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ISSN (Print) 0017-5749 - ISSN (Online) 1468-3288
Published by BMJ Publishing Group Homepage  [57 journals]
  • Potential of butyrate to influence food intake in mice and men
    • Authors: Fluitman, K. S; Wijdeveld, M, Nieuwdorp, M, IJzerman, R. G.
      Pages: 1203 - 1204
      Abstract: In recent years, many studies have been dedicated towards elucidating the role of the intestinal microbiota in metabolic health. It was suggested that specific intestinal microbial compositions can either protect from—or contribute to obesity and metabolic diseases. A causal relation between the microbiota and host metabolic profile was demonstrated when faecal microbiota of lean and obese subjects was transferred into mice, which then exhibited corresponding phenotypes.1 Short chain fatty acids (SCFAs) have broadly been proposed as key mediators in the microbiota-induced metabolic effects on the host. They are produced by bacterial fermentation of otherwise indigestible nutrients. The most abundant SCFAs are propionate, acetate and butyrate. All have been extensively studied in murine models for their possible influence on colonic health, glucose and lipid metabolism, as well as appetite and energy expenditure. Although various mechanisms by which these SCFAs exert their effect were suggested,2–7
      Keywords: Open access, Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-315543
      Issue No: Vol. 67, No. 7 (2018)
  • Take me to the liver: adipose tissue macrophages coordinate hepatic
           neutrophil recruitment
    • Authors: Pernes, G; Lancaster, G. I, Murphy, A. J.
      Pages: 1204 - 1206
      Abstract: In the lean, healthy state, adipose tissue (AT) has critical roles in maintaining organismal homeostasis. Paramount among the various roles of AT is the regulation of whole body metabolism. While adipocytes per se are key players in metabolic homeostasis, for example, by storing nutrients and releasing soluble factors, work over the last decade has revealed that AT-resident immune cells have a profound impact on AT function. Obesity is a risk factor for numerous conditions, including cardiovascular disease, type 2 diabetes, cancer, osteoarthritis, sleep apnoea and infertility. Obesity is also a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), an effect that is primarily attributable to increased hepatic lipid accumulation and inflammation. During the development of obesity, the AT expands and the AT-resident immune cell profile is dramatically altered,1 ultimately initiating AT inflammation and altered whole body metabolism. Most prominent...
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-315393
      Issue No: Vol. 67, No. 7 (2018)
  • Loss of KRAS control as consequence of downregulated microRNA-622 in
           hepatocellular carcinoma and its potential therapeutic implication
    • Authors: Bantel, H; Canbay, A.
      Pages: 1206 - 1207
      Abstract: Hepatocellular carcinoma (HCC) represents a serious and urgent global health problem because of its increasing incidence and the limited therapeutic options.1 2 The standard treatment for patients with advanced HCC is the multikinase inhibitor sorafenib, which shows only modest survival improvement of approximately 2–3 months and remains associated with disease progression in a large number of patients.3 4 Therefore, to improve the survival of patients with advanced HCC, it is fundamental to understand the mechanisms of sorafenib resistance. The antitumour efficacy of sorafenib is mainly based on the inhibition of the proliferative RAF/mitogen-activated protein kinase (MAPK) pathway, which is regulated by upstream RAS proteins.5 6 The majority of human HCCs shows an activation of this pathway, which is associated with shorter survival.6–9 In contrast to other human tumours, RAS activation in...
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-315630
      Issue No: Vol. 67, No. 7 (2018)
  • Consensus guidelines on the optimal management in interventional EUS
           procedures: results from the Asian EUS group RAND/UCLA expert panel
    • Authors: Teoh, A. Y. B; Dhir, V, Kida, M, Yasuda, I, Jin, Z. D, Seo, D. W, Almadi, M, Ang, T. L, Hara, K, Hilmi, I, Itoi, T, Lakhtakia, S, Matsuda, K, Pausawasdi, N, Puri, R, Tang, R. S, Wang, H.-P, Yang, A. M, Hawes, R, Varadarajulu, S, Yasuda, K, Ho, L. K. Y.
