hopx+ cells could form spheroids in culture. Ablation of Hopx cells after DSS injury led to apoptosis of the hypertrophic crypts and shorter colons. An in vitro epithelial monolayer was created by dissociating colonic spheroids into single cells and plating onto Transwell membranes submerged in medium for 7 days, before exposing them to an air–liquid interface (ALI). Hopx, but not Lgr5, labelled cells were expressed at the start of regeneration, which gave rise to the monolayer. Re-submerging and then re-exposing the monolayer to the ALI recapitulated the injury-regeneration cycle. Hopx was temporarily lost then re-emerged. Cellular stress was mediated by low oxygen tension, as it induced HIF1-mediated signalling. The authors give evidence that Hopx+ cells function as regenerative stem cells in colitis and oxygen tension acts as a switch between injury and regeneration. ### Targeting gut bacteria to treat alcoholic hepatitis Duan Y, Llorente C, Lang S, et al . Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019;575:505–11. doi:10.1038/s41586-019-1742-x. Alcoholic hepatitis (AH) continues to have a high mortality with limited treatment options available. In this article …

    更新日期:2020-01-07
  • Hepatitis D prevalence: problems with extrapolation to global population estimates
    Gut (IF 17.943) Pub Date : 2020-02-01
    Alexander J Stockdale; Benno Kreuels; Marc R Y Henrion; Emanuele Giorgi; Irene Kyomuhangi; Anna Maria Geretti

    We read the meta-analysis of global hepatitis D prevalence by Chen et al and have some serious concerns relating to the proposed epidemiological estimates.1 Seroprevalence of hepatitis delta virus (HDV) was not adequately defined. In the methods, hepatitis delta antibody (anti-HDV), HDV RNA and HDV antigen (HDAg) were described as markers of HDV infection. In Supplementary Table S8, it is evident that total, IgG and IgM anti-HDV and HDAg were variably used to define HDV infection. HDAg is a transient marker of HDV infection, whereas IgM expression is inconsistently associated with both acute and chronic infection; neither are suitable epidemiological markers of chronic HDV infection.2 A total of 50 cohorts were used to inform the primary outcome, global HDV seroprevalence in the general population; of these, 30 were conducted in the last 20 years. The authors estimated …

    更新日期:2020-01-07
  • Reduced efficacy of low FODMAPs diet in patients with IBS-D carrying sucrase-isomaltase (SI) hypomorphic variants
    Gut (IF 17.943) Pub Date : 2020-02-01
    Tenghao Zheng; Shanti Eswaran; Amanda L Photenhauer; Juanita L Merchant; William D Chey; Mauro D’Amato

    Recently in Gut and elsewhere,1–3 rare and common hypomorphic sucrase-isomaltase ( SI ) gene variants have been linked to an increased risk of IBS. Similar to congenital SI deficiency (a form of carbohydrate malabsorption caused by homozygous SI loss-of-function mutations),4 reduced SI enzymatic activity may trigger IBS symptoms via colonic accumulation of undigested disaccharides from starch and sucrose, resulting in fermentation with gas production and osmotic diarrhoea. This information holds potential for patients’ stratification, and the identification of IBS subgroups better suited to benefit from specific dietary restrictions. For instance, diets low in short chain carbohydrates like the FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols that are poorly absorbed in the small intestine) have been shown to be effective in reducing GI symptoms in some patients with IBS,5 6 though this has not been studied in relation to SI genotype and/or function. While sucrose and, in part, starch are not specifically restricted in a standard low FODMAP diet, such a therapeutic approach may be less effective in individuals whose reduced SI activity contributes …

    更新日期:2020-01-07
  • Follow-on rifaximin for the prevention of recurrence following standard treatment of infection with Clostridium difficile: a competing risks analysis provides a full picture of possible treatment effects
    Gut (IF 17.943) Pub Date : 2020-02-01
    Maja Katharina von Cube; Martin Schumacher; Martin Wolkewitz

