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Les derniers abstracts de la revue Gut current issue :


    Date de mise en ligne : Samedi 11 mars 2017
    Tulchinsky, E.
    Colorectal cancer cells use the negative feedback regulators of WNT signalling to activate epithelial-mesenchymal transition pathways

    Epithelial–mesenchymal transition (EMT) is a reversible embryonic genetic programme pathologically activated in cancer. The EMT phenomenon has been considered in the context of distant metastases in different carcinoma types including colorectal cancer (CRC). The hallmark of EMT is dissolution of epithelial intercellular junctions and global reorganisation of the cytoskeleton leading to the loss of epithelial features and gain of mesenchymal morphology. EMT programmes are controlled by several groups of embryonic transcription factors (EMT-TFs), of which TWIST1, SNAIL1, ZEB1 and ZEB2 expression correlated with poor prognosis in patients with CRC.1 The role of EMT in cancer is not limited to enhanced invasion; a growing body of evidence implicates EMT-TFs in control of cell division, drug resistance, escape from senescence and oncogenic transformation. Activation of EMT pathways by driver oncogenic mutations was proposed to couple neoplastic transformation with the formation of quiescent circulating tumour cells (CTCs), dormant metastases and...


    Date de mise en ligne : Samedi 11 mars 2017
    Wang, S., Ding, W.-X.
    A small RNA in neutrophils protects against acute-on-chronic alcoholic liver injury

    Alcoholic liver disease (ALD) is a major cause of chronic liver injury worldwide.1 2 Clinically, jaundice and liver failure are hallmark presentations of patients with severe alcoholic hepatitis (AH) who typically have been drinking up to the time of admission or have stopped drinking within 4–6 weeks of their presentation of symptoms. The liver histology of AH has features of steatohepatitis, hepatic neutrophil infiltration, cholestasis and florid inflammation.3 Among patients with ALD, liver-related mortality is much higher in patients with AH than those with only simple steatosis.3 Current recommended treatments for AH include corticosteroids or pentoxifylline and nutritional supplements, but they only have moderate therapeutic effects.3

    A major barrier preventing drug development against AH is our lack of understanding of the regulatory pathways involved in the pathogenesis of AH despite decades of research on ALD. One reason for this knowledge...


    Date de mise en ligne : Samedi 11 mars 2017
    Ramachandran, A., Jaeschke, H.
    PGAM5: a new player in immune-mediated liver injury

    Mechanisms of cell death are critical in any pathophysiology and hence have been extensively investigated in a number of different organ systems. Initially, the term ‘programmed cell death’ was exclusively applied to apoptosis, where molecular mediators and signalling pathways involved in the process were relatively well characterised. The other form of cell death, namely necrosis, was considered to be an uncontrolled process, where catastrophic events within the cell resulted in a rupture of the plasma membrane with release of cell contents. However, this paradigm has been rapidly evolving as new pathways and mediators, which control necrotic cell death, are discovered. It is now clear that whenever cells die by necrosis, they do so in an ordered systematic manner, which, not surprisingly, shares some components with the apoptotic pathway. This is especially relevant in the liver, where apoptosis was considered to be the main form of cell death in a...


    Date de mise en ligne : Samedi 11 mars 2017
    Cammarota, G., Ianiro, G., Tilg, H., Rajilic-Stojanovic, M., Kump, P., Satokari, R., Sokol, H., Arkkila, P., Pintus, C., Hart, A., Segal, J., Aloi, M., Masucci, L., Molinaro, A., Scaldaferri, F., Gasbarrini, G., Lopez-Sanroman, A., Link, A., de Groot, P., de Vos, W. M., Högenauer, C., Malfertheiner, P., Mattila, E., Milosavljevic, T., Nieuwdorp, M., Sanguinetti, M., Simren, M., Gasbarrini, A., The European FMT Working Group
    European consensus conference on faecal microbiota transplantation in clinical practice

    Faecal microbiota transplantation (FMT) is an important therapeutic option for Clostridium difficile infection. Promising findings suggest that FMT may play a role also in the management of other disorders associated with the alteration of gut microbiota. Although the health community is assessing FMT with renewed interest and patients are becoming more aware, there are technical and logistical issues in establishing such a non-standardised treatment into the clinical practice with safety and proper governance. In view of this, an evidence-based recommendation is needed to drive the practical implementation of FMT. In this European Consensus Conference, 28 experts from 10 countries collaborated, in separate working groups and through an evidence-based process, to provide statements on the following key issues: FMT indications; donor selection; preparation of faecal material; clinical management and faecal delivery and basic requirements for implementing an FMT centre. Statements developed by each working group were evaluated and voted by all members, first through an electronic Delphi process, and then in a plenary consensus conference. The recommendations were released according to best available evidence, in order to act as guidance for physicians who plan to implement FMT, aiming at supporting the broad availability of the procedure, discussing other issues relevant to FMT and promoting future clinical research in the area of gut microbiota manipulation. This consensus report strongly recommends the implementation of FMT centres for the treatment of C. difficile infection as well as traces the guidelines of technicality, regulatory, administrative and laboratory requirements.