      Pages: 1209 - 1228
      Abstract: ObjectivesInterventional endoscopic ultrasonography (EUS) procedures are gaining popularity and the most commonly performed procedures include EUS-guided drainage of pancreatic pseudocyst, EUS-guided biliary drainage, EUS-guided pancreatic duct drainage and EUS-guided celiac plexus ablation. The aim of this paper is to formulate a set of practice guidelines addressing various aspects of the above procedures.MethodsFormulation of the guidelines was based on the best scientific evidence available. The RAND/UCLA appropriateness methodology (RAM) was used. Panellists recruited comprised experts in surgery, interventional EUS, interventional radiology and oncology from 11 countries. Between June 2014 and October 2016, the panellists met in meetings to discuss and vote on the clinical scenarios for each of the interventional EUS procedures in question.ResultsA total of 15 statements on EUS-guided drainage of pancreatic pseudocyst, 15 statements on EUS-guided biliary drainage, 12 statements on EUS-guided pancreatic duct drainage and 14 statements on EUS-guided celiac plexus ablation were formulated. The statements addressed the indications for the procedures, technical aspects, pre- and post-procedural management, management of complications, and competency and training in the procedures. All statements except one were found to be appropriate. Randomised studies to address clinical questions in a number of aspects of the procedures are urgently required.ConclusionsThe current guidelines on interventional EUS procedures are the first published by an endoscopic society. These guidelines provide an in-depth review of the current evidence and standardise the management of the procedures.
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-314341
      Issue No: Vol. 67, No. 7 (2018)
  • Diagnosis and risk stratification of Barretts dysplasia by flow cytometric
           DNA analysis of paraffin-embedded tissue
    • Authors: Choi, W.-T; Tsai, J.-H, Rabinovitch, P. S, Small, T, Huang, D, Mattis, A. N, Kakar, S.
      Pages: 1229 - 1238
      Abstract: ObjectiveThe diagnosis of dysplasia in Barrett’s oesophagus (BO) can be challenging, and reliable ancillary techniques are not available. This study examines if DNA content abnormality detected by flow cytometry can serve as a diagnostic marker of dysplasia and facilitate risk stratification of low-grade dysplasia (LGD) and indefinite for dysplasia (IND) patients using formalin-fixed paraffin-embedded (FFPE) BO samples with varying degrees of dysplasia.DesignDNA flow cytometry was performed on 80 FFPE BO samples with high-grade dysplasia (HGD), 38 LGD, 21 IND and 14 negative for dysplasia (ND). Three to four 60-micron thick sections were cut from each tissue block, and the area of interest was manually dissected.ResultsDNA content abnormality was identified in 76 HGD (95%), 8 LGD (21.1%), 2 IND (9.5%) and 0 ND samples. As a diagnostic marker of HGD, the estimated sensitivity and specificity of DNA content abnormality were 95% and 85%, respectively. For patients with DNA content abnormality detected at baseline LGD or IND, the univariate HRs for subsequent detection of HGD or oesophageal adenocarcinoma (OAC) were 7.0 and 20.0, respectively (p =
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-313815
      Issue No: Vol. 67, No. 7 (2018)
  • Dynamics of Helicobacter pylori infection as a determinant of progression
           of gastric precancerous lesions: 16-year follow-up of an eradication trial
    • Authors: Mera, R. M; Bravo, L. E, Camargo, M. C, Bravo, J. C, Delgado, A. G, Romero-Gallo, J, Yepez, M. C, Realpe, J. L, Schneider, B. G, Morgan, D. R, Peek, R. M, Correa, P, Wilson, K. T, Piazuelo, M. B.
      Pages: 1239 - 1246
      Abstract: ObjectiveTo evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions.Design795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1–6). The score difference between baseline and 16 years was modelled by generalised linear models.ResultsIndividuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2016-311685
      Issue No: Vol. 67, No. 7 (2018)
  • Epidermal growth factor receptor inhibition downregulates Helicobacter
           pylori-induced epithelial inflammatory responses, DNA damage and gastric
    • Authors: Sierra, J. C; Asim, M, Verriere, T. G, Piazuelo, M. B, Suarez, G, Romero-Gallo, J, Delgado, A. G, Wroblewski, L. E, Barry, D. P, Peek, R. M, Gobert, A. P, Wilson, K. T.
