TY  - JOUR
AB  - BACKGROUND: The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity. OBJECTIVE: To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues. DESIGN: Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose). RESULTS: Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes. CONCLUSION: These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.
AU  - Castells-Nobau, A.*
AU  - Moreno-Navarrete, J.M.*
AU  - de la Vega-Correa, L.*
AU  - Puig, I.*
AU  - Federici, M.*
AU  - Sun, J.*
AU  - Burcelin, R.*
AU  - Guzylack-Piriou, L.*
AU  - Gourdy, P.*
AU  - Cazals, L.*
AU  - Arnoriaga-Rodríguez, M.*
AU  - Fruhbeck, G.*
AU  - Seoane, L.M.*
AU  - López-Miranda, J.*
AU  - Tinahones, F.J.*
AU  - Dieguez, C.*
AU  - Dumas, M.E.*
AU  - Pérez-Brocal, V.*
AU  - Moya, A.*
AU  - Perakakis, N.
AU  - Mingrone, G.*
AU  - Bornstein, S.R.
AU  - Rodriguez Hermosa, J.I.*
AU  - Castro, E.*
AU  - Fernández-Real, J.M.*
AU  - Mayneris-Perxachs, J.*
C1  - 71893
C2  - 56481
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
TI  - Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism.
JO  - Gut
PB  - Bmj Publishing Group
PY  - 2024
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). DESIGN: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice. RESULTS: Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. CONCLUSION: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.
AU  - Vogt, M.A.*
AU  - Dudvarski Stankovic, N.*
AU  - Cruz Garcia, Y.*
AU  - Hofstetter, J.*
AU  - Schneider, K.*
AU  - Kuybu, F.*
AU  - Hauck, T.E.*
AU  - Adhikari, B.*
AU  - Hamann, A.*
AU  - Rocca, Y.*
AU  - Grysczyk, L.*
AU  - Martin, B.*
AU  - Gebhardt-Wolf, A.*
AU  - Wiegering, A.*
AU  - Diefenbacher, M.
AU  - Gasteiger, G.*
AU  - Knapp, S.*
AU  - Saur, D.*
AU  - Eilers, M.*
AU  - Rosenfeldt, M.*
AU  - Erhard, F.*
AU  - Vos, S.M.*
AU  - Wolf, E.*
C1  - 70786
C2  - 56001
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
TI  - Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.
JO  - Gut
PB  - Bmj Publishing Group
PY  - 2024
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.
AU  - Akhlaghpour, M.*
AU  - Haritunians, T.*
AU  - More, S.K.*
AU  - Thomas, L.S.*
AU  - Stamps, D.T.*
AU  - Dube, S.*
AU  - Li, D.*
AU  - Yang, S.*
AU  - Landers, C.J.*
AU  - Mengesha, E.*
AU  - Hamade, H.*
AU  - Murali, R.*
AU  - Potdar, A.A.*
AU  - Wolf, A.J.*
AU  - Botwin, G.J.*
AU  - Khrom, M.*
AU  - Ananthakrishnan, A.N.*
AU  - Faubion, W.A.*
AU  - Jabri, B.*
AU  - Lira, S.A.*
AU  - Newberry, R.D.*
AU  - Sandler, R.S.*
AU  - Sartor, R.B.*
AU  - Xavier, R.J.*
AU  - Brant, S.R.*
AU  - Cho, J.H.*
AU  - Duerr, R.H.*
AU  - Lazarev, M.G.*
AU  - Rioux, J.D.*
AU  - Schumm, L.P.*
AU  - Silverberg, M.S.*
AU  - Zaghiyan, K.*
AU  - Fleshner, P.*
AU  - Melmed, G.Y.*
AU  - Vasiliauskas, E.A.*
AU  - Ha, C.S.R.*
AU  - Rabizadeh, S.*
AU  - Syal, G.*
AU  - Bonthala, N.N.*
AU  - Ziring, D.A.*
AU  - Targan, S.R.*
AU  - Long, M.D.*
AU  - McGovern, D.P.B.*
AU  - International IBD Genetics Consortium (IIBDGC) (Gieger, C.)
C1  - 70153
C2  - 55025
SP  - 2068-2080
TI  - Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.