    With interest we read the article by Major et al 1 on the effect of rifaximin ‘follow-on’ treatment to prevent recurrent Clostridium difficile infection (rCDI). Major et al point out the advantage of their study sample being composed of elderly patients who represent the frailties and comorbidities of the target population. The frailty of the sample is reflected by the, compared with other trials on new agents, higher mortality rate, which is considered to increase the generalisability of the results to daily clinical practice. A main statistical challenge when studying a frail patient population using a non-fatal endpoint is dealing with mortality.2 Patients who died without rCDI are no longer at risk of a recurrent infection. Thus, death is a competing risk of rCDI. In their analysis, Major et al first exclude patients who have died or have withdrawn from the study before end of follow-up by using generalised estimating equations to estimate the risk difference (RD) of rCDI. Second, they treat them equally as randomly censored by using a Kaplan-Meier estimator (K-M) to estimate the …

    更新日期:2020-01-07
  • Identification of trimethylamine N-oxide (TMAO)-producer phenotype is interesting, but is it helpful?
    Gut (IF 17.943) Pub Date : 2020-02-01
    Arduino Arduini; Victor A Zammit; Mario Bonomini

    We read with great interest the paper by Wu et al 1 reporting on the development of a carnitine challenge test to facilitate the identification of trimethylamine N-oxide (TMAO)-producer phenotype and host-diet-gut dysbiosis. Such a test assumes that, according to a partial reading of the literature, TMAO plays a key role in cardiovascular disease (CVD). Accordingly, the authors assert the implied importance of the potential for adverse CVD-inducing actions of compounds generating TMAO subsequent to the action of gut microbiota on dietary carnitine. However, a more objective reading of the literature shows that the biomedical community is still debating the potential involvement of TMAO in inducing …

    更新日期:2020-01-07
  • Microscopic heterogeneity in ulcerative colitis: implications for microscopic measurement of disease activity
    Gut (IF 17.943) Pub Date : 2020-02-01
    Noam Harpaz; Samuel Ballentine; Jean-Frederic Colombel; Bruce E Sands; Huabin Mabel Ko

    Growing interest in histological measurements of inflammatory activity to determine therapeutic efficacy and endpoints in IBD has been accompanied by progress in developing and validating scoring instruments for this purpose.1–5 Four histological grading instruments, the Geboes score, Nancy index, Robarts Histological Index (RHI) and modified Riley score, have recently demonstrated responsiveness to clinical changes based on data from a phase II trial of ozanimod.6 Further refinement of the operating characteristics of these instruments and definition of threshold values for remission can be expected.7 Less attention has been given to pre-analytical factors which might affect the histological assessment of disease activity and the definition of therapeutic endpoints, such as biopsy sampling density and target selection. Clinical consensus guidelines have thus far provided only empirical guidance. The European Crohn’s and Colitis Organisation (ECCO) guidelines for initial IBD diagnosis recommend two forceps biopsies from each of five sites in the colorectum and terminal ileum and separate biopsies from endoscopically distinct regions8 but do not address sampling density and target selection in other clinical situations. Likewise, uniform standards for biopsy sampling in therapeutic drug trials are lacking. One study has reported good endoscopic concordance between the rectosigmoid and proximal colon at baseline …

    更新日期:2020-01-07
  • Biliary dilatation in a 67-year-old woman: seeing is believing
    Gut (IF 17.943) Pub Date : 2020-02-01
    Peng Pan; Sheng-bing Zhao; Shuling Wang; Zhaoshen Li; Yu Bai

    A 67-year-old woman presented with paroxysmal epigastric pain for 3 months, without jaundice. She gave a history of cholecystectomy. Physical examination and blood tests were unremarkable. Magnetic resonance cholangiopancreatography showed cystic dilatation of the common bile duct (CBD), intrahepatic and extrahepatic bile duct dilatation and suspicious intrahepatic bile duct stones (figure 1). CT scan showed intrahepatic and extrahepatic bile duct dilatation and multiple intrahepatic bile duct stones (figure 2). Figure 1 Magnetic resonance cholangiopancreatography showed cystic dilatation of the common bile duct, intrahepatic …