      Pages: 1247 - 1260
      Abstract: ObjectiveGastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.DesignWe evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr (Efgrepi mice) were also used.ResultsIn C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected Egfrepi versus Egfrfl/fl control mice. In H. pylori-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from Efgrepi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.ConclusionsThese findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals.
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2016-312888
      Issue No: Vol. 67, No. 7 (2018)
  • Increased risk of acute arterial events in young patients and severely
           active IBD: a nationwide French cohort study
    • Authors: Kirchgesner, J; Beaugerie, L, Carrat, F, Andersen, N. N, Jess, T, Schwarzinger, M, for the BERENICE study group
      Pages: 1261 - 1268
      Abstract: ObjectiveMagnitude and independent drivers of the risk of acute arterial events in IBD are still unclear. We addressed this question in patients with IBD compared with the general population at a nationwide level.DesignUsing the French National Hospital Discharge Database from 2008 to 2013, all patients aged 15 years or older and diagnosed with IBD were identified and followed up until 31 December 2013. The rates of incident acute arterial events were calculated and the impact of time with active disease (period around hospitalisation for IBD flare or IBD-related surgery) on the risk was assessed by Cox regression adjusted for traditional cardiovascular risk factors.ResultsAmong 210 162 individuals with IBD (Crohn’s disease (CD), n=97 708; UC, n=112 454), 5554 incident acute arterial events were identified. Both patients with CD and UC had a statistically significant overall increased risk of acute arterial events (standardised incidence ratio (SIR) 1.35; 95% CI 1.30 to 1.41 and SIR 1.10; 95 CI 1.06 to 1.13, respectively). The highest risk was observed in patients under the age of 55 years, both in CD and UC. The 3-month periods before and after IBD-related hospitalisation were associated with an increased risk of acute arterial events in both CD and UC (HR 1.74; 95 CI 1.44 to 2.09 and 1.87; 95% CI 1.58 to 2.22, respectively).ConclusionPatients with IBD are at increased risk of acute arterial events, with the highest risk in young patients. Disease activity may also have an independent impact on the risk.
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-314015
      Issue No: Vol. 67, No. 7 (2018)
  • Butyrate reduces appetite and activates brown adipose tissue via the
           gut-brain neural circuit
    • Authors: Li, Z; Yi, C.-X, Katiraei, S, Kooijman, S, Zhou, E, Chung, C. K, Gao, Y, van den Heuvel, J. K, Meijer, O. C, Berbee, J. F. P, Heijink, M, Giera, M, Willems van Dijk, K, Groen, A. K, Rensen, P. C. N, Wang, Y.
      Pages: 1269 - 1279
      Abstract: ObjectiveButyrate exerts metabolic benefits in mice and humans, the underlying mechanisms being still unclear. We aimed to investigate the effect of butyrate on appetite and energy expenditure, and to what extent these two components contribute to the beneficial metabolic effects of butyrate.DesignAcute effects of butyrate on appetite and its method of action were investigated in mice following an intragastric gavage or intravenous injection of butyrate. To study the contribution of satiety to the metabolic benefits of butyrate, mice were fed a high-fat diet with butyrate, and an additional pair-fed group was included. Mechanistic involvement of the gut-brain neural circuit was investigated in vagotomised mice.ResultsAcute oral, but not intravenous, butyrate administration decreased food intake, suppressed the activity of orexigenic neurons that express neuropeptide Y in the hypothalamus, and decreased neuronal activity within the nucleus tractus solitarius and dorsal vagal complex in the brainstem. Chronic butyrate supplementation prevented diet-induced obesity, hyperinsulinaemia, hypertriglyceridaemia and hepatic steatosis, largely attributed to a reduction in food intake. Butyrate also modestly promoted fat oxidation and activated brown adipose tissue (BAT), evident from increased utilisation of plasma triglyceride-derived fatty acids. This effect was not due to the reduced food intake, but explained by an increased sympathetic outflow to BAT. Subdiaphragmatic vagotomy abolished the effects of butyrate on food intake as well as the stimulation of metabolic activity in BAT.ConclusionButyrate acts on the gut-brain neural circuit to improve energy metabolism via reducing energy intake and enhancing fat oxidation by activating BAT.