    Date de mise en ligne : Samedi 11 mars 2017
    Wang, Z., Dai, J., Hu, N., Miao, X., Abnet, C. C., Yang, M., Freedman, N. D., Chen, J., Burdette, L., Zhu, X., Chung, C. C., Ren, C., Dawsey, S. M., Wang, M., Ding, T., Du, J., Gao, Y.-T., Zhong, R., Giffen, C., Pan, W., Koh, W.-P., Dai, N., Liao, L. M., Yan, C., Qiao, Y.-L., Jiang, Y., Shu, X.-O., Chen, J., Wang, C., Ma, H., Su, H., Zhang, Z., Wang, L., Wu, C., Xiang, Y.-B., Hu, Z., Yuan, J.-M., Xie, L., Zheng, W., Lin, D., Chanock, S. J., Shi, Y., Goldstein, A. M., Jin, G., Taylor, P. R., Shen, H.
    Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies
    Objective

    Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer.

    Design

    We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages.

    Results

    The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21x10–11). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20x10–4). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71x10–19), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28x10–17). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (Pconditional=3.47x10–8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations.

    Conclusion

    These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.


    Date de mise en ligne : Samedi 11 mars 2017
    Gower-Rousseau, C., Sarter, H., Savoye, G., Tavernier, N., Fumery, M., Sandborn, W. J., Feagan, B. G., Duhamel, A., Guillon-Dellac, N., Colombel, J.-F., Peyrin-Biroulet, L., and the International Programme to Develop New Indexes for Crohn's Disease (IPNIC) group, International Programme to Develop New Indexes for Crohn's Disease (IPNIC) group, Reinisch, Tilg, Kamm, D'Haens, Louis, Van Assche, Feagan, Jan Irvine, Michetti, Hibi, Schölmerich, Schreiber, Munkholm, Panes, Alarcos, Colombel, Cosnes, Lemann, Lewin, Mary, Pariente, peyrin-Biroulet, Travis, Chowers, Danese, Vecchi, Hommes, Oresland, Fletcher, Loftus, Sandborn, Sands
    Validation of the Inflammatory Bowel Disease Disability Index in a population-based cohort
    Background

    IBDs are chronic destructive disorders that negatively affect the functional status of patients. Recently, the Inflammatory Bowel Disease Disability Index (IBD-DI) was developed according to standard WHO processes. The aims of the current study were to validate the IBD-DI in an independent patient cohort, to develop an index-specific scoring system and to describe the disability status of a well-defined population-based cohort of French patients with IBD.

    Methods

    From February 2012 to March 2014, the IBD-DI questionnaire was administered to a random sample of adult patients with an established diagnosis of IBD issued from a French population-based registry. The IBD-DI consists of 28 items that evaluate the four domains of body functions, activity participation, body structures and environmental factors. Validation included item reduction and data structure, construct validity, internal consistency, interobserver and intraobserver reliability evaluations.

    Results

    150 patients with Crohn's disease (CD) and 50 patients with UC completed the IBD-DI validation phase. The intraclass correlation coefficient for interobserver reliability was 0.91 and 0.54 for intraobserver reliability. Cronbach's α of internal consistency was 0.86. IBD-DI scores varied from 0 to 100 with a mean of 35.3 (Q1=19.6; Q3=51.8). IBD-DI scores were highly correlated with Inflammatory Bowel Disease Questionnaire (–0.82; p<0.001) and SF-36 (–0.61; p<0.05) scores. Female gender (p<0.001), clinical disease activity (p<0.0001) and disease duration (p=0.02) were associated with higher IBD-DI scores.

    Conclusions

    The IBD-DI has been validated for use in clinical trials and epidemiological studies. The IBD-DI showed high internal consistency, interobserver reliability and construct validity, and a moderate intraobserver reliability. It comprises 14 questions and ranges from 0 to 100. The mean IBD-DI score was 35.3 and was associated with gender, clinical disease activity and disease duration. Further research is needed to confirm the structural validity and to assess the responsiveness of IBD-DI.

