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Journal Cover Gut
  [SJR: 6.474]   [H-I: 222]   [168 followers]  Follow
   Full-text available via subscription Subscription journal
   ISSN (Print) 0017-5749 - ISSN (Online) 1468-3288
   Published by BMJ Publishing Group Homepage  [57 journals]
  • Illusions regarding Helicobacter pylori clinical trials and treatment
    • Authors: Graham D. Y.
      Pages: 2043 - 2046
      Abstract: Introduction Identification of reliable Helicobacter pylori eradication therapy has proved difficult, in part because brief exposure of H. pylori to commonly used antimicrobials such as macrolides, nitroimidazoles or quinolones often results in resistance (bystander effect). Most treatment studies and meta-analyses contains major flaws preventing generalisability that making reliable treatment recommendations and guidelines an illusion (box 1). Box 1Helicobacter pylori treatment illusions
      Most apparently well done treatment studies and meta-analyses are valid.
      Studies reporting one regimen as superior to another can generally be believed.
      Meta-analyses identifying the best H. pylori treatment regimen can generally be believed.
      Treatment results without susceptibility testing are generally valid.
      High overall cure rates validate use of successive low cure rate first, second and third-line treatments.
      Increasing the number of antibiotic to 3 or 4 (eg, concomitant or quintuple therapies) is a rational approach to overcoming...
      Keywords: Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-314744
      Issue No: Vol. 66, No. 12 (2017)
  • Gastro-oesophageal reflux events: just another trigger in chronic
    • Authors: Houghton, L. A; Smith, J. A.
      Pages: 2047 - 2048
      Abstract: GORD is considered a common cause of chronic cough, either alone or in association with nasal disease and/or asthma.1 This, along with the fact that there are currently no specific therapies approved for the treatment of chronic cough, has led to extensive use of acid suppressants, such that one US study in patients with extraoesophageal manifestations of GORD, of which 50% had cough, estimated costs to be four to five times those associated with their use in typical GORD.2 Despite this widespread use, a significant proportion of patients with chronic cough thought to be due to GORD remain refractory to acid suppression. Indeed, multiple studies and meta-analyses have failed to document a therapeutic benefit of acid suppression in chronic cough.3 A growing number of studies suggest that in 30%–48% of patients, coughing episodes seem to be temporally linked to reflux events, irrespective of...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-314027
      Issue No: Vol. 66, No. 12 (2017)
  • Janus-like monocytes regulate postoperative ileus
    • Authors: Mowat A. M.
      Pages: 2049 - 2050
      Abstract: In Gut, Farro et al and Pohl et al present new findings on the role of myeloid cells in postoperative ileus (POI).1 2 POI is a frequent consequence of abdominal surgery that can lead to costly delays in patient recovery.3 The failure of peristalsis reflects paralysis of the smooth muscles of the intestine and several studies have suggested that this is dependent on macrophages in the muscularis externa (ME) layer of the gut wall that produce nitric oxide (NO).4 The intestine contains one of the largest pools of macrophages in the body, the majority of which is located in the lamina propria (LP) of the mucosa, near the epithelium. However macrophages are also present between the longitudinal and circular muscle layers of the ME, where they are in close proximity to the myenteric plexus.5 6 Recent studies indicate...
      Keywords: Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-314360
      Issue No: Vol. 66, No. 12 (2017)
  • SENP1 activity sustains cancer stem cell in hypoxic HCC
    • Authors: Conigliaro, A; Tripodi, M, Parola, M.
      Pages: 2051 - 2052
      Abstract: Hepatocellular carcinoma (HCC) represents the fifth most common cancer and the third leading cause of cancer mortality worldwide, with a minority of patients surviving at 5 years from diagnosis, despite treatment.1 HCC usually develops in conditions of chronic liver disease (CLD), mostly on the background of a cirrhotic liver, with liver transplantation at present being the only treatment strategy to cure both HCC and the specific CLD. All the other therapeutic strategies, because of the underlying liver cirrhosis, have to take into account, and may be limited in their feasibility, by the residual liver function of the individual patient, a critical parameter affecting the patient's prognosis.2 Indeed, even when the surgical intervention is feasible, according to current guidelines, efficient removal of the primary lesions is not often conclusive since intrahepatic recurrence, as well as extrahepatic metastasis, are very frequent and associated with poor prognosis for patients.