JO  - Gut
VL  - 72
IS  - 11
PY  - 2023
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Luo, S.
AU  - Ru, J.
AU  - Khan Mirzaei, M.
AU  - Xue, J.
AU  - Peng, X.
AU  - Ralser, A.*
AU  - Hadi, J.L.
AU  - Mejías-Luque, R.*
AU  - Gerhard, M.*
AU  - Deng, L.
C1  - 68730
C2  - 54939
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
TI  - Helicobacter pylori infection alters gut virome by expanding temperate phages linked to increased risk of colorectal cancer.
JO  - Gut
PB  - Bmj Publishing Group
PY  - 2023
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Helicobacter pylori infection is the most prevalent bacterial infection worldwide. Besides being the most important risk factor for gastric cancer development, epidemiological data show that infected individuals harbour a nearly twofold increased risk to develop colorectal cancer (CRC). However, a direct causal and functional connection between H. pylori infection and colon cancer is lacking. DESIGN: We infected two Apc-mutant mouse models and C57BL/6 mice with H. pylori and conducted a comprehensive analysis of H. pylori-induced changes in intestinal immune responses and epithelial signatures via flow cytometry, chip cytometry, immunohistochemistry and single cell RNA sequencing. Microbial signatures were characterised and evaluated in germ-free mice and via stool transfer experiments. RESULTS: H. pylori infection accelerated tumour development in Apc-mutant mice. We identified a unique H. pylori-driven immune alteration signature characterised by a reduction in regulatory T cells and pro-inflammatory T cells. Furthermore, in the intestinal and colonic epithelium, H. pylori induced pro-carcinogenic STAT3 signalling and a loss of goblet cells, changes that have been shown to contribute-in combination with pro-inflammatory and mucus degrading microbial signatures-to tumour development. Similar immune and epithelial alterations were found in human colon biopsies from H. pylori-infected patients. Housing of Apc-mutant mice under germ-free conditions ameliorated, and early antibiotic eradication of H. pylori infection normalised the tumour incidence to the level of uninfected controls. CONCLUSIONS: Our studies provide evidence that H. pylori infection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation of H. pylori status into preventive measures of CRC should be considered.
AU  - Ralser, A.*
AU  - Dietl, A.*
AU  - Jarosch, S.*
AU  - Engelsberger, V.*
AU  - Wanisch, A.*
AU  - Janssen, K.P.*
AU  - Middelhoff, M.*
AU  - Vieth, M.*
AU  - Quante, M.*
AU  - Haller, D.*
AU  - Busch, D.*
AU  - Deng, L.
AU  - Mejías-Luque, R.*
AU  - Gerhard, M.*
C1  - 67629
C2  - 53936
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 1258-1270
TI  - Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature.
JO  - Gut
VL  - 72
IS  - 7
PB  - Bmj Publishing Group
PY  - 2023
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.
AU  - Belda, E.*
AU  - Voland, L.*
AU  - Tremaroli, V.*
AU  - Falony, G.*
AU  - Adriouch, S.*
AU  - Assmann, K.E.*
AU  - Prifiti, E.*
AU  - Aron-Wisnewsky, J.*
AU  - Debédat, J.*
AU  - Le Roy, T.*
AU  - Nielsen, T.*
AU  - Amouyal, C.*
AU  - Andre, S.*
AU  - Andreelli, F.*
AU  - Blüher, M.*
AU  - Chakaroun, R.*
AU  - Chilloux, J.*
AU  - Coelho, L.P.*
AU  - Dao, M.C.*
AU  - Das, P.*
AU  - Fellahi, S.*
AU  - Forslund, S.K.*
AU  - Galleron, N.*
AU  - Hansen, T.H.*
AU  - Holmes, B.*
AU  - Ji, B.*
AU  - Krogh Pedersen, H.*
AU  - Le, P.*
AU  - Le Chatelier, E.*
AU  - Lewinter, C.*
AU  - Mannerås-Holm, L.*
AU  - Marquet, F.*
AU  - Myridakis, A.*
AU  - Pelloux, V.*
AU  - Pons, N.*
AU  - Quinquis, B.*
AU  - Rouault, C.*
AU  - Roume, H.*
AU  - Salem, J.E.*
AU  - Sokolovska, N.*
AU  - Søndertoft, N.B.*
AU  - Touch, S.*
AU  - Vieira-Silva, S.*
AU  - Galan, P.*
AU  - Holst, J.*
AU  - Gøtze, J.P.*
AU  - Køber, L.*
AU  - Vestergaard, H.*
AU  - Hansen, T.*
AU  - Hercberg, S.*
AU  - Oppert, J.M.*
AU  - Nielsen, J.*
AU  - Letunic, I.*
AU  - Dumas, M.E.*
AU  - Stumvoll, M.