    Trial registration number

    2011-A00877-34


    Date de mise en ligne : Samedi 11 mars 2017
    Lin, W., Ma, C., Su, F., Jiang, Y., Lai, R., Zhang, T., Sun, K., Fan, L., Cai, Z., Li, Z., Huang, H., Li, J., Wang, X.
    Raf kinase inhibitor protein mediates intestinal epithelial cell apoptosis and promotes IBDs in humans and mice
    Objective

    Raf kinase inhibitor protein (RKIP) appears to control cancer cell metastasis and its expression in colonic tissue is related to colonic cancer development. We sought to identify the roles of RKIP in maintaining homeostasis of GI tract.

    Design

    The expression of RKIP was determined by immunohistochemistry and western blot analysis. RKIP knockout and wild-type mice were administered dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis, and the mice were assessed based on colitis symptoms and biochemical approaches. The mechanism was analysed using immunoprecipitation and pull-down experiments.

    Results

    The RKIP expression is positively correlated with the severity of IBD. RKIP deficiency protects mice from DSS-induced or TNBS-induced colitis and accelerated recovery from colitis. RKIP deficiency inhibits DSS-induced infiltration of acute-phase immune cells and reduces production of proinflammatory cytokines and chemokines in colon. RKIP deficiency inhibits DSS-induced or TNBS-induced colonic epithelial barrier damage and intestinal epithelial cell (IEC) apoptosis. RKIP deficiency also inhibits tumour necrosis factor-alpha-induced IEC apoptosis and colitis. Mechanistically, RKIP enhances the induction of P53-upregulated modulator of apoptosis by interacting with TGF-β-activated kinase 1 (TAK1) and promoting TAK1-mediated NF-B activation. This is supported by the observation that TAK1 activation is positively correlated with the expression of RKIP in human clinical samples and the development of IBD.

    Conclusions

    RKIP contributes to colitis development by promoting inflammation and mediating IEC apoptosis and might represent a therapeutic target of IBD.


    Date de mise en ligne : Samedi 11 mars 2017
    Kummen, M., Holm, K., Anmarkrud, J. A., Nygard, S., Vesterhus, M., Hoivik, M. L., Troseid, M., Marschall, H.-U., Schrumpf, E., Moum, B., Rosjo, H., Aukrust, P., Karlsen, T. H., Hov, J. R.
    The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls
    Objective

    Gut microbiota could influence gut, as well as hepatic and biliary immune responses. We therefore thoroughly characterised the gut microbiota in primary sclerosing cholangitis (PSC) compared with healthy controls (HC) and patients with ulcerative colitis without liver disease.

    Design

    We prospectively collected 543 stool samples. After a stringent exclusion process, bacterial DNA was submitted for 16S rRNA gene sequencing. PSC and HC were randomised to an exploration panel or a validation panel, and only significant results (p<0.05, QFDR<0.20) in both panels were reported, followed by a combined comparison of all samples against UC.

    Results

    Patients with PSC (N=85) had markedly reduced bacterial diversity compared with HC (N=263, p<0.0001), and a different global microbial composition compared with both HC (p<0.001) and UC (N=36, p<0.01). The microbiota of patients with PSC with and without IBD was similar. Twelve genera separated PSC and HC, out of which 11 were reduced in PSC. However, the Veillonella genus showed a marked increase in PSC compared with both HC (p<0.0001) and UC (p<0.02). Using receiver operating characteristic analysis, Veillonella abundance yielded an area under the curve (AUC) of 0.64 to discriminate PSC from HC, while a combination of PSC-associated genera yielded an AUC of 0.78.

    Conclusions

    Patients with PSC exhibited a gut microbial signature distinct from both HC and UC without liver disease, but similar in PSC with and without IBD. The Veillonella genus, which is also associated with other chronic inflammatory and fibrotic conditions, was enriched in PSC.


    Date de mise en ligne : Samedi 11 mars 2017
    Duparc, T., Plovier, H., Marrachelli, V. G., Van Hul, M., Essaghir, A., Stahlman, M., Matamoros, S., Geurts, L., Pardo-Tendero, M. M., Druart, C., Delzenne, N. M., Demoulin, J.-B., van der Merwe, S. W., van Pelt, J., Bäckhed, F., Monleon, D., Everard, A., Cani, P. D.
    Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism
    Objective

    To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.

    Design

    To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).

    Results

    Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.

    Conclusions

    Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.