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-313946
      Issue No: Vol. 66, No. 12 (2017)
  • Prioritising treatment among people who inject drugs in order to eliminate
           hepatitis C: addressing reluctance with sound economic analyses
    • Authors: Hutin, Y. J.-F; Wiktor, S. Z.
      Pages: 2052 - 2053
      Abstract: In May 2016, the World Health Assembly, the governing body of WHO, endorsed the first-ever global hepatitis strategy.1 This document, termed the Global Health Sector Strategy on Viral Hepatitis (GHSS-VH), proposes ambitious prevention and treatment targets with the ultimate goal of eliminating hepatitis as a public health threat by 2030. The GHSS-VH defines elimination as a 90% reduction in incidence of chronic HBV and HCV infections and a 65% reduction in hepatitis-related mortality. Achieving the goals of the global strategy will require scaling up prevention and treatment services, which in turn will require increases in financial resources and political commitment. In addition, national health planners will need to decide how best to allocate these resources so that they have maximal impact. A solid understanding of the epidemiology of hepatitis infection in the country, in particular identifying groups at highest risk of infection and those at highest risk...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-312636
      Issue No: Vol. 66, No. 12 (2017)
  • Lumen-apposing metal stents (LAMS) for pancreatic fluid collection (PFC)
           drainage: may not be business as usual
    • Authors: Bang, J. Y; Hasan, M, Navaneethan, U, Hawes, R, Varadarajulu, S.
      Pages: 2054 - 2056
      Abstract: Message Lumen-apposing metal stents (LAMS) have been recently developed to improve treatment outcomes in the endoscopic management of pancreatic fluid collections (PFC), particularly in walled-off necrosis (WON), to facilitate better drainage of necrotic contents and minimise the risk of perforation and peritoneal leakage. In an ongoing randomised trial, we observed serious adverse events that included delayed bleeding, buried stent syndrome and biliary stricture that necessitated a change in the management protocol for patients with PFC treated with LAMS. In more detail Randomised trials comparing endoscopic and surgical techniques for the management of PFCs have favoured the endoscopic approach.1 2 Endoscopy is less expensive, associated with shorter hospital stay and the clinical outcomes are comparable. To compare the clinical outcomes of patients undergoing endoscopic drainage of WON using LAMS or plastic stents, a randomised trial (NCT02685865) was initiated at our institution. Included in...
      Keywords: Open access
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-312812
      Issue No: Vol. 66, No. 12 (2017)
  • Determinants of reflux-induced chronic cough
    • Authors: Herregods, T. V. K; Pauwels, A, Jafari, J, Sifrim, D, Bredenoord, A. J, Tack, J, Smout, A. J. P. M.
      Pages: 2057 - 2062
      Abstract: ObjectiveGastro-oesophageal reflux is considered to be an important contributing factor in chronic unexplained cough. It remains unclear why some reflux episodes in the same patient causes cough while others do not. To understand more about the mechanism by which reflux induces cough, we aimed to identify factors which are important in triggering cough.DesignIn this multicentre study, 49 patients with reflux-associated chronic cough were analysed using 24-hour pH-impedance-pressure monitoring. The characteristics of reflux episodes that were followed by cough were compared with reflux episodes not associated with cough.ResultsThe majority (72.4%) of the reflux episodes were acidic (pH
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-313721
      Issue No: Vol. 66, No. 12 (2017)
  • Discrepancies between patient-reported outcomes, and endoscopic and
           histological appearance in UC
    • Authors: Colombel, J.-F; Keir, M. E, Scherl, A, Zhao, R, de Hertogh, G, Faubion, W. A, Lu, T. T.