      Keywords: Editor's choice, Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-314050
      Issue No: Vol. 67, No. 7 (2018)
  • Colonoscopic full-thickness resection using an over-the-scope device: a
           prospective multicentre study in various indications
    • Authors: Schmidt, A; Beyna, T, Schumacher, B, Meining, A, Richter-Schrag, H.-J, Messmann, H, Neuhaus, H, Albers, D, Birk, M, Thimme, R, Probst, A, Faehndrich, M, Frieling, T, Goetz, M, Riecken, B, Caca, K.
      Pages: 1280 - 1289
      Abstract: ObjectiveEndoscopic full-thickness resection (EFTR) is a novel treatment of colorectal lesions not amenable to conventional endoscopic resection. The aim of this prospective multicentre study was to assess the efficacy and safety of the full-thickness resection device.Design181 patients were recruited in 9 centres with the indication of difficult adenomas (non-lifting and/or at difficult locations), early cancers and subepithelial tumours (SET). Primary endpoint was complete en bloc and R0 resection.ResultsEFTR was technically successful in 89.5%, R0 resection rate was 76.9%. In 127 patients with difficult adenomas and benign histology, R0 resection rate was 77.7%. In 14 cases, lesions harboured unsuspected cancer, another 15 lesions were primarily known as cancers. Of these 29 cases, R0 resection was achieved in 72.4%; 8 further cases had deep submucosal infiltration>1000 µm. Therefore, curative resection could only be achieved in 13/29 (44.8%). In the subgroup with SET (n=23), R0 resection rate was 87.0%. In general, R0 resection rate was higher with lesions ≤2 cm vs>2 cm (81.2% vs 58.1%, p=0.0038). Adverse event rate was 9.9% with a 2.2% rate of emergency surgery. Three-month follow-up was available from 154 cases and recurrent/residual tumour was evident in 15.3%.ConclusionEFTR has a reasonable technical efficacy especially in lesions ≤2 cm with acceptable complication rates. Curative resection rate for early cancers was too low to recommend its primary use in this indication. Further comparative studies have to show the clinical value and long-term outcome of EFTR in benign colorectal lesions.Trial registration numberNCT02362126; Results.
      Keywords: Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2016-313677
      Issue No: Vol. 67, No. 7 (2018)
  • Differential preventive activity of sulindac and atorvastatin in
           Apc+/Min-FCCCmice with or without colorectal adenomas
    • Authors: Chang, W.-C. L; Jackson, C, Riel, S, Cooper, H. S, Devarajan, K, Hensley, H. H, Zhou, Y, Vanderveer, L. A, Nguyen, M. T, Clapper, M. L.
      Pages: 1290 - 1298
      Abstract: ObjectiveThe response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation.DesignMale mice (6–8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both.ResultsThe multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1).ConclusionsThe tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.
      Keywords: Open access, Gut
      PubDate: 2018-06-07T07:50:18-07:00
      DOI: 10.1136/gutjnl-2017-313942
      Issue No: Vol. 67, No. 7 (2018)
  • The somatic mutation landscape of premalignant colorectal adenoma
    • Authors: Lin, S.-H; Raju, G. S, Huff, C, Ye, Y, Gu, J, Chen, J.-S, Hildebrandt, M. A. T, Liang, H, Menter, D. G, Morris, J, Hawk, E, Stroehlein, J. R, Futreal, A, Kopetz, S, Mishra, L, Wu, X.
      Pages: 1299 - 1305
      Abstract: ObjectiveThere are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma.DesignWhole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC.ResultsSimilar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941.ConclusionThe findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.