    更新日期:2020-01-07
  • The epidemiology of hepatitis delta virus infection in Cameroon
    Gut (IF 17.943) Pub Date : 2020-01-06
    Camille Besombes; Richard Njouom; Juliette Paireau; Guillaume Lachenal; Gaëtan Texier; Mathurin Tejiokem; Simon Cauchemez; Jacques Pépin; Arnaud Fontanet

    Objective To investigate the distribution and risk factors of hepatitis delta virus (HDV) infection in Cameroon. Design We tested for hepatitis B virus (HBV) surface antigen (HBsAg) and anti-HDV antibody 14 150 samples collected during a survey whose participants were representative of the Cameroonian adult population. The samples had already been tested for hepatitis C virus and HIV antibodies. Results Overall, 1621/14 150 (weighted prevalence=11.9%) participants were HBsAg positive, among whom 224/1621 (10.6%) were anti-HDV positive. In 2011, the estimated numbers of HBsAg positive and HDV seropositives were 1 160 799 and 122 910 in the 15–49 years age group, respectively. There were substantial regional variations in prevalence of chronic HBV infection, but even more so for HDV (from 1% to 54%). In multivariable analysis, HDV seropositivity was independently associated with living with an HDV-seropositive person (OR=8.80; 95% CI: 3.23 to 24.0), being HIV infected (OR=2.82; 95% CI: 1.32 to 6.02) and living in the South (latitude <4°N) while having rural/outdoor work (OR=15.2; 95% CI: 8.35 to 27.6, when compared with living on latitude ≥4°N and not having rural/outdoor work). Conclusion We found evidence for effective intra-household transmission of HDV in Cameroon. We also identified large differences in prevalence between regions, with cases concentrated in forested areas close to the Equator, as described in other tropical areas. The reasons underlying these geographical variations in HDV prevalence deserve further investigation.

    更新日期:2020-01-07
  • Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas
    Gut (IF 17.943) Pub Date : 2020-01-06
    Quentin Bayard; Stefano Caruso; Gabrielle Couchy; Sandra Rebouissou; Paulette Bioulac Sage; Charles Balabaud; Valerie Paradis; Nathalie Sturm; Anne de Muret; Catherine Guettier; Benjamin Bonsang; Christiane Copie; Eric Letouzé; Julien Calderaro; Sandrine Imbeaud; Jean-Charles Nault; Jessica Zucman-Rossi

    Background Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype. Methods 657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing. Results We identified 296 IHCA (45%), 81% of them were mutated in either IL6ST (61%), FRK (8%), STAT3 (5%), GNAS (3%) or JAK1 (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving ROS1, FRK or IL6 genes. ROS1 fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver ( PLG , RBP4 , APOB ) fused with exon 33–35 to 43 of ROS1 including the tyrosine kinase domain. In two cases a truncated ROS1 transcript from exon 36 to 43 was identified. ROS1 rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to ROS1 overexpression. Among the 5 IHCA with FRK rearrangements, 5 different partners were identified ( MIA3 , MIA2 , LMO7 , PLEKHA5, SEC16B ) fused to a common region in FRK that included exon 3–8. No overexpression of FRK transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2–SH3 domains. In two IHCA, we identified truncated 3’UTR of IL6 associated with overexpression of the transcript. Conclusion Recurrent chromosomal alterations involving ROS1 , FRK or IL6 genes lead to activation of the JAK/STAT pathway in IHCAs.