      Pages: 2063 - 2068
      Abstract: ObjectiveBoth endoscopy and histology may be included in the definition of mucosal healing in UC. This study aimed to establish the association between patient-reported outcomes, specifically symptom measures, and the presence of inflammation as measured by endoscopy and histology in UC.DesignUsing patient data from an observational multicentre study of UC (n=103), rectal bleeding (RB) and stool frequency (SF) symptom subscores of the Mayo Clinic Score (MCS) were compared with the endoscopic subscore (MCSe) and histology. Faecal calprotectin and biopsy cytokine expression were also evaluated.ResultsWhen identifying UC patients with inactive disease, RB scores were superior to SF scores and the combination (sensitivity/specificity: MCSe=0/1, RB 77%/81%, SF 62%/95%, RB+SF 54%/95%; MCSe=0, RB 87%/66%, SF 76%/83%, RB+SF 68%/86%). Across different definitions of mucosal healing (MCSe≤1; 0; or 0 plus inactive histology), a larger subset of patients reported increased SF (39%, 25% and 27%, respectively) compared with RB (24%, 13% and 10%). Faecal calprotectin and inflammatory cytokine expression were higher in patients with active disease compared with patients with mucosal healing, but there were no differences between patients using increasingly stringent definitions of mucosal healing.ConclusionsEndoscopically inactive disease is associated with absence of RB but not with complete normalisation of SF. Achieving histological remission did not improve symptomatic relief. In addition, in these patients, higher inflammatory biomarker levels were not observed. These data suggest that non-inflammatory changes, such as bowel damage, may contribute to SF in UC.
      Keywords: Open access
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-312307
      Issue No: Vol. 66, No. 12 (2017)
  • Thinking out of the Gut: a case of obscure lower GI bleeding
    • Authors: Koh, F. H; Chan, H.-L, Petersson, F, Chong, C.-S.
      Pages: 2068 - 2159
      Abstract: Clinical presentationA middle-aged man was admitted for episodes of fresh per-rectal bleeding, which were not associated with defecation. He was recently investigated for macrocytic anaemia in the outpatient haematology clinic. Examination of the perineum revealed grade 1 internal haemorrhoids with no signs of bleeding.Initial laboratory tests revealed macrocytic anaemia (haemoglobin 10.5 g/dL, normal 12.9–17.0  g/dL; mean corpuscular haemoglobin 95.3 fL, normal 80.0–95.0  fL). Peripheral blood film showing blasts, dysplastic neutrophils, nucleated red blood cells and hypogranular platelets.The patient underwent a sigmoidoscopy and rubber band ligation of the internal haemorrhoids after persistent fresh per-rectal bleeding. The bleeding persisted with the development of hypotension and a significant drop of haemoglobin to 4.8 g/dL requiring blood transfusions and intensive care monitoring. Repeated endoscopy, including intubation of the terminal ileum, revealed uncomplicated right-sided diverticulosis. CT mesenteric angiography performed during an episode of significant bleeding revealed extravasation of contrast in the ileum, but mesenteric angiography was unsuccessful, possibly due to a temporary cessation of bleeding. Bleeding subsequently recurred and in light of the persistent bleeding with no clear source and with a total of 12 units of packed cell transfused, exploratory laparotomy, on-table enteroscopy (figure 1) with small bowel resection was performed. Histopathological examination of the specimen was performed (figures 2–4).Figure 1Multiple ileal lesions with stigmata of recent bleed.Figure 2Area of ulceration associated with atypical mononuclear infiltrate.Figure 3Atypical mononuclear infiltrate composed of cells with enlarged, irregular nuclei containing variably prominent nucleoli.Figure 4Atypical cells displayed cytoplasmic expression of myeloperoxidase.QuestionWhat is the diagnosis'
      Keywords: GUT Snapshot
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313252
      Issue No: Vol. 66, No. 12 (2017)
  • Alterations in the epithelial stem cell compartment could contribute to
           permanent changes in the mucosa of patients with ulcerative colitis
    • Authors: Dotti, I; Mora-Buch, R, Ferrer-Picon, E, Planell, N, Jung, P, Masamunt, M. C, Leal, R. F, Martin de Carpi, J, Llach, J, Ordas, I, Batlle, E, Panes, J, Salas, A.
      Pages: 2069 - 2079
      Abstract: ObjectiveUC is a chronic inflammatory disease of the colonic mucosa. Growing evidence supports a role for epithelial cell defects in driving pathology. Moreover, long-lasting changes in the epithelial barrier have been reported in quiescent UC. Our aim was to investigate whether epithelial cell defects could originate from changes in the epithelial compartment imprinted by the disease.DesignEpithelial organoid cultures (EpOCs) were expanded ex vivo from the intestinal crypts of non-IBD controls and patients with UC. EpOCs were induced to differentiate (d-EpOCs), and the total RNA was extracted for microarray and quantitative real-time PCR (qPCR) analyses. Whole intestinal samples were used to determine mRNA expression by qPCR, or protein localisation by immunostaining.ResultsEpOCs from patients with UC maintained self-renewal potential and the capability to give rise to differentiated epithelial cell lineages comparable with control EpOCs. Nonetheless, a group of genes was differentially regulated in the EpOCs and d-EpOCs of patients with UC, including genes associated with antimicrobial defence (ie, LYZ, PLA2G2A), with secretory (ie, ZG16, CLCA1) and absorptive (ie, AQP8, MUC12) functions, and with a gastric phenotype (ie, ANXA10, CLDN18 and LYZ). A high rate of concordance was found in the expression profiles of the organoid cultures and whole colonic tissues from patients with UC.ConclusionsPermanent changes in the colonic epithelium of patients with UC could be promoted by alterations imprinted in the stem cell compartment. These changes may contribute to perpetuation of the disease.