    Date de mise en ligne : Samedi 11 mars 2017
    Flemer, B., Lynch, D. B., Brown, J. M. R., Jeffery, I. B., Ryan, F. J., Claesson, M. J., O'Riordain, M., Shanahan, F., O'Toole, P. W.
    Tumour-associated and non-tumour-associated microbiota in colorectal cancer
    Objective

    A signature that unifies the colorectal cancer (CRC) microbiota across multiple studies has not been identified. In addition to methodological variance, heterogeneity may be caused by both microbial and host response differences, which was addressed in this study.

    Design

    We prospectively studied the colonic microbiota and the expression of specific host response genes using faecal and mucosal samples (‘ON’ and ‘OFF’ the tumour, proximal and distal) from 59 patients undergoing surgery for CRC, 21 individuals with polyps and 56 healthy controls. Microbiota composition was determined by 16S rRNA amplicon sequencing; expression of host genes involved in CRC progression and immune response was quantified by real-time quantitative PCR.

    Results

    The microbiota of patients with CRC differed from that of controls, but alterations were not restricted to the cancerous tissue. Differences between distal and proximal cancers were detected and faecal microbiota only partially reflected mucosal microbiota in CRC. Patients with CRC can be stratified based on higher level structures of mucosal-associated bacterial co-abundance groups (CAGs) that resemble the previously formulated concept of enterotypes. Of these, Bacteroidetes Cluster 1 and Firmicutes Cluster 1 were in decreased abundance in CRC mucosa, whereas Bacteroidetes Cluster 2, Firmicutes Cluster 2, Pathogen Cluster and Prevotella Cluster showed increased abundance in CRC mucosa. CRC-associated CAGs were differentially correlated with the expression of host immunoinflammatory response genes.

    Conclusions

    CRC-associated microbiota profiles differ from those in healthy subjects and are linked with distinct mucosal gene-expression profiles. Compositional alterations in the microbiota are not restricted to cancerous tissue and differ between distal and proximal cancers.


    Date de mise en ligne : Samedi 11 mars 2017
    Pellise, M., Burgess, N. G., Tutticci, N., Hourigan, L. F., Zanati, S. A., Brown, G. J., Singh, R., Williams, S. J., Raftopoulos, S. C., Ormonde, D., Moss, A., Byth, K., P'Ng, H., Mahajan, H., McLeod, D., Bourke, M. J.
    Endoscopic mucosal resection for large serrated lesions in comparison with adenomas: a prospective multicentre study of 2000 lesions
    Objective

    Endoscopic mucosal resection (EMR) is effective for large laterally spreading flat and sessile lesions (LSLs). Sessile serrated adenomas/polyps (SSA/Ps) are linked to the relative failure of colonoscopy to prevent proximal colorectal cancer. We aimed to examine the technical success, adverse events and recurrence following EMR for large SSA/Ps in comparison with large conventional adenomas.

    Design

    Over 74 months till August 2014, prospective multicentre data of LSLs ≥20 mm were analysed. A standardised dye-based conventional EMR technique followed by scheduled surveillance colonoscopy was used.

    Results

    From a total of 2000 lesions, 323 SSA/Ps in 246 patients and 1527 adenomas in 1425 patients were included for analysis. Technical success for EMR was superior in SSA/Ps compared with adenomas (99.1% vs 94.5%, p<0.001). Significant bleeding and perforation were similar in both cohorts. The cumulative recurrence rates for adenomas after 6, 12, 18 and 24 months were 16.1%, 20.4%, 23.4% and 28.4%, respectively. For SSA/Ps, they were 6.3% at 6 months and 7.0% from 12 months onwards (p<0.001). Following multivariable adjustment, the HR of recurrence for adenomas versus SSA/Ps was 1.7 (95% CI 0.9 to 3.0, p=0.097). Subgroup analysis by lesion size revealed an eightfold increased risk of recurrence for 20–25 mm adenomas versus SSA/Ps, but no significantly different risk between lesion types in larger lesion groups.

    Conclusion

    Recurrence after EMR of 20–25 mm LSLs is significantly less frequent in SSA/Ps compared with adenomatous lesions. SSA/Ps can be more effectively removed than adenomatous LSLs with equivalent safety. Ensuring complete initial resection is imperative for avoiding recurrence.

    Trial registration number

    ClinicalTrials.gov NCT01368289.


    Date de mise en ligne : Samedi 11 mars 2017
    Hur, K., Toiyama, Y., Okugawa, Y., Ide, S., Imaoka, H., Boland, C. R., Goel, A.
    Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer
    Background and aims

    Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis.

    Methods

    MiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation.

    Results

    MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls.

    Conclusions

    High levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.