      Keywords: Open access, Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2016-313573
      Issue No: Vol. 67, No. 7 (2018)
  • Cancer risk and survival in path_MMR carriers by gene and gender up to 75
           years of age: a report from the Prospective Lynch Syndrome Database
    • Authors: Moller, P; Seppälä, T. T, Bernstein, I, Holinski-Feder, E, Sala, P, Gareth Evans, D, Lindblom, A, Macrae, F, Blanco, I, Sijmons, R. H, Jeffries, J, Vasen, H. F. A, Burn, J, Nakken, S, Hovig, E, Rodland, E. A, Tharmaratnam, K, de Vos tot Nederveen Cappel, W. H, Hill, J, Wijnen, J. T, Jenkins, M. A, Green, K, Lalloo, F, Sunde, L, Mints, M, Bertario, L, Pineda, M, Navarro, M, Morak, M, Renkonen-Sinisalo, L, Valentin, M. D, Frayling, I. M, Plazzer, J.-P, Pylvanainen, K, Genuardi, M, Mecklin, J.-P, Moeslein, G, Sampson, J. R, Capella, G, in collaboration with The Mallorca Group
      Pages: 1306 - 1316
      Abstract: BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website to facilitate this.
      Keywords: Clinical trials (epidemiology), Open access, Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-314057
      Issue No: Vol. 67, No. 7 (2018)
  • Adipose tissue macrophages induce hepatic neutrophil recruitment and
           macrophage accumulation in mice
    • Authors: Bijnen, M; Josefs, T, Cuijpers, I, Maalsen, C. J, van de Gaar, J, Vroomen, M, Wijnands, E, Rensen, S. S, Greve, J. W. M, Hofker, M. H, Biessen, E. A. L, Stehouwer, C. D. A, Schalkwijk, C. G, Wouters, K.
      Pages: 1317 - 1327
      Abstract: ObjectiveObesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c+ proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development.DesignvAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr-/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH.ResultsTransplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c+ and CD11c– macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c+ ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes.ConclusionATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2016-313654
      Issue No: Vol. 67, No. 7 (2018)
  • Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated
           therapeutic target for hepatocellular carcinoma and contributes to
           sorafenib resistance
    • Authors: Dietrich, P; Koch, A, Fritz, V, Hartmann, A, Bosserhoff, A. K, Hellerbrand, C.
      Pages: 1328 - 1341
      Abstract: ObjectiveSorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC.DesignHuman HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model.ResultsExpression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis.ConclusionsKRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-315402
      Issue No: Vol. 67, No. 7 (2018)
  • Favouring modulation of circulating lipoproteins and lipid loading
           capacity by direct antiviral agents grazoprevir/elbasvir or
           ledipasvir/sofosbuvir treatment against chronic HCV infection
    • Authors: Sun, H.-Y; Cheng, P.-N, Tseng, C.-Y, Tsai, W.-J, Chiu, Y.-C, Young, K.-C.
      Pages: 1342 - 1350
      Abstract: ObjectiveLipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment.DesignTwenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unitResultsDAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism.ConclusionThe DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-313832
      Issue No: Vol. 67, No. 7 (2018)
  • Too hard to swallow!
    • Authors: Siau, K; Aziz, A, Liew, L, Ishaq, S.
      Pages: 1350 - 1350
      Abstract: Introduction An 80-year-old woman presented with a 4-month history of intermittent oropharyngeal dysphagia and aspiration, particularly after eating peas. She had no significant medical history and denied additional symptomatology. Gastroscopy revealed a smooth lesion arising in the pharynx abutting the epiglottis (figure 1) but was otherwise unremarkable. Pillow sign was negative. No neck masses were palpable on examination after endoscopy. Question
      What is the endoscopic finding and what are the differential diagnoses'
      How will you manage it' Answer Endoscopically, there was an extrinsic posterior hypopharyngeal mass with normal mucosa. Differential diagnoses include: lymphoma, lipoma, cystic lesions, schwannoma and anterior cervical osteophyte. The patient underwent barium swallow and X-ray (figure 2), which confirmed pharyngeal compression by anterior cervical osteophytes at the level of C3-C4 with ossification of the anterior longitudinal ligament (ALL) down to C7. ALL ossification affecting ≥4 contiguous vertebrae,...
      Keywords: GUT Snapshot, Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-314727
      Issue No: Vol. 67, No. 7 (2018)
  • Modern diagnosis of GERD: the Lyon Consensus
    • Authors: Gyawali, C. P; Kahrilas, P. J, Savarino, E, Zerbib, F, Mion, F, Smout, A. J. P. M, Vaezi, M, Sifrim, D, Fox, M. R, Vela, M. F, Tutuian, R, Tack, J, Bredenoord, A. J, Pandolfino, J, Roman, S.