AU  - Pedersen, O.B.*
AU  - Bork, P.*
AU  - Ehrlich, S.D.*
AU  - Zucker, J.D.*
AU  - Bäckhed, F.*
AU  - Raes, J.*
AU  - Clément, K.*
C1  - 64077
C2  - 51811
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 2463-2480
TI  - Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: Effect of biotin and prebiotic supplementation on improved metabolism.
JO  - Gut
VL  - 71
IS  - 12
PB  - Bmj Publishing Group
PY  - 2022
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Onogi, Y.
AU  - Ussar, S.
C1  - 63425
C2  - 51429
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 2147-2148
TI  - Is epiploic fat the dermal fat of the intestine?
JO  - Gut
VL  - 71
IS  - 11
PB  - Bmj Publishing Group
PY  - 2022
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Human white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism. DESIGN: Mesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR. RESULTS: While mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels. CONCLUSION: Multi-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.
AU  - Krieg, L.*
AU  - Didt, K.*
AU  - Karkossa, I.*
AU  - Bernhart, S.H.*
AU  - Kehr, S.*
AU  - Subramanian, N.*
AU  - Lindhorst, A.*
AU  - Schaudinn, A.*
AU  - Tabei, S.*
AU  - Keller, M.
AU  - Stumvoll, M.*
AU  - Dietrich, A.*
AU  - von Bergen, M.*
AU  - Stadler, P.F.*
AU  - Laurencikiene, J.*
AU  - Krüger, M.*
AU  - Blüher, M.
AU  - Gericke, M.*
AU  - Schubert, K.*
AU  - Kovacs, P.*
AU  - Chakaroun, R.*
AU  - Massier, L.*
C1  - 63181
C2  - 51372
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
TI  - Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance.
JO  - Gut
PB  - Bmj Publishing Group
PY  - 2021
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. RESULTS: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar. CONCLUSION: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.
AU  - Thangapandi, V.R.*
AU  - Knittelfelder, O.*
AU  - Brosch, M.*
AU  - Patsenker, E.*
AU  - Vvedenskaya, O.*
AU  - Buch, S.*
AU  - Hinz, S.*
AU  - Hendricks, A.*
AU  - Nati, M.*
AU  - Herrmann, A.*
AU  - Rekhade, D.R.*
AU  - Berg, T.*
AU  - Matz-Soja, M.*
AU  - Huse, K.*
AU  - Klipp, E.*
AU  - Pauling, J.K.*
AU  - Wodke, J.A.*
AU  - Miranda Ackerman, J.*
AU  - Bonin, M.V.*
AU  - Aigner, E.*
AU  - Datz, C.*
AU  - von Schönfels, W.*
AU  - Nehring, S.*
AU  - Zeissig, S.*
AU  - Röcken, C.*
AU  - Dahl, A.*
AU  - Chavakis, T.
AU  - Stickel, F.*
AU  - Shevchenko, A.*
AU  - Schafmayer, C.*
AU  - Hampe, J.*
AU  - Subramanian, P.*
C1  - 59517
C2  - 48839
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 940-950
TI  - Loss of hepatic Mboat7 leads to liver fibrosis.
JO  - Gut
VL  - 70
IS  - 5
PB  - Bmj Publishing Group
PY  - 2021
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Objective Reduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn's disease (CD). PCs reside in proximity to Lgr5(+) intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance.Design Ileal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60(Delta/Delta ISC)) and CD-like ileitis (TNF Delta ARE), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function.Results In patients with CD and TNF Delta ARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNF Delta ARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNF Delta ARE mice-derived crypts to form organoids.Conclusion We provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.