    Date de mise en ligne : Samedi 11 mars 2017
    Barresi, L., Tarantino, I., Ligresti, D., Curcio, G., Granata, A., Chiarello, G., Traina, M.
    An unusual endoscopic ultrasound diagnosis in kidney-transplant patient
    Clinical presentation

    A 29-year-old man who had undergone kidney transplantation in 1999 for chronic glomerular disease, on treatment with ciclosporin, azathioprine and steroids, was admitted for severe, diffuse abdominal pain. No fever or other symptoms were present. Multidetector CT (MDCT) scan showed several chest and abdominal lymphadenopathies and pericardial, pleural and abdominal effusions. A post-transplant lymphoproliferative disorder (PTLD) was suspected and, therefore, azathioprine and ciclosporin were suspended with resolution of serosal effusions. However, cytology and cytofluorimetry from ascites and pleural effusion and surgical histology from supraclavicular lymph node showed no lymphoproliferative disease. Epstein-Barr virus (EBV)-DNA was repeatedly negative, as was serology for HIV. A new MDCT scan confirmed marked reduction of chest and abdominal lymphadenopathies, and resolution of serosal effusion. However, because of persistence of moderate abdominal pain, a (18)F-fluorodeoxyglucose-positron emission tomography-CT scan ((18)F-FDG-PET-CT scans) was performed, and detected multiple areas of accumulation of the radiopharmaceutical in the...


    Date de mise en ligne : Samedi 11 mars 2017
    de Barrios, O., Gyorffy, B., Fernandez-Acenero, M. J., Sanchez-Tillo, E., Sanchez-Moral, L., Siles, L., Esteve-Arenys, A., Roue, G., Casal, J. I., Darling, D. S., Castells, A., Postigo, A.
    ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1
    Objective

    Understand the role of ZEB1 in the tumour initiation and progression beyond inducing an epithelial-to-mesenchymal transition.

    Design

    Expression of the transcription factor ZEB1 associates with a worse prognosis in most cancers, including colorectal carcinomas (CRCs). The study uses survival analysis, in vivo mouse transgenic and xenograft models, gene expression arrays, immunostaining and gene and protein regulation assays.

    Results

    The poorer survival determined by ZEB1 in CRCs depended on simultaneous high levels of the Wnt antagonist DKK1, whose expression was transcriptionally activated by ZEB1. In cancer cells with mutant TP53, ZEB1 blocked the formation of senescence-associated heterochromatin foci at the onset of senescence by triggering a new regulatory cascade that involves the subsequent activation of DKK1, mutant p53, Mdm2 and CtBP to ultimately repress macroH2A1 (H2AFY). In a transgenic mouse model of colon cancer, partial downregulation of Zeb1 was sufficient to induce H2afy and to trigger in vivo tumour senescence, thus resulting in reduced tumour load and improved survival. The capacity of ZEB1 to induce tumourigenesis in a xenograft mouse model requires the repression of H2AFY by ZEB1. Lastly, the worst survival effect of ZEB1 in patients with CRC ultimately depends on low expression of H2AFY and of senescence-associated genes.

    Conclusions

    The tumourigenic capacity of ZEB1 depends on its inhibition of cancer cell senescence through the activation of a herein identified new molecular pathway. These results set ZEB1 as a potential target in therapeutic strategies aimed at inducing senescence.


    Date de mise en ligne : Samedi 11 mars 2017
    Arnold, M., Sierra, M. S., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F.
    Global patterns and trends in colorectal cancer incidence and mortality
    Objective

    The global burden of colorectal cancer (CRC) is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In this study, we aim to describe the recent CRC incidence and mortality patterns and trends linking the findings to the prospects of reducing the burden through cancer prevention and care.

    Design

    Estimates of sex-specific CRC incidence and mortality rates in 2012 were extracted from the GLOBOCAN database. Temporal patterns were assessed for 37 countries using data from Cancer Incidence in Five Continents (CI5) volumes I–X and the WHO mortality database. Trends were assessed via the annual percentage change using joinpoint regression and discussed in relation to human development levels.

    Results

    CRC incidence and mortality rates vary up to 10-fold worldwide, with distinct gradients across human development levels, pointing towards widening disparities and an increasing burden in countries in transition. Generally, CRC incidence and mortality rates are still rising rapidly in many low-income and middle-income countries; stabilising or decreasing trends tend to be seen in highly developed countries where rates remain among the highest in the world.

    Conclusions

    Patterns and trends in CRC incidence and mortality correlate with present human development levels and their incremental changes might reflect the adoption of more western lifestyles. Targeted resource-dependent interventions, including primary prevention in low-income, supplemented with early detection in high-income settings, are needed to reduce the number of patients with CRC in future decades.