      Pages: 1351 - 1362
      Abstract: Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET)>6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET
      Keywords: GUT Recent advances in clinical practice, Open access, Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-314722
      Issue No: Vol. 67, No. 7 (2018)
  • GI highlights from the literature
    • Authors: McLean M. H.
      Pages: 1363 - 1364
      Abstract: Basic scienceThe importance of the small bowel microbiota in nutrition Martinez-Guryn K, Hubert N, Frazier K, et al. Small Intestine Microbiota Regulate Host Digestive and Absorptive Adaptive Responses to Dietary Lipids. Cell Host Microbe 2018 23:458–469. The small intestine, a major site of nutrient digestion and absorption, harbours a complex array of microbes albeit less numerous and diverse than the large intestine. Studies interrogating the small intestinal microbiota in relation to caloric intake and the effect of dietary manipulation are limited. Microbial populations in the small intestine are subjected to a number of adverse environmental factors, including rapid transit time, low pH, bile acids and the presence of antimicrobial peptides. Bacterial populations which reside in the small intestine have been shown to be more tolerant of these factors. The impact of high-fat diet on small intestinal bacterial composition has not been assessed. Martinez-Guryn and colleagues demonstrated that...
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2018-316763
      Issue No: Vol. 67, No. 7 (2018)
  • Improving future studies in chronic pancreatitis: a paradigm shift in our
    • Authors: Hopper, A. D; Campbell, J. A.
      Pages: 1365 - 1366
      Abstract: We read with interest the study by de la Iglesia-García et al1 The authors present a detailed, well-conducted meta-analysis of the efficacy of pancreatic enzyme replacement therapy (PERT) in patients with chronic pancreatitis (CP) who also have evidence of exocrine pancreatic insufficiency (EPI). Using level 1 evidence studies, the primary endpoint of fat absorption is shown to increase with PERT, with additional improvements shown in GI symptoms and quality of life. The authors should be commended for their work clarifying the beneficial use of PERT in this group of patients, but they and the preceding commentary by Windsor2 highlight the heterogenicity of the criteria used to diagnose CP and the greater need for a clear consensus to help target and guide dosing of PERT. Although a recent consensus to produce a mechanistic definition for CP has been undertaken,3 it is acknowledged that there is heterogeneity...
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-315067
      Issue No: Vol. 67, No. 7 (2018)
  • Genome-wide association studies identified loci contribute to phenotypic
           variance of gastric cancer
    • Authors: Yan, C; Zhu, M, Huang, T, Yu, F, Jin, G.
      Pages: 1366 - 1368
      Abstract: We read with great interest the article by Mocellin et al,1 who conducted a comprehensive meta-analysis that nominated 11 germline variants at nine loci significantly associated with gastric cancer (GC) with high level of summary evidence. Moreover, they also identified 38 single nucleotide polymorphisms (SNPs) with intermediate quality significant associations. Most of these loci were resulted from hypothesis-driven studies based on biological relevance, but most of these studies were small sample size and might lead to publication bias. In order to further evaluate their relevance with GC in individual large studies, we analysed these variants directly or their strong linkage disequilibrium SNPs using existing genome-wide association study (GWAS) datasets (including 2631 cases and 4373 controls) in Chinese populations, including those from Nanjing and Beijing populations conducted by our group2 and from Henan and Shanxi populations conducted by the USA National Cancer Institute.3 After exclusion...
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-315230
      Issue No: Vol. 67, No. 7 (2018)
  • The CTRB1-CTRB2 risk allele for chronic pancreatitis discovered in
           European populations does not contribute to disease risk variation in the
           Chinese population due to near allele fixation
    • Authors: Tang, X.-Y; Zou, W.-B, Masson, E, Hu, L.-H, Ferec, C, Chen, J.-M, Li, Z.-S, Liao, Z.