AU  - Khaloian, S.*
AU  - Rath, E.*
AU  - Hammoudi, N.*
AU  - Gleisinger, E.*
AU  - Blutke, A.
AU  - Giesbertz, P.*
AU  - Berger, E.*
AU  - Metwaly, A.*
AU  - Waldschmitt, N.*
AU  - Allez, M.*
AU  - Haller, D.*
C1  - 58599
C2  - 48532
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 1939-1951
TI  - Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn's disease recurrence.
JO  - Gut
VL  - 69
IS  - 11
PB  - Bmj Publishing Group
PY  - 2020
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Massier, L.*
AU  - Chakaroun, R.*
AU  - Kovacs, P.*
AU  - Heiker, J.T.
C1  - 60274
C2  - 49090
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 1801-1802
TI  - Blurring the picture in leaky gut research: How shortcomings of zonulin as a biomarker mislead the field of intestinal permeability.
JO  - Gut
VL  - 70
IS  - 9
PB  - Bmj Publishing Group
PY  - 2020
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Tjalma, J.J.J.*
AU  - Koller, M.*
AU  - Linssen, M.D.*
AU  - Hartmans, E.*
AU  - de Jongh, S.*
AU  - Jorritsma-Smit, A.*
AU  - Karrenbeld, A.*
AU  - de Vries, E.G.*
AU  - Kleibeuker, J.H.*
AU  - Pennings, J.P.*
AU  - Havenga, K.*
AU  - Hemmer, P.H.*
AU  - Hospers, G.A.P.*
AU  - Van Etten, B.*
AU  - Ntziachristos, V.
AU  - van Dam, G.M.*
AU  - Robinson, D.J.*
AU  - Nagengast, W.B.*
C1  - 56976
C2  - 47448
SP  - 406-410
TI  - Quantitative fluorescence endoscopy: An innovative endoscopy approach to evaluate neoadjuvant treatment response in locally advanced rectal cancer.
JO  - Gut
VL  - 69
IS  - 3
PY  - 2020
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Objective: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children. Design: The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case-control design. From this design, 83 CDA case-control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling. Results: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake. Conclusions: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.
AU  - Lindfors, K.*
AU  - Lin, J.*
AU  - Lee, H.S.*
AU  - Hyöty, H.*
AU  - Nykter, M.*
AU  - Kurppa, K.*
AU  - Liu, E.*
AU  - Koletzko, S.*
AU  - Rewers, M.*
AU  - Hagopian, W.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Akolkar, B.*
AU  - Krischer, J.P.*
AU  - Petrosino, J.F.*
AU  - Lloyd, R.E.*
AU  - Agardh, D.*
C1  - 57373
C2  - 47766
SP  - 1416–1422
TI  - Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: The TEDDY study.
JO  - Gut
VL  - 69
PY  - 2019
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Nagengast, W.B.*
AU  - Hartmans, E.*
AU  - Garcia-Allende, P.
AU  - Peters, F.T.M.*
AU  - Linssen, M.D.*
AU  - Koch, M.
AU  - Köller, M.*
AU  - Tjalma, J.J.J.*
AU  - Karrenbeld, A.*
AU  - Jorritsma-Smit, A.*
AU  - Kleibeuker, J.H.*
AU  - van Dam, G.M.*
AU  - Ntziachristos, V.
C1  - 52812
C2  - 43903
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 7-10
TI  - Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A.
JO  - Gut
VL  - 68
IS  - 1
PB  - Bmj Publishing Group
PY  - 2019
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Objective Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.Results We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95%CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.Conclusion An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
AU  - Rosendahl, J.*
AU  - Kirsten, H.*
AU  - Hegyi, E.*
AU  - Kovacs, P.*
AU  - Weiss, F.U.*
AU  - Laumen, H.*
AU  - Lichtner, P.