    Date de mise en ligne : Samedi 11 mars 2017
    Amicarella, F., Muraro, M. G., Hirt, C., Cremonesi, E., Padovan, E., Mele, V., Governa, V., Han, J., Huber, X., Droeser, R. A., Zuber, M., Adamina, M., Bolli, M., Rosso, R., Lugli, A., Zlobec, I., Terracciano, L., Tornillo, L., Zajac, P., Eppenberger-Castori, S., Trapani, F., Oertli, D., Iezzi, G.
    Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer
    Background

    The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated.

    Objective

    To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells.

    Methods

    IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments.

    Results

    IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival.

    Conclusions

    Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.


    Date de mise en ligne : Samedi 11 mars 2017
    Li, M., He, Y., Zhou, Z., Ramirez, T., Gao, Y., Gao, Y., Ross, R. A., Cao, H., Cai, Y., Xu, M., Feng, D., Zhang, P., Liangpunsakul, S., Gao, B.
    MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils
    Objectives

    Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice.

    Designs

    Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol.

    Results

    Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47phox. Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47phox expression in neutrophils. Deletion of the p47phox gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47phox expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls.

    Conclusions

    miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady.


    Date de mise en ligne : Samedi 11 mars 2017
    He, G.-W., Günther, C., Kremer, A. E., Thonn, V., Amann, K., Poremba, C., Neurath, M. F., Wirtz, S., Becker, C.
    PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury
    Objectives

    Autoimmune hepatitis (AIH) is a severe necroinflammatory liver disease associated with significant mortality. Although loss of hepatocytes is generally recognised as a key trigger of liver inflammation and liver failure, the regulation of hepatic cell death causing AIH remains poorly understood. The aim of this study was to identify molecular mechanisms that drive hepatocyte cell death in the pathogenesis of acute liver injury.

    Design

    Acute liver injury was modelled in mice by intravenous administration of concanavalin A (ConA). Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. PGAM5-deficient mice (PGAM5–/–) were used to determine its role in experimental hepatitis. Mdivi-1 was used as an inhibitor of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Mitochondrial fission and the expression of PGAM5 were compared between liver biopsies derived from patients with AIH and control patients.

    Results

    PGAM5 was highly expressed in hepatocytes of patients with AIH and in mice with ConA-induced experimental hepatitis. Deficiency of PGAM5 protected mice from ConA-induced hepatocellular death and liver injury. PGAM5 regulated ConA-induced mitochondrial fission in hepatocytes. Administration of the Drp1-inhibitor Mdivi-1 blocked mitochondrial fission, diminished hepatocyte cell death and attenuated liver tissue damage induced by ConA.

    Conclusions

    Our data demonstrate for the first time that PGAM5 plays an indispensable role in the pathogenesis of ConA-induced liver injury. Downstream of PGAM5, Drp1-mediated mitochondrial fission is an obligatory step that drives the execution of hepatic necrosis and tissue damage. Our data highlight the PGAM5-Drp1 axis as a potential therapeutic target for acute immune-mediated liver injury.


    Date de mise en ligne : Samedi 11 mars 2017
    Serti, E., Park, H., Keane, M., O'Keefe, A. C., Rivera, E., Liang, T. J., Ghany, M., Rehermann, B.
    Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFN{alpha}
    Objective

    Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy.

    Design

    Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα.

    Results

    The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα.

    Conclusions

    IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries.

    Trial registration numbers

    NCT01888900 and NCT00718172.


    Date de mise en ligne : Samedi 11 mars 2017
    Pares, A.
    Juan Rodes. A successful and extraordinary life of a visionary hepatologist

    Dr Juan Rodés, architect of the Liver Unit of the Hospital Clinic of the University of Barcelona, an internationally renowned centre for research in liver disease, died in Barcelona on 10 January 2017, aged 78 years. He was one of the most inspiring and influential leaders in the field of clinical hepatology and the physician who changed modern medical practice in Spain.

    Juan graduated from the University of Barcelona School of Medicine, Barcelona, in 1962, and trained in Internal Medicine at the Hospital Clinic. The centre has had the privilege of having Dr Rodés as Head of Hepatology Professor of Medicine, Director and Chief Executive Officer, till his retirement.

    Dr Rodés and five other doctors started The Liver Unit informally in 1969 in the Catalan town of Montferri, Tarragona. Prior to this, Juan had completed a 1-year fellowship in Paris with Professor Caroli. From the beginning, each...