    更新日期:2020-01-07
  • Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn’s disease: results from two large prospective cohort studies
    Gut (IF 17.943) Pub Date : 2020-01-03
    Hamed Khalili; Niclas Håkansson; Simon S Chan; Ye Chen; Paul Lochhead; Jonas F Ludvigsson; Andrew T Chan; Andrew R Hart; Ola Olén; Alicja Wolk

    Objective To examine the relationship between Mediterranean diet and risk of later-onset Crohn’s disease (CD) or ulcerative colitis (UC). Design We conducted a prospective cohort study of 83 147 participants (age range: 45–79 years) enrolled in the Cohort of Swedish Men and Swedish Mammography Cohort. A validated food frequency questionnaire was used to calculate an adherence score to a modified Mediterranean diet (mMED) at baseline in 1997. Incident diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modelling to calculate HRs and 95% CI. Results Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC with an average follow-up of 17 years. Higher mMED score was associated with a lower risk of CD (Ptrend=0.03) but not UC (Ptrend=0.61). Compared with participants in the lowest category of mMED score (0–2), there was a statistically significant lower risk of CD (HR=0.42, 95% CI 0.22 to 0.80) but not UC (HR=1.08, 95% CI 0.74 to 1.58). These associations were not modified by age, sex, education level, body mass index or smoking (all Pinteraction >0.30). The prevalence of poor adherence to a Mediterranean diet (mMED score=0–2) was 27% in our cohorts, conferring a population attributable risk of 12% for later-onset CD. Conclusion In two prospective studies, greater adherence to a Mediterranean diet was associated with a significantly lower risk of later-onset CD.

    更新日期:2020-01-04
  • Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation
    Gut (IF 17.943) Pub Date : 2020-01-03
    Xia Chen; Pan Li; Mian Liu; Huimin Zheng; Yan He; Mu-Xuan Chen; Wenli Tang; Xiaojing Yue; Yongxin Huang; Lingling Zhuang; Zhijian Wang; Mei Zhong; Guibao Ke; Haoyue Hu; Yinglin Feng; Yun Chen; Yanhong Yu; Hongwei Zhou; Liping Huang

    Objective Pre-eclampsia (PE) is one of the malignant metabolic diseases that complicate pregnancy. Gut dysbiosis has been identified for causing metabolic diseases, but the role of gut microbiome in the pathogenesis of PE remains unknown. Design We performed a case–control study to compare the faecal microbiome of PE and normotensive pregnant women by 16S ribosomal RNA (rRNA) sequencing. To address the causative relationship between gut dysbiosis and PE, we used faecal microbiota transplantation (FMT) in an antibiotic-treated mouse model. Finally, we determined the microbiome translocation and immune responses in human and mouse placental samples by 16S rRNA sequencing, quantitative PCR and in situ hybridisation. Results Patients with PE showed reduced bacterial diversity with obvious dysbiosis. Opportunistic pathogens, particularly Fusobacterium and Veillonella , were enriched, whereas beneficial bacteria, including Faecalibacterium and Akkermansia , were markedly depleted in the PE group. The abundances of these discriminative bacteria were correlated with blood pressure (BP), proteinuria, aminotransferase and creatinine levels. On successful colonisation, the gut microbiome from patients with PE triggered a dramatic, increased pregestational BP of recipient mice, which further increased after gestation. In addition, the PE-transplanted group showed increased proteinuria, embryonic resorption and lower fetal and placental weights. Their T regulatory/helper-17 balance in the small intestine and spleen was disturbed with more severe intestinal leakage. In the placenta of both patients with PE and PE-FMT mice, the total bacteria, Fusobacterium , and inflammatory cytokine levels were significantly increased. Conclusions This study suggests that the gut microbiome of patients with PE is dysbiotic and contributes to disease pathogenesis.