AU  - Ruffert, C.*
AU  - Chen, J.M.*
AU  - Masson, E.*
AU  - Beer, S.*
AU  - Zimmer, C.*
AU  - Seltsam, K.*
AU  - Algül, H.*
AU  - Bühler, F.*
AU  - Bruno, M.J.*
AU  - Bugert, P.*
AU  - Burkhardt, R.*
AU  - Cavestro, G.M.*
AU  - Cichoz-Lach, H.*
AU  - Farré, A.*
AU  - Frank, J.*
AU  - Gambaro, G.*
AU  - Gimpfl, S.*
AU  - Grallert, H.
AU  - Griesmann, H.*
AU  - Grützmann, R.*
AU  - Hellerbrand, C.*
AU  - Hegyi, P.*
AU  - Hollenbach, M.*
AU  - Iordache, S.*
AU  - Jurkowska, G.*
AU  - Keim, V.*
AU  - Kiefer, F.*
AU  - Krug, S.*
AU  - Landt, O.*
AU  - Leo, M.D.*
AU  - Lerch, M.M.*
AU  - Lévy, P.*
AU  - Löffler, M.*
AU  - Löhr, M.*
AU  - Ludwig, M.*
AU  - Macek, M.*
AU  - Malats, N.*
AU  - Malecka-Panas, E.*
AU  - Malerba, G.*
AU  - Mann, K.*
AU  - Mayerle, J.*
AU  - Mohr, S.*
AU  - Te Morsche, R.H.M.*
AU  - Motyka, M.*
AU  - Mueller, S.*
AU  - Müller, T.*
AU  - Nöthen, M.M.*
AU  - Pedrazzoli, S.*
AU  - Pereira, S.P.*
AU  - Peters, A.
AU  - Pfützer, R.*
AU  - Real, F.X.*
AU  - Rebours, V.*
AU  - Ridinger, M.*
AU  - Rietschel, M.*
AU  - Rösmann, E.*
AU  - Saftoiu, A.*
AU  - Schneider, A.*
AU  - Schulz, H.U.*
AU  - Soranzo, N.*
AU  - Soyka, M.*
AU  - Simon, P.*
AU  - Skipworth, J.*
AU  - Stickel, F.*
AU  - Strauch, K.
AU  - Stumvoll, M.*
AU  - Testoni, P.A.*
AU  - Tönjes, A.*
AU  - Werner, L.*
AU  - Werner, J.*
AU  - Wodarz, N.*
AU  - Ziegler, M.*
AU  - Masamune, A.*
AU  - Mössner, J.*
AU  - Férec, C.*
AU  - Michl, P.*
AU  - P H Drenth, J.*
AU  - Witt, H.*
AU  - Scholz, M.*
AU  - Sahin-Tóth, M.*
C1  - 51628
C2  - 43324
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 1855–186
TI  - Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.
JO  - Gut
VL  - 67
IS  - 10
PB  - Bmj Publishing Group
PY  - 2018
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300 mM SM for 1 h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50 mu M BER for 24 h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate-kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies.
AU  - Hanin, G.*
AU  - Yayon, N.*
AU  - Tzur, Y.*
AU  - Haviv, R.*
AU  - Bennett, E.R.*
AU  - Udi, S.*
AU  - Krishnamoorthy, Y.R.*
AU  - Kotsiliti, E.
AU  - Zangen, R.*
AU  - Efron, B.*
AU  - Tam, J.*
AU  - Pappo, O.*
AU  - Shteyer, E.*
AU  - Pikarsky, E.*
AU  - Heikenwälder, M.
AU  - Greenberg, D.S.*
AU  - Soreq, H.*
C1  - 50903
C2  - 42994
CY  - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland
SP  - 1124-1134
TI  - miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression.
JO  - Gut
VL  - 67
IS  - 6
PB  - Elsevier Ireland Ltd
PY  - 2017
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Objective Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP.Design We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))-a model to study AIP development-with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens.Results p21 deficiency in LT mice (LT p21(-/-)) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappa B) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T-B cell infiltration. Interestingly, LT and LT p21(-/-) mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-kappa B pathway activation remained impaired in LT p21(-/-) pancreata.Conclusions Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.
AU  - Seleznik, G.M.*
AU  - Reding, T.*
AU  - Peter, L.*
AU  - Gupta, A.*
AU  - Steiner, S.G.*
AU  - Sonda, S.*
AU  - Verbeke, C.S.*
AU  - Dejardin, E.*
AU  - Khatkov, I.*
AU  - Segerer, S.*
AU  - Heikenwälder, M.