    Date de mise en ligne : Samedi 11 mars 2017
    Fang, J. Y.
    A tribute to Professor Shu Dong Xiao (1931-2016)

    Great sadness and deep affection marked the recent passing of Professor and Dr Shu Dong Xiao, a renowned and respected gastroenterologist, the emeritus director of Shanghai Institute of Digestive Disease and the emeritus professor of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, who had dedicated his whole life to the academic and clinical study of digestive diseases. Professor Xiao died from cardiopulmonary failure on 22 July 2016 at the age of 85.

    Professor Xiao was born in 1931 in Huangpi city, Hubei Province, China. He graduated from the Shanghai Second Medical College (currently known as Shanghai Jiaotong University School of Medicine) in 1955, majoring in medicine. Because of his excellent performance he remained working as a resident of the Department of Internal Medicine in Hongren Hospital after graduation and later transferred to the Department of Internal Medicine of Renji Hospital. In 1978, he was promoted as the...


    Date de mise en ligne : Samedi 11 mars 2017
    Bachmann, R., Leonard, D., Delzenne, N., Kartheuser, A., Cani, P. D.
    Novel insight into the role of microbiota in colorectal surgery

    Recent literature undeniably supports the idea that the microbiota has a strong influence on the healing process of an intestinal anastomosis. Understanding the mechanisms by which the bacterial community of the gut influences intestinal healing could open the door for new preventive and therapeutic approaches. Among the different mechanisms, data have shown that the production of specific reactive oxygen species (ROS) and the activation of specific formyl peptide receptors (FPRs) regulate intestinal wound healing. Evidence suggests that specific gut microbes such as Lactobacillus spp and Akkermansia muciniphila help to regulate healing processes through both ROS-dependent and FPR-dependent mechanisms. In this review, we will discuss the current knowledge and future perspectives concerning the impact of microbiota on wound healing. We will further review available evidence on whether mechanical bowel preparation and the use of specific antibiotics are beneficial or harmful procedures, an ongoing matter of debate. These practices have a profound effect on the gut microbiota composition at the level of both the mucosal and the luminal compartments. Therefore, a key question remains unanswered: should we continue to prepare the gut before surgical intervention? Current knowledge and data do not clearly support the use of one technique or another to avoid complications such as anastomotic leak. There is an urgent need for appropriate interventions with a deep microbiota analysis to investigate both the surgical technical benefits of a proper anastomosis compared with the potential effect of the gut microbes (beneficial vs harmful) on the processes of wound healing and anastomotic leakage reduction.


    Date de mise en ligne : Samedi 11 mars 2017
    McLean, M. H.
    GI highlights from the literature
    Basic ScienceUnravelling the complexities of signalling networks in hepatocellular carcinoma

    Kim W, Khan SK, Gvozdenovic-Jeremic J, et al. Hippo signaling interactions with Wnt/ beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 2017;127:137–52.

    Dysregulation of signalling pathways has been associated with the development and progression of a range of human cancers including hepatocellular carcinoma (HCC). A detailed understanding of how such pathways interact in vivo is essential to allow therapeutic targeting of these pathways. In this study, the authors have dissected the role of a complex signalling network involving the Hippo, Notch and Wnt/β-catenin pathways on HCC formation and growth. Inactivation of liver Hippo signalling using transgenic mice deficient for mammalian sterile 20-like kinases (MST1 and MST2) resulted in augmentation of the activity of the transcription factors YAP and TAZ and the spontaneous development of HCC in 100% of mice. Hence, the authors confirmed a...


    Date de mise en ligne : Samedi 11 mars 2017
    Katayama, Y., Toyoda, K., Kusano, Y., Suda, T., Adachi, S., Terauchi, I., Oka, S., Takahashi, M., Tamano, M.
    Efficacy of vonoprazan-based second-line Helicobacter pylori eradication therapy in patients for whom vonoprazan-based first-line treatment failed

    We read with great interest the article by Murakami et al,1 who performed a randomised, double-blinded study of vonoprazan-based Helicobacter pylori (H. pylori) eradication therapy. They showed high success rates for vonoprazan-based first-line and second-line H. pylori treatments, with eradication rates of 92.6% and 98%, respectively. However, the study populations of second-line therapy included patients for whom both lansoprazole-based and vonoprazan-based first-line treatments failed, and those for whom vonoprazan-based first-line therapy failed numbered only 14. In terms of second-line therapy, we think that the eradication rate in patients for whom vonoprazan-based first-line therapy failed is more important.