    更新日期:2020-01-04
  • Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes
    Gut (IF 17.943) Pub Date : 2020-01-02
    Ning Ding; Xin Zhang; Xue Di Zhang; Jun Jing; Shan Shan Liu; Yun Ping Mu; Li Li Peng; Yun Jing Yan; Geng Miao Xiao; Xin Yun Bi; Hao Chen; Fang Hong Li; Bing Yao; Allan Z Zhao

    Objective High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility. Design Faecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin. Results Transplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus Bacteroides and Prevotella , both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of Bacteroides-Prevotella and sperm motility, and a positive correlation between blood endotoxin and Bacteroides abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice. Conclusion We revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes. Trial registration number [NCT03634644][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03634644&atom=%2Fgutjnl%2Fearly%2F2020%2F01%2F02%2Fgutjnl-2019-319127.atom

    更新日期:2020-01-04
  • Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease
    Gut (IF 17.943) Pub Date : 2020-01-02
    Silvia Sookoian; Adrian Salatino; Gustavo Osvaldo Castaño; Maria Silvia Landa; Cinthia Fijalkowky; Martin Garaycoechea; Carlos Jose Pirola

    Objective We aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosis, as differences in the host phenotypic features—from moderate to severe obesity—may be associated with significant changes in the microbial DNA profile. Design and methods Liver tissue samples from 116 individuals, comprising of 47 NAFLD overweight or moderately obese patients, 50 NAFLD morbidly obese patients elected for bariatric surgery and 19 controls, were analysed using high-throughput 16S rRNA gene sequencing. Results Liver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Bacteroidetes (p=1.8e-18) and Firmicutes (p=0.0044) were over-represented in morbidly obese patients and Proteobacteria (p=5.2e-10)—specifically Gammaproteobacteria and Alphaproteobacteria, and Deinococcus-Thermus (p=0.00012)—were over-represented in the non-morbidly obese cohort. Cohort-specific analysis of liver microbial DNA signatures shows patterns linked to obesity. The imbalance in Proteobacteria (Alpha or Gamma) among non-morbidly obese patients, and Peptostreptococcaceae, Verrucomicrobia, Actinobacteria and Gamma Proteobacteria DNA among morbidly obese patients was associated with histological severity. Decreased amounts of bacterial DNA from the Lachnospiraceae family were associated with more severe histological features. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences. Conclusion This is the first comprehensive study showing that the liver tissue of NAFLD patients contains a diverse repertoire of bacterial DNA (up to 2.5×104 read counts). The liver metataxonomic signature may explain differences in the NAFLD pathogenic mechanisms as well as physiological functions of the host.

    更新日期:2020-01-04
  • Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting
    Gut (IF 17.943) Pub Date : 2019-12-26
    Matias A Avila; Jean-François Dufour; Alexander L Gerbes; Fabien Zoulim; Ramon Bataller; Patrizia Burra; Helena Cortez-Pinto; Bin Gao; Ian Gilmore; Philippe Mathurin; Christophe Moreno; Vladimir Poznyak; Bernd Schnabl; Gyongyi Szabo; Maja Thiele; Mark R Thursz

    Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area. In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.

    更新日期:2019-12-27
  • Antibiotic use and colorectal cancer: a causal association?
    Gut (IF 17.943) Pub Date : 2019-12-24
    Wenjie Ma; Andrew T Chan

    Antibiotics have revolutionised our ability to fight infectious diseases that are major causes of morbidity and mortality. However, the widespread use of these powerful agents has led to unintended consequences that reflect their broad effects on microbial community structure. Even short-term antibiotic treatment causes shifts in gut microbiota including, but not limited to, alterations in the abundance of specific taxa and a decrease in overall diversity. Clostridium difficile colitis and vaginal candidiasis are established examples of conditions that originate from gut dysbiosis and opportunistic pathogen colonisation induced by short-term antibiotics. Emerging data also suggest that antibiotic-induced perturbations can persist for years after treatment and contribute to long-term dysregulation of host immune homeostasis.1 In turn, this can potentially increase susceptibility to chronic disorders with an immune basis, including asthma, inflammatory bowel disease and obesity. Recent epidemiological studies have extended the association between antibiotic exposure and chronic disease to risk of colorectal adenoma and colorectal cancer (CRC).2 In parallel, increasing evidence has demonstrated a pivotal role for the interplay between the gut microbiome and lifestyle factors in initiating and promoting CRC.3 Several species of bacteria have been shown to be potential drivers of carcinogenesis through specific biological mechanisms. For example, Fusobacterium nucleatum expresses adhesins, including FadA and Fap2, which bind to tumour cells and directly promote carcinogenesis by activating oncogenic Wnt/β-catenin signalling and dysregulating immune cell infiltration and antitumour immunity. Enterotoxigenic Bacteroides fragilis forms biofilms in the colonic mucosal membrane, …