AU  - Graf, R.*
C1  - 53011
C2  - 44263
CY  - British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
SP  - 1663-1673
TI  - Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation.
JO  - Gut
VL  - 67
IS  - 9
PB  - Bmj Publishing Group
PY  - 2017
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Sommer, F.*
AU  - Rühlemann, M.C.*
AU  - Bang, C.*
AU  - Höppner, M.*
AU  - Rehman, A.*
AU  - Kaleta, C.*
AU  - Schmitt-Kopplin, P.
AU  - Dempfle, A.*
AU  - Weidinger, S.*
AU  - Ellinghaus, E.*
AU  - Krauss-Etschmann, S.*
AU  - Schmidt-Arras, D.*
AU  - Aden, K.*
AU  - Schulte, D.*
AU  - Ellinghaus, D.*
AU  - Schreiber, S.*
AU  - Tholey, A.*
AU  - Rupp, J.*
AU  - Laudes, M.*
AU  - Baines, J.F.*
AU  - Rosenstiel, P.*
AU  - Franke, A.*
C1  - 51574
C2  - 43315
CY  - London
SP  - 1734-1738
TI  - Microbiomarkers in inflammatory bowel diseases: Caveats come with caviar.
JO  - Gut
VL  - 66
IS  - 10
PB  - Bmj Publishing Group
PY  - 2017
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Kirsten, H.*
AU  - Scholz, M.*
AU  - Kovacs, P.*
AU  - Grallert, H.
AU  - Peters, A.
AU  - Strauch, K.
AU  - Frank, J.*
AU  - Rietschel, M.*
AU  - Nöthen, M.M.*
AU  - Witt, H.*
AU  - Rosendahl, J.*
C1  - 44080
C2  - 36784
SP  - 184-185
TI  - Genetic variants of lipase activity in chronic pancreatitis.
JO  - Gut
VL  - 65
IS  - 1
PY  - 2016
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. DESIGN: We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. RESULTS: Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. CONCLUSIONS: These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.
AU  - Kong, B.*
AU  - Wu, W.*
AU  - Cheng, T.*
AU  - Schlitter, A.M.*
AU  - Qian, C.*
AU  - Bruns, P.
AU  - Jian, Z.*
AU  - Jager, C.*
AU  - Regel, I.*
AU  - Raulefs, S.*
AU  - Behler, N.*
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Friess, H.*
AU  - Erkan, M.*
AU  - Siveke, J.T.*
AU  - Tannapfel, A.*
AU  - Hahn, S.A.*
AU  - Theis, F.J.
AU  - Esposito, I.*
AU  - Kleeff, J.*
AU  - Michalski, C.W.*
C1  - 43151
C2  - 36032
CY  - London
SP  - 647-657
TI  - A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling.
JO  - Gut
VL  - 65
IS  - 4
PB  - Bmj Publishing Group
PY  - 2016
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras(G12D)-driven pancreatic ductal adenocarcinoma. Quantitative expression data were analysed and extensively modelled in silico. RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.
AU  - Kong, B.*
AU  - Bruns, P.
AU  - Behler, N.A.*
AU  - Chang, L.*
AU  - Schlitter, A.M.*
AU  - Cao, J.*
AU  - Gewies, A.
AU  - Ruland, J.*
AU  - Fritzsche, S.*
AU  - Valkovskaya, N.*
AU  - Jian, Z.*
AU  - Regel, I.*
AU  - Raulefs, S.*
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Friess, H.*
AU  - Erkan, M.*
AU  - Müller, N.S.
AU  - Roth, S.*
AU  - Hackert, T.*
AU  - Esposito, I.*
AU  - Theis, F.J.
AU  - Kleeff, J.*
AU  - Michalski, C.W.*
C1  - 49526
C2  - 30096
CY  - London
SP  - 146-156
TI  - Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy.