      Keywords: Open access
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-312609
      Issue No: Vol. 66, No. 12 (2017)
  • ROC-king onwards: intraepithelial lymphocyte counts, distribution & role
           in coeliac disease mucosal interpretation
    • Authors: Rostami, K; Marsh, M. N, Johnson, M. W, Mohaghegh, H, Heal, C, Holmes, G, Ensari, A, Aldulaimi, D, Bancel, B, Bassotti, G, Bateman, A, Becheanu, G, Bozzola, A, Carroccio, A, Catassi, C, Ciacci, C, Ciobanu, A, Danciu, M, Derakhshan, M. H, Elli, L, Ferrero, S, Fiorentino, M, Fiorino, M, Ganji, A, Ghaffarzadehgan, K, Going, J. J, Ishaq, S, Mandolesi, A, Mathews, S, Maxim, R, Mulder, C. J, Neefjes-Borst, A, Robert, M, Russo, I, Rostami-Nejad, M, Sidoni, A, Sotoudeh, M, Villanacci, V, Volta, U, Zali, M. R, Srivastava, A.
      Pages: 2080 - 2086
      Abstract: ObjectivesCounting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on>400 mucosal biopsy specimens.DesignThe study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.ResultsThe mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.ConclusionOur ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.
      Keywords: Open access, Editor's choice, Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-314297
      Issue No: Vol. 66, No. 12 (2017)
  • Uncoupling of mucosal gene regulation, mRNA splicing and adherent
           microbiota signatures in inflammatory bowel disease
    • Authors: Häsler, R; Sheibani-Tezerji, R, Sinha, A, Barann, M, Rehman, A, Esser, D, Aden, K, Knecht, C, Brandt, B, Nikolaus, S, Schäuble, S, Kaleta, C, Franke, A, Fretter, C, Müller, W, Hütt, M.-T, Krawczak, M, Schreiber, S, Rosenstiel, P.
      Pages: 2087 - 2097
      Abstract: ObjectiveAn inadequate host response to the intestinal microbiota likely contributes to the manifestation and progression of human inflammatory bowel disease (IBD). However, molecular approaches to unravelling the nature of the defective crosstalk and its consequences for intestinal metabolic and immunological networks are lacking. We assessed the mucosal transcript levels, splicing architecture and mucosa-attached microbial communities of patients with IBD to obtain a comprehensive view of the underlying, hitherto poorly characterised interactions, and how these are altered in IBD.DesignMucosal biopsies from Crohn's disease and patients with UC, disease controls and healthy individuals (n=63) were subjected to microbiome, transcriptome and splicing analysis, employing next-generation sequencing. The three data levels were integrated by different bioinformatic approaches, including systems biology-inspired network and pathway analysis.ResultsMicrobiota, host transcript levels and host splicing patterns were influenced most strongly by tissue differences, followed by the effect of inflammation. Both factors point towards a substantial disease-related alteration of metabolic processes. We also observed a strong enrichment of splicing events in inflamed tissues, accompanied by an alteration of the mucosa-attached bacterial taxa. Finally, we noted a striking uncoupling of the three molecular entities when moving from healthy individuals via disease controls to patients with IBD.ConclusionsOur results provide strong evidence that the interplay between microbiome and host transcriptome, which normally characterises a state of intestinal homeostasis, is drastically perturbed in Crohn's disease and UC. Consequently, integrating multiple OMICs levels appears to be a promising approach to further disentangle the complexity of IBD.