    更新日期:2019-12-25
  • Dysphagia in a young female patient: it’s not always that simple
    Gut (IF 17.943) Pub Date : 2019-12-24
    Joana Carvão; Armando Peixoto; Elisabete Rios; Guilherme Macedo

    A 42-year-old female patient was referred to our gastroenterology department with a 4-month history of weekly symptoms of dysphagia for solids and liquids. The patient also reported occasional symptoms of food impaction and heartburn. She denied nausea, vomiting, weight loss or a recent change in bowel habits. The patient was not under any medication. Medical or surgical history was unremarkable. There was no family history of gastrointestinal cancer. Physical examination was normal, and laboratory tests did not reveal anaemia or other abnormalities. She underwent an oesophagogastroduodenoscopy, and the oesophagus is shown in figure 1. Biopsies were performed in the upper and lower parts of the oesophagus and …

    更新日期:2019-12-25
  • Reply to ‘Are the 5-hydroxymethylcytosine-based wd-scores really superior over α-fetoprotein for the early diagnosis of hepatocellular carcinoma?’
    Gut (IF 17.943) Pub Date : 2019-12-23
    Jiabin Cai; Zhou Zhang; Chuan He; Wei Zhang; Jia Fan

    We thank Chen and Lin for their interest in our article.1 They raised concerns about the comparison between α-fetoprotein (AFP) and the 5-hydroxymethylcytosine (5hmC)-based weighted diagnostic (wd)-scores,2 a debate worth further clarification. First, it should be clarified that Chen and Lin’s description did not represent the overall picture of the wd-scores.1 The performance measures mentioned by Chen and Lin were specifically for distinguishing early hepatocellular carcinoma (HCC) and non-HCC (including not just chronic hepatitis B (CHB) virus infection but also benign liver lesions, liver cirrhosis (LC) and healthy controls) in the validation set. Notably, the 5hmC-based wd-scores consistently outperformed AFP in both training and validation sets for HCC versus non-HCC, early HCC versus CHB/LC, and early HCC versus controls (healthy individuals, benign liver lesions). Compared with AFP alone, the 5hmC-based wd-scores performed especially well when detecting early …

    更新日期:2019-12-23
  • Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis: results from the TRUST&UC study
    Gut (IF 17.943) Pub Date : 2019-12-20
    Christian Maaser; Frauke Petersen; Ulf Helwig; Imma Fischer; Alexander Roessler; Stefan Rath; Dorothee Lang; Torsten Kucharzik

    Objective Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice. Design TRansabdominal Ultrasonography of the bowel in Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography. Results At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%–38.6%; descending colon 83.0%–42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001). Conclusions IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.