JO  - Gut
VL  - 67
IS  - 1
PB  - Bmj Publishing Group
PY  - 2016
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Objective Iron deficiency is a common complication in patients with IBD and oral iron therapy is suggested to exacerbate IBD symptoms. We performed an openlabelled clinical trial to compare the effects of per oral (PO) versus intravenous (IV) iron replacement therapy (IRT). Design The study population included patients with Crohn's disease (CD; N=31), UC (N=22) and control subjects with iron deficiency (non-inflamed, NI=19). After randomisation, participants received iron sulfate (PO) or iron sucrose (IV) over 3 months. Clinical parameters, faecal bacterial communities and metabolomes were assessed before and after intervention. Results Both PO and IV treatments ameliorated iron deficiency, but higher ferritin levels were observed with IV. Changes in disease activity were independent of iron treatment types. Faecal samples in IBD were characterised by marked interindividual differences, lower phylotype richness and proportions of Clostridiales. Metabolite analysis also showed separation of both UC and CD from control anaemic participants. Major shifts in bacterial diversity occurred in approximately half of all participants after IRT, but patients with CD were most susceptible. Despite individual-specific changes in phylotypes due to IRT, PO treatment was associated with decreased abundances of operational taxonomic units assigned to the species Faecalibacterium prausnitzii, Ruminococcus bromii, Dorea sp. and Collinsella aerofaciens. Clear IV-specific and PO-specific fingerprints were evident at the level of metabolomes, with changes affecting cholesterol-derived host substrates. Conclusions Shifts in gut bacterial diversity and composition associated with iron treatment are pronounced in IBD participants. Despite similar clinical outcome, oral administration differentially affects bacterial phylotypes and faecal metabolites compared with IV therapy.
AU  - Lee, T.*
AU  - Clavel, T.*
AU  - Smirnov, K.
AU  - Schmidt, A.*
AU  - Lagkouvardos, I.*
AU  - Walker, A.
AU  - Lucio, M.
AU  - Michalke, B.
AU  - Schmitt-Kopplin, P.
AU  - Fedorak, R.*
AU  - Haller, D.*
C1  - 47959
C2  - 39827
CY  - London
SP  - 863-871
TI  - Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD.
JO  - Gut
VL  - 66
IS  - 5
PB  - Bmj Publishing Group
PY  - 2016
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Objective Lymphotoxin ß receptor (LTßR) signalling has been implicated in inflammation-associated tumour development in different tissues. We have analysed the role of LTßR and alternative NF-κB signalling in Helicobacter pylori-mediated gastric inflammation and pathology. Design We analysed several ligands and receptors of the alternative NF-κB pathway, RelB, p52 nuclear translocation and target genes in tissue samples of H. pylori-infected patients with different degrees of gastritis or early gastric tumours by in situ hybridisation, immunohistochemistry, Western blot and real-time PCR analyses. Molecular mechanisms involved in LTßR activation by H. pylori were assessed in vitro using human gastric cancer cell lines and distinct H. pylori isolates. The effects of blocking or agonistically activating LTßR on gastric pathology during challenge with a human pathogenic H. pylori strain were studied in a mouse model. Results Among the tested candidates, LT was significantly increased and activated alternative NF-κB signalling was observed in the gastric mucosa of H. pylori-infected patients. H. pylori induced LTßR-ligand expression in a type IV secretion system-dependent but CagA-independent manner, resulting in activation of the alternative NF-κB pathway, which was further enhanced by blocking canonical NF-κB during infection. Blocking LTßR signalling in vivo suppressed H. pylori-driven gastritis, whereas LTßR activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology. Conclusions LTßR-triggered activation of alternative NF- κB signalling in gastric epithelial cells executes H. pyloriinduced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited by H. pylori, while exclusively targeting canonical NF-κB may aggravate pathology by enhancing the alternative pathway.
AU  - Mejías-Luque, R.*
AU  - Zöller, J.
AU  - Anderl, F.*
AU  - Loew-Gil, E.*
AU  - Vieth, M.*
AU  - Adler, T.
AU  - Engler, D.B.*
AU  - Urban, S.*
AU  - Browning, J.L.*
AU  - Müller, A.*
AU  - Gerhard, M.*
AU  - Heikenwälder, M.
C1  - 48588
C2  - 41210
CY  - London
SP  - 1369-1381
TI  - Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner.