    We conducted a multicenter cohort study of vonoprazan-based second-line therapy among patients for whom vonoprazan-based first-line treatment failed. Primary end points were eradication rates and adverse events in first-line and second-line treatments. First-line and second-line H. pylori eradication rates were 90.6% (95% CI 86.3% to 93.9%) and 87.0% (95% CI...


    Date de mise en ligne : Samedi 11 mars 2017
    Rühlemann, M. C., Heinsen, F.-A., Zenouzi, R., Lieb, W., Franke, A., Schramm, C.
    Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis

    Dear Sir,

    Primary sclerosing cholangitis (PSC) is a progressive disease of unknown aetiology. The presumed involvement of the gut–liver axis in disease pathogenesis1 has prompted investigations into mucosal2 and faecal intestinal microbiota composition, as has been reported by Kummen et al3 in this journal. Microbiota as diagnostic biomarkers of disease are of interest from the clinician’s point of view and Kummen et al3 have suggested a panel of taxa and even a single genus (Veillonella) with a reasonable diagnostic accuracy differentiating PSC and healthy controls (HCs).

    We here report on a cohort study from northern Germany, using stool samples of 98 HC subjects, 73 patients with well-characterised PSC and 88 subjects with UC for 16S rDNA sequencing of the V1-V2 variable region. The PSC subgroup included 38 subjects with concomitant UC (PSC-UC). The data were subjected to quality control and operational...


    Date de mise en ligne : Samedi 11 mars 2017
    Wang, Y., Liao, Z., Wang, P., Chen, J., Guo, J., Fu, H., Dong, Y., Li, Z., Du, Y.
    Treatment strategy for video capsule retention by double-balloon enteroscopy

    We read with great interest the recent endoscopy news reported by Gluck et al,1 presenting a novel prepless X-ray imaging capsule for colon cancer screening. The capsule emits low-dose X-rays that can penetrate the colon contents and identify polyps without the need for bowel preparation. However, one capsule retention occurred in 46 asymptomatic volunteers in a pilot study and it was retrieved by colonoscopy. Actually, capsule endoscopy retention is not rare even in patient without suspected Crohn's disease or bowel obstruction, with a retention rate of around 1.0%.2 3 Most retained capsules remain harmless but some can cause bowel obstruction, perforation or even capsule fragmentation.4 Several case reports described the use of double-balloon enteroscopy (DBE) for capsule extraction.5 6

    In this investigation, we aimed to evaluate the use of DBE for retrieval of endoscopic capsules and identify...


    Date de mise en ligne : Samedi 11 mars 2017
    Kummen, M., Hov, J. R.
    Response to 'Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis by Rühlemann et al

    We read with great interest and enthusiasm the letter from Rühlemann et al1 regarding the possible diagnostic role of the faecal microbial profile in primary sclerosing cholangitis (PSC). In the study, 73 well-characterised patients with PSC were compared with 98 healthy control (HC) subjects and 88 subjects with UC in order to validate a diagnostic panel of microbial markers identified in our recent study of PSC.2

    Out of 12 taxa included in a diagnostic panel, 10 were also identified in the German dataset. Using these 10 taxa, Rühlemann et al obtained the area under the curves (AUCs) of 0.86 and 0.79 for discriminating HC from PSC, and UC from PSC, respectively, validating our previous findings. Although the Veillonella genus was elevated in PSC compared with controls, as seen in our study, the abundance was similar in PSC and UC and did not have significant discriminatory...


    Date de mise en ligne : Samedi 11 mars 2017
    Jankipersadsing, S. A., Hadizadeh, F., Bonder, M. J., Tigchelaar, E. F., Deelen, P., Fu, J., Andreasson, A., Agreus, L., Walter, S., Wijmenga, C., Hysi, P., D'Amato, M., Zhernakova, A.
    A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency

    Stool consistency and frequency patterns are complex traits that are often altered in GI disease, and recent studies published in Gut highlight the importance of stool frequency in relation to gut microbiota composition and the efficacy of pharmacological and dietary treatments in IBS.1–3

    Despite reported heritability in invertebrates4 and similar evidence from open-field defaecation models in rats,5 the genetics of stool frequency has not been explored in humans. We undertook a genome-wide association study (GWAS) in two well-characterised population-based cohorts with genotype and defaecation data available: LifeLines-Deep (LLD) from the Netherlands (N=1546; 58% females; mean age 44 years (range 18–86)) and PopCol (PC) from Sweden (N=284; 60% females; mean age 54 years (range 22–71)).6 7 The average number of bowel movements per day (BM/d) was extracted from daily records kept by both populations and did not differ...