    更新日期:2019-12-21
  • Faecal haemoglobin concentration among subjects with negative FIT results is associated with the detection rate of neoplasia at subsequent rounds: a prospective study in the context of population based screening programmes in Italy
    Gut (IF 17.943) Pub Date : 2019-12-19
    Carlo Senore; Marco Zappa; Cinzia Campari; Sergio Crotta; Paola Armaroli; Arrigo Arrigoni; Paola Cassoni; Rossana Colla; Mario Fracchia; Fabrizio Gili; Grazia Grazzini; Roberto Lolli; Patrizia Menozzi; Lorenzo Orione; Salvatore Polizzi; Stefano Rapi; Emilia Riggi; Tiziana Rubeca; Romano Sassatelli; Carmen Visioli; Nereo Segnan

    Objective To estimate the predictive role of faecal haemoglobin (f-Hb) concentration among subjects with faecal immunochemical test (FIT) results below the positivity cut-off for the subsequent risk of advanced neoplasia (AN: colorectal cancer—CRC—or advanced adenoma). Design Prospective cohort of subjects aged 50–69 years, undergoing their first FIT between 1 January 2004 and 31 December 2010 in four population-based programmes in Italy. Methods All programmes adopted the same analytical procedure (OC Sensor, Eiken Japan), performed every 2 years, on a single sample, with the same positivity cut-off (20 µg Hb/g faeces). We assessed the AN risk at subsequent exams, the cumulative AN detection rate (DR) over the 4-year period following the second FIT and the interval CRC (IC) risk following two negative FITs by cumulative amount of f-Hb concentration over two consecutive negative FITs, using multivariable logistic regression models and the Kaplan-Meier method. Results The cumulative probability of a positive FIT result over the subsequent two rounds ranged between 7.8% (95% CI 7.5 to 8.2) for subjects with undetectable f-Hb at the initial two tests (50% of the screenees) and 48.4% (95% CI 44.0 to 53.0) among those (0.7% of the screenees) with a cumulative f-Hb concentration ≥20 µg/g faeces. The corresponding figures for cumulative DR were: 1.4% (95% CI 1.3 to 1.6) and 25.5% (95% CI 21.4 to 30.2) for AN; 0.17% (95% CI 0.12 to 0.23) and 4.5% (95% CI 2.8 to 7.1) for CRC. IC risk was also associated with cumulative f-Hb levels. Conclusion The association of cumulative f-Hb concentration with subsequent AN and IC risk may allow to design tailored strategies to optimise the utilisation of endoscopy resources: subjects with cumulative f-Hb concentration ≥20 µg/g faeces over two negative tests could be referred immediately for total colonoscopy (TC), while screening interval might be extended for those with undetectable f-Hb.

    更新日期:2019-12-20
  • Effect of Helicobacter pylori on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer
    Gut (IF 17.943) Pub Date : 2019-12-19
    Yang Guo; Yang Zhang; Markus Gerhard; Juan-Juan Gao; Raquel Mejias-Luque; Lian Zhang; Michael Vieth; Jun-Ling Ma; Monther Bajbouj; Stepan Suchanek; Wei-Dong Liu; Kurt Ulm; Michael Quante; Zhe-Xuan Li; Tong Zhou; Roland Schmid; Meinhard Classen; Wen-Qing Li; Wei-Cheng You; Kai-Feng Pan

    Objective Gastrointestinal microbiota may be involved in Helicobacter pylori- associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from H. pylori infection. Design Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti- H. pylori treatment, relative to 49 H . pylori negative subjects. Results In H. pylori positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in H. pylori positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between Helicobacter and Fusobacterium , Neisseria , Prevotella , Veillonella , Rothia were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased Bifidobacterium after successful H. pylori eradication and more upregulated drug-resistant functional orthologs after failed treatment. Conclusion H. pylori infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful H. pylori eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.

    更新日期:2019-12-20
  • Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study
    Gut (IF 17.943) Pub Date : 2019-12-18
    Magdy El-Salhy; Jan Gunnar Hatlebakk; Odd Helge Gilja; Anja Bråthen Kristoffersen; Trygve Hausken