JO  - Gut
VL  - 66
IS  - 8
PB  - Bmj Publishing Group
PY  - 2016
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The recent availability of novel antiviral drugs has raised new hope for a more effective treatment of hepatitis C virus (HCV) infection and its severe sequelae. However, in the case of non-responding or relapsing patients, alternative strategies are needed. To this end we have used chimeric antigen receptors (CARs), a very promising approach recently used in several clinical trials to redirect primary human T cells against different tumours. In particular, we designed the first CARs against HCV targeting the HCV/E2 glycoprotein (HCV/E2). DESIGN: Anti-HCV/E2 CARs were composed of single-chain variable fragments (scFvs) obtained from a broadly cross-reactive and cross-neutralising human monoclonal antibody (mAb), e137, fused to the intracellular signalling motif of the costimulatory CD28 molecule and the CD3ζ domain. Activity of CAR-grafted T cells was evaluated in vitro against HCV/E2-transfected cells as well as hepatocytes infected with cell culture-derived HCV (HCVcc). RESULTS: In this proof-of-concept study, retrovirus-transduced human T cells expressing anti-HCV/E2 CARs were endowed with specific antigen recognition accompanied by degranulation and secretion of proinflammatory and antiviral cytokines, such as interferon γ, interleukin 2 and tumour necrosis factor α. Moreover, CAR-grafted T cells were capable of lysing target cells of both hepatic and non-hepatic origin expressing on their surface the HCV/E2 glycoproteins of the most clinically relevant genotypes, including 1a, 1b, 2a, 3a, 4 and 5. Finally, and more importantly, they were capable of lysing HCVcc-infected hepatocytes. CONCLUSIONS: Clearance of HCV-infected cells is a major therapeutic goal in chronic HCV infection, and adoptive transfer of anti-HCV/E2 CARs-grafted T cells represents a promising new therapeutic tool.
AU  - Sautto, G.A.*
AU  - Wisskirchen, K.
AU  - Clementi, N.*
AU  - Castelli, M.*
AU  - Diotti, R.A.*
AU  - Graf, J.
AU  - Clementi, M.*
AU  - Burioni, R.*
AU  - Protzer, U.
AU  - Mancini, N.*
C1  - 43269
C2  - 36377
CY  - London
SP  - 512-523
TI  - Chimeric Antigen Receptor (CAR)-engineered T cells redirected against Hepatitis C Virus (HCV) E2 glycoprotein.
JO  - Gut
VL  - 65
IS  - 3
PB  - Bmj Publishing Group
PY  - 2016
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort. DESIGN: We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships. RESULTS: Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). CONCLUSIONS: The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.
AU  - Derikx, M.H.*
AU  - Kovacs, P.*
AU  - Scholz, M.*
AU  - Masson, E.*
AU  - Chen, J.M.*
AU  - Ruffert, C.*
AU  - Lichtner, P.
AU  - Te Morsche, R.H.*
AU  - Cavestro, G.M.*
AU  - PanEuropean Working group on Alcoholic Chronic Pancreatitis (*)
AU  - Férec, C.*
AU  - Drenth, J.P.*
AU  - Witt, H.*
AU  - Rosendahl, J.*
C1  - 32383
C2  - 35018
CY  - London
SP  - 1426-1433
TI  - Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.
JO  - Gut
VL  - 64
IS  - 9
PB  - Bmj Publishing Group
PY  - 2015
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis. DESIGN: Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study. RESULTS: Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells. CONCLUSIONS: The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.
AU  - Garnelo, M.*
AU  - Tan, A.*
AU  - Her, Z.*
AU  - Yeong, J.*
AU  - Lim, C.J.*
AU  - Chen, J.*
AU  - Lim, K.H.*
AU  - Weber, A.*
AU  - Chow, P.*
AU  - Chung, A.*
AU  - Ooi, L.L.*
AU  - Toh, H.C.*
AU  - Heikenwälder, M.
AU  - Ng, I.O.*
AU  - Nardin, A.*
AU  - Chen, Q.*
AU  - Abastado, J.-P.*
AU  - Chew, V.*
C1  - 47551
C2  - 40664
CY  - London
SP  - 342-351
TI  - Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma.
JO  