      Keywords: Open access
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-311651
      Issue No: Vol. 66, No. 12 (2017)
  • CCR2-dependent monocyte-derived macrophages resolve inflammation and
           restore gut motility in postoperative ileus
    • Authors: Farro, G; Stakenborg, M, Gomez-Pinilla, P. J, Labeeuw, E, Goverse, G, Giovangiulio, M. D, Stakenborg, N, Meroni, E, DErrico, F, Elkrim, Y, Laoui, D, Lisowski, Z. M, Sauter, K. A, Hume, D. A, Van Ginderachter, J. A, Boeckxstaens, G. E, Matteoli, G.
      Pages: 2098 - 2109
      Abstract: ObjectivePostoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility.DesignIM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2–/– mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (Ms) during onset and resolution of ME inflammation.ResultsAt early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2–/– mice. However, GI transit recovery after IM was significantly delayed in Ccr2–/– mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived Ms acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with M colony-stimulating factor 1 enhanced monocyte recruitment and M differentiation and ameliorated GI transit in Ccr2–/– mice.ConclusionOur study reveals a critical role for monocyte-derived Ms in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing M physiological repair functions.
      Keywords: Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313144
      Issue No: Vol. 66, No. 12 (2017)
  • Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome
           regulate monocyte and macrophage activation and intestinal peristalsis in
           postoperative ileus
    • Authors: Pohl, J.-M; Gutweiler, S, Thiebes, S, Volke, J. K, Klein-Hitpass, L, Zwanziger, D, Gunzer, M, Jung, S, Agace, W. W, Kurts, C, Engel, D. R.
      Pages: 2110 - 2120
      Abstract: ObjectivePostoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction.DesignPOI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment.ResultsWe found that Cd11c-Cre+ Irf4flox/flox mice lack CD103+CD11b+ DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C– macrophages and infiltrating chemokine receptor 2-dependent Ly6C+ monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C+ monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI.ConclusionsOur findings reveal that CD103+CD11b+ DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI.
      Keywords: Open access, Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-313856
      Issue No: Vol. 66, No. 12 (2017)
  • Stress activates pronociceptive endogenous opioid signalling in DRG
           neurons during chronic colitis
    • Authors: Guerrero-Alba, R; Valdez-Morales, E. E, Jimenez-Vargas, N. N, Lopez-Lopez, C, Jaramillo-Polanco, J, Okamoto, T, Nasser, Y, Bunnett, N. W, Lomax, A. E, Vanner, S. J.
      Pages: 2121 - 2131
      Abstract: Aims and backgroundPsychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.MethodsMouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+ imaging techniques.ResultsSupernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein β subunits.ConclusionsStress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-311456
      Issue No: Vol. 66, No. 12 (2017)
  • Subclonal diversity arises early even in small colorectal tumours and
           contributes to differential growth fates
    • Authors: Sievers, C. K; Zou, L. S, Pickhardt, P. J, Matkowskyj, K. A, Albrecht, D. M, Clipson, L, Bacher, J. W, Pooler, B. D, Moawad, F. J, Cash, B. D, Reichelderfer, M, Vo, T. N, Newton, M. A, Larget, B. R, Halberg, R. B.
      Pages: 2132 - 2140
      Abstract: Objective and designThe goal of the study was to determine whether the mutational profile of early colorectal polyps correlated with growth behaviour. The growth of small polyps (6–9 mm) that were first identified during routine screening of patients was monitored over time by interval imaging with CT colonography. Mutations in these lesions with known growth rates were identified by targeted next-generation sequencing. The timing of mutational events was estimated using computer modelling and statistical inference considering several parameters including allele frequency and fitness.ResultsThe mutational landscape of small polyps is varied both within individual polyps and among the group as a whole but no single alteration was correlated with growth behaviour. Polyps carried 0–3 pathogenic mutations with the most frequent being in APC, KRAS/NRAS, BRAF, FBXW7 and TP53. In polyps with two or more pathogenic mutations, allele frequencies were often variable, indicating the presence of multiple populations within a single tumour. Based on computer modelling, detectable mutations occurred at a mean polyp size of 30±35 crypts, well before the tumour is of a clinically detectable size.ConclusionsThese data indicate that small colon polyps can have multiple pathogenic mutations in crucial driver genes that arise early in the existence of a tumour. Understanding the molecular pathway of tumourigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps are more likely to progress into adenocarcinomas and which patients are at greater risk of developing advanced disease.