    Objective Faecal microbiota transplantation (FMT) from healthy donors to patients with irritable bowel syndrome (IBS) has been attempted in two previous double-blind, placebo-controlled studies. While one of those studies found improvement of the IBS symptoms, the other found no effect. The present study was conducted to clarify these contradictory findings. Design This randomised, double-blind, placebo-controlled study randomised 165 patients with IBS to placebo (own faeces), 30 g FMT or 60 g FMT at a ratio of 1:1:1. The material for FMT was obtained from one healthy, well-characterised donor, frozen and administered via gastroscope. The primary outcome was a reduction in the IBS symptoms at 3 months after FMT (response). A response was defined as a decrease of 50 or more points in the total IBS symptom score. The secondary outcome was a reduction in the dysbiosis index (DI) and a change in the intestinal bacterial profile, analysed by 16S rRNA gene sequencing, at 1 month following FMT. Results Responses occurred in 23.6%, 76.9% (p<0.0001) and 89.1% (p<00.0001) of the patients who received placebo, 30 g FMT and 60 g FMT, respectively. These were accompanied by significant improvements in fatigue and the quality of life in patients who received FMT. The intestinal bacterial profiles changed also significantly in the groups received FMT. The FMT adverse events were mild self-limiting gastrointestinal symptoms. Conclusions FMT is an effective treatment for patients with IBS. Utilising a well-defined donor with a normal DI and favourable specific microbial signature is essential for successful FMT. The response to FMT increases with the dose. Trial registration [www.clinicaltrials.gov][1] ([NCT03822299][2]) and [www.cristin.no][3] (ID657402). [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03822299&atom=%2Fgutjnl%2Fearly%2F2019%2F12%2F18%2Fgutjnl-2019-319630.atom [3]: http://www.cristin.no

    更新日期:2019-12-19
  • Meta-analysis of the efficacy and safety of PD-1/PD-L1 inhibitors administered alone or in combination with anti-VEGF agents in advanced hepatocellular carcinoma
    Gut (IF 17.943) Pub Date : 2019-12-18
    Zhichao Feng; Pengfei Rong; Wei Wang

    We read with great interest the article by Gerbes et al, 1 which indicated the prospects of immune-based therapies in hepatocellular carcinoma (HCC) and that by Zhu et al, 2 which proposed their new strategy for sensitising HCC to anti-programmed death-ligand 1 (PD-L1) blockade. As they suggest, immunotherapy for HCC has great potential, and combination therapy may further improve survival benefits. Many patients with HCC have advanced stage disease (aHCC) at the time of diagnosis, and some of them even have progressive disease after first-line therapy. Recently, the clinical benefits of immunotherapy for HCC have emerged. Blocking the PD‐1/PD‐L1 signalling pathway with humanised monoclonal antibodies is effective in alleviating immune escape and enhancing T cell‐mediated antitumour immunity. However, no more than 20% of patients with HCC robustly respond to anti-programmed cell death protein 1 (PD-1)/PD-L1 monotherapy.3 4 The combination of anti-vascular endothelial growth factor (VEGF) agents with PD‐1/PD‐L1 blockade may synergistically reverse the immunosuppressive microenvironment.5 Preclinical and …

    更新日期:2019-12-19
  • ‘Blast from the past’ colonoscopy complication treated with a novel approach
    Gut (IF 17.943) Pub Date : 2019-12-17
    Mohamed Shiha; Stuart Laidlaw; Lesley Hunt; Andrew D Hopper

    A 72-year-old man was referred for a flexible sigmoidoscopy because of transfusion-dependent rectal bleeding. The patient had undergone an allogeneic stem cell transplant for acute myeloid leukaemia and had previous radiotherapy for prostate cancer. A previous sigmoidoscopy had diagnosed a solitary rectal ulcer and diffuse bleeding from radiation proctitis treated with haemostatic powder. Blood tests prior to the repeat sigmoidoscopy showed thrombocytopaenia (47×109/L) and neutropaenia (0.33×109/L) and normal coagulation. A platelet transfusion and a phosphate enema were administered preprocedure, and a flexible sigmoidoscopy was performed to the descending colon using carbon dioxide insufflation. There was no evidence …

    更新日期:2019-12-18
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