      Pages: 1368 - 1369
      Abstract: We read with great interest the article by Rosendahl et al1 reporting the identification of CTRB1-CTRB2 (chymotrypsin B1 and chymotrypsin B2) as a new chronic pancreatitis (CP) risk locus by means of genome-wide association study, with the lead single nucleotide polymorphism (SNP) rs8055167 having an OR of 1.35. Moreover, they found that a previously reported 16.6 kb inversion in the CTRB1-CTRB2 locus2 was in linkage disequilibrium with the CP-associated SNPs and optimally tagged by rs8048956. Furthermore, they provided in silico and in vivo evidence showing that the inversion variant changes the expression ratio of the CTRB1 and CTRB2 isoforms, the major risk allele being associated with increased CTRB1 and decreased CTRB2 mRNA expression as compared with the minor allele. Finally, they provided in vitro evidence that CTRB1 was less efficient in degrading anionic trypsinogen (PRSS2) than CTRB2 (note that rapid degradation of PRSS2 conferred by a PRSS2 missense...
      Keywords: Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-315180
      Issue No: Vol. 67, No. 7 (2018)
  • Proton pump inhibitor use associated with changes in gut microbiota
    • Authors: Reveles, K. R; Ryan, C. N, Chan, L, Cosimi, R. A, Haynes, W. L.
      Pages: 1369 - 1370
      Abstract: We read with great interest the recent publications in Gut by Imhann et al and Jackson et al, which assessed the impact of proton pump inhibitor (PPI) use on gut microbiota diversity and composition in humans.1 2 PPIs are one of the most commonly used drug classes worldwide. Once initiated, they are often used chronically without clear therapeutic intent.3 PPIs alter GI pH4 and delay gastric emptying rate,5 which could directly affect gut microbiota and survival of enteric pathogens. Using three independent cohorts (211 PPI users and 1604 non-users), Imhann et al1 reported a significant decrease in alpha diversity and changes in 20% of bacterial taxa in PPI users compared with non-users. Among 1827 healthy twins, Jackson et al2 also found a significant decrease in alpha diversity and alteration of bacterial composition in PPI users. Notably,...
      Keywords: Open access, Gut
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-315306
      Issue No: Vol. 67, No. 7 (2018)
  • Pioglitazone for the treatment of NASH in patients with prediabetes or
           type 2 diabetes mellitus
    • Authors: Cusi K.
      Pages: 1371 - 1371
      Abstract: I read with great interest the recent comprehensive review by Rotman and Sanyal.1 I would just like to point out an error in table 1 (row 1), where the authors inadvertently state that pioglitazone has shown histological benefit only in secondary analyses and not been studied in patients with diabetes and nonalcoholic fatty liver disease (NAFLD). Benefit with the thiazolidinedione has been reported for the primary histological outcome in two randomised controlled trials (RCTs) in patients with prediabetes or type 2 diabetes mellitus (T2DM). This is most likely an oversight as in the text the authors quote our early proof-of-concept study by Belfort et al ( ref. 2; reference 28 in the review) where pioglitazone improved the NAFLD activity score (NAS) in 73% compared with 24% of placebo-treated patients (p
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-313958
      Issue No: Vol. 67, No. 7 (2018)
  • Pioglitazone for the treatment of NASH in patients with prediabetes or
           type 2 diabetes mellitus--authors' response
    • Authors: Rotman, Y; Sanyal, A. J.
      Pages: 1372 - 1372
      Abstract: We would like to thank Professor Cusi1 for pointing out the omission of the important randomised controlled trial,2 in which he and his colleagues have essentially confirmed and consolidated the proof for the effectiveness of pioglitazone in treating non-alcoholic steatohepatitis (NASH). We agree with Professor Cusi that pioglitazone could be considered a valid and effective treatment option for patients with NASH, although effectiveness has to be weighed against the concerns about its long-term safety. We can only hope that our review3 and his commentary on it will enhance awareness and raise the current limited acceptance of its use.4 ContributorsYR and AJS wrote the text jointly. FundingNational Institute of Diabetes and Digestive and Kidney Diseases (Intramural Research Program). Competing interestsAS: Consultant for Echosens-Sandhil and Sequana. Provenance and peer reviewNot commissioned; internally peer reviewed. Intramural Research ProgramNational Institute...
      PubDate: 2018-06-07T07:50:19-07:00
      DOI: 10.1136/gutjnl-2017-314263
      Issue No: Vol. 67, No. 7 (2018)
School of Mathematical and Computer Sciences
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