      Keywords: Open access
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-312232
      Issue No: Vol. 66, No. 12 (2017)
  • BCL-2 system analysis identifies high-risk colorectal cancer patients
    • Authors: Lindner, A. U; Salvucci, M, Morgan, C, Monsefi, N, Resler, A. J, Cremona, M, Curry, S, Toomey, S, O'Byrne, R, Bacon, O, Stühler, M, Flanagan, L, Wilson, R, Johnston, P. G, Salto-Tellez, M, Camilleri-Broët, S, McNamara, D. A, Kay, E. W, Hennessy, B. T, Laurent-Puig, P, Van Schaeybroeck, S, Prehn, J. H. M.
      Pages: 2141 - 2148
      Abstract: ObjectiveThe mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC).DesignAbsolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project.ResultsHigh-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling.ConclusionsDR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors.
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-312287
      Issue No: Vol. 66, No. 12 (2017)
  • SENP1 promotes hypoxia-induced cancer stemness by HIF-1{alpha}
           deSUMOylation and SENP1/HIF-1{alpha} positive feedback loop
    • Authors: Cui, C.-P; Wong, C. C.-L, Kai, A. K.-L, Ho, D. W.-H, Lau, E. Y.-T, Tsui, Y.-M, Chan, L.-K, Cheung, T.-T, Chok, K. S.-H, Chan, A. C. Y, Lo, R. C.-L, Lee, J. M.-F, Lee, T. K.-W, Ng, I. O. L.
      Pages: 2149 - 2159
      Abstract: ObjectiveWe investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.DesignHCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.ResultsWe showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.ConclusionsTaken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
      Keywords: Open access
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313264
      Issue No: Vol. 66, No. 12 (2017)
  • Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C
           virus: impact on production of lipo-viro-particles
    • Authors: Beilstein, F; Lemasson, M, Pene, V, Rainteau, D, Demignot, S, Rosenberg, A. R.
      Pages: 2160 - 2169
      Abstract: ObjectiveHCV is intimately linked with the liver lipid metabolism, devoted to the efflux of triacylglycerols stored in lipid droplets (LDs) in the form of triacylglycerol-rich very-low-density lipoproteins (VLDLs): (i) the most infectious HCV particles are those of lowest density due to association with triacylglycerol-rich lipoproteins and (ii) HCV-infected patients frequently develop hepatic steatosis (increased triacylglycerol storage). The recent identification of lysophosphatidylcholine acyltransferase 1 (LPCAT1) as an LD phospholipid-remodelling enzyme prompted us to investigate its role in liver lipid metabolism and HCV infectious cycle.DesignHuh-7.5.1 cells and primary human hepatocytes (PHHs) were infected with JFH1-HCV. LPCAT1 depletion was achieved by RNA interference. Cells were monitored for LPCAT1 expression, lipid metabolism and HCV production and infectivity. The density of viral particles was assessed by isopycnic ultracentrifugation.ResultsUpon HCV infection, both Huh-7.5.1 cells and PHH had decreased levels of LPCAT1 transcript and protein, consistent with transcriptional downregulation. LPCAT1 depletion in either naive or infected Huh-7.5.1 cells resulted in altered lipid metabolism characterised by LD remodelling, increased triacylglycerol storage and increased secretion of VLDL. In infected Huh-7.5.1 cells or PHH, LPCAT1 depletion increased production of the viral particles of lowest density and highest infectivity.ConclusionsWe have identified LPCAT1 as a modulator of liver lipid metabolism downregulated by HCV, which appears as a viral strategy to increase the triacylglycerol content and hence infectivity of viral particles. Targeting this metabolic pathway may represent an attractive therapeutic approach to reduce both the viral titre and hepatic steatosis.
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-311508
      Issue No: Vol. 66, No. 12 (2017)
  • A genetic roadmap of pancreatic cancer: still evolving
    • Authors: Notta, F; Hahn, S. A, Real, F. X.
      Pages: 2170 - 2178
      Abstract: A diagnosis of pancreatic ductal adenocarcinoma (PDA) is often fatal. PDA is widely recognised as one of the ‘incurable cancers’ because therapies against this tumour type are generally ineffective. The fatal nature of this tumour is due to its aggressive clinical course. Pancreatic cancer commonly presents at the metastatic stage; even in cases where tumours are localised to the pancreas at diagnosis, metastatic seeds have often been invariably been spawned off, frustrating surgical attempts to cure the cancer. The key principles of pancreatic cancer mutational development were outlined nearly two decades ago using the genetics of precursor lesions to position the various stages of tumour progression. Since then, there has been a cavalcade of new data. How these recent studies impact the classical perceptions of pancreatic cancer development is a work in progress. Given that significant improvements in patient outcomes are not in sight for this disease, it is likely that broadening the current perspectives and acquiring deeper biological insights into the morphogenetic route of tumour development will be needed to foster new strategies for more effective cancer control.
      Keywords: GUT Recent advances in basic science, Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313317
      Issue No: Vol. 66, No. 12 (2017)
  • Early intervention in Crohns disease: towards disease modification trials
    • Authors: Danese, S; Fiorino, G, Peyrin-Biroulet, L.
      Pages: 2179 - 2187
      Abstract: Crohn’s disease (CD) is a chronic progressive destructive inflammatory bowel disease. As in rheumatoid arthritis, there is increasing evidence that early treatment initiation with disease-modifying agents, such as biological drugs, may lead to complete disease control, prevention of disease progression thus protecting against irreversible damage and restoration of normal quality of life. Data from randomised clinical trials with immunosuppressants and biologics suggest that treating patients with a disease duration of
      Keywords: GUT Recent advances in clinical practice, Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-314519
      Issue No: Vol. 66, No. 12 (2017)
  • The principles and practice of nutritional support
    • Authors: Lal S.
      Pages: 2188 - 2188
      Abstract: This book provides exactly what it says on the cover: a useful practical guide for multidisciplinary health professionals in nutrition support. It is, of course, strengthened by the expertise and reputation of Dr O'Keefe in the field, and I agree with Dr O'Keefe that the book's single authorship avoids overlap and allows focus on the common principles of nutritional support that are applicable to various disease states. The book is divided into three parts: ‘the principles' and ‘the practice’ of general nutrition support and a final part that reviews nutritional support in different diseases, along with a succinct overview of the more complex conditions of intestinal failure and small bowel transplantation. Part 1 gives an excellent introduction to the importance of nutritional support by providing a simple understanding of cellular function, taking the reader next to a whole body understanding of the physiology of starvation and obesity and then...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313122
      Issue No: Vol. 66, No. 12 (2017)
  • Correction: Quality standards in upper gastrointestinal endoscopy: a
           position statement of the British Society of Gastroenterology (BSG) and
           Association of Upper Gastrointestinal Surgeons of Great Britain and
           Ireland (AUGIS)
    • Pages: 2188 - 2188
      Abstract: Beg S, Ragunath K, Wyman A, et al. Quality standards in upper gastrointestinal endoscopy: a position statement of the British Society of Gastroenterology (BSG) and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS). Gut 2017;66:1886–99. doi:10.1136/gutjnl-2017-314109.The sixth author’s name has been corrected to DM Pritchard.
      Keywords: Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-314109corr1
      Issue No: Vol. 66, No. 12 (2017)
  • GI highlights from the literature
    • Authors: McLean M. H.
      Pages: 2189 - 2190
      Abstract: Basic scienceCigarettes and IBD: it’s in your genes Yadav P, Ellinghaus D, Rémy G, et al. Genetic factors interact with tobacco smoke to modify risk for inflammatory bowel disease in humans and mice. Gastroenterology 2017;153:550–565. The relationship between smoking and IBD risk is unclear. Gene–smoking interactions in IBD were explored at a genome-wide level in this paper using data from the International IBD Genetics Consortium. Immunochip custom array data from 20 000 IBD cases were compared with control cases in a meta-analysis of smokers versus non-smokers. Sixty-four single nucleotide polymorphisms (SNPs) were identified for which the associated risk of IBD was affected by smoking. Nearly half of these SNPs were close to SNPs known to be related to IBD, and many were located near genes linked with mucosal barrier regulation and immune response. Twenty SNPs were within the human leucocyte antigen region at 6p21, so the effect on...
      Keywords: Gut
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-315354
      Issue No: Vol. 66, No. 12 (2017)
  • Response to letter to the editor
    • Authors: Bang, J. Y; Varadarajulu, S.
      Pages: 2192 - 2193
      Abstract: Dear editor, Adverse events are captured more accurately during the conduct of a randomised trial1 than when an audit is performed and reported retrospectively.2 As observed in our study, the majority of adverse events were encountered beyond the 4-week time frame when the walled-off necrosis (WON) had (nearly) resolved. Buried stent syndrome was noted when the lumen-apposing metal stents were deployed in the proximal stomach, particularly the region of the gastric cardia. We did not observe any specific factors that could explain the reason for delayed bleeding in our patient cohort except that all patients had WON that was more than 60 mm in largest dimension with greater than 30% necrosis. After a change in the study protocol whereby the stents are now extracted at 4 weeks, provided the WON have resolved on cross-sectional imaging, we have not encountered any stent-related adverse events in our study...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313657
      Issue No: Vol. 66, No. 12 (2017)
  • Re-evaluation of the role of lumen-apposing metal stents (LAMS) for
           pancreatic fluid collection drainage
    • Authors: Zhu, H; Lin, H, Jin, Z, Du, Y.
      Pages: 2192 - 2192
      Abstract: We read with great interest the recent endoscopy news reported by Bang et al,1 discussing the lumen-apposing metal stents (LAMS) for pancreatic fluid collection (PFC) drainage. Patients with walled-off necrosis (WON) treated by using LAMS in their centre occurred a 50% (6/12) rate of adverse events including delayed bleeding (3/12), buried stent syndrome (2/12) and biliary stricture (1/12), which is higher than we expected on our experiences. As the authors reported all three patients presented with severe bleeding were confirmed with pseudoaneurysms. But another data from Sharaiha et al2 showed that LAMS method was safe for PFC. In 124 patients with WON underwent endoscopic transmural drainage using LAMS, where only 2 patients developed an acute haemorrhage during direct endoscopic necrosectomy (DEN), not associated with stents, none of them developed buried LAMS syndrome or biliary strictures. LAMS caused some rare complication like small-bowel obstruction due to...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-313949
      Issue No: Vol. 66, No. 12 (2017)
  • Epithelial organoid cultures from patients with ulcerative colitis and
           Crohn's disease: a truly long-term model to study the molecular basis for
           inflammatory bowel disease'
    • Authors: Noben, M; Verstockt, B, de Bruyn, M, Hendriks, N, Van Assche, G, Vermeire, S, Verfaillie, C, Ferrante, M.
      Pages: 2193 - 2195
      Abstract: With great interest we read the paper by Dotti et al,1 who identified a set of differentially expressed genes in epithelial organoid cultures (EpOCs) derived from patients with UC compared with EpOCs from healthy controls. Similarly, we created an EpOC library from patients with UC (n=17), Crohn's disease (CD, n=12) and healthy controls (n=10). First, we assessed the potential of isolated intestinal crypts to grow into organoids (colony forming units). We observed that a similar percentage of organoids was formed from intestinal crypts isolated from controls and patients with UC or CD. Moreover, intestinal crypts isolated from macroscopically inflamed and non-inflamed tissue had similar potential to form organoids (figure 1A). Although we used a slightly divergent differentiation medium,2 the expansion and differentiation capacity of our organoids was similar as demonstrated by Dotti et al. Next, we characterised the organoids through mRNA expression (quantitative...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2016-313667
      Issue No: Vol. 66, No. 12 (2017)
  • In vitro and in silico evidence against a significant effect of the SPINK1
           c.194G>A variant on pre-mRNA splicing
    • Authors: Wu, H; Boulling, A, Cooper, D. N, Li, Z.-S, Liao, Z, Chen, J.-M, Ferec, C.
      Pages: 2195 - 2196
      Abstract: We read with interest the recent publication of Beer and Sahin-Tóth1 reporting that exonic variants affecting pre-mRNA splicing contribute to the genetic burden in chronic pancreatitis. One particular variant, affecting the last nucleotide of exon 3 of the SPINK1 gene, c.194G>A, was found to cause an ~80% reduction in SPINK1 mRNA expression as compared with the wild type in a minigene assay performed in human embryonic kidney 293T (HEK293T) cells. The SPINK1 sequence inserted into the minigene expression vector however comprised only exon 1, exon 2, exon 3, intron 3 and exon 4 of the four-exon gene.1 It should be noted that the potential effect of c.194G>A as a missense mutation (p.Arg65Gln) on protein function has previously been analysed; engineered expression of the full-length mutant coding sequence in Chinese hamster ovary cells and HEK293T cells showed a consistent 50%–60% reduction in protein secretion as compared...
      PubDate: 2017-11-10T03:08:33-08:00
      DOI: 10.1136/gutjnl-2017-313948
      Issue No: Vol. 66, No. 12 (2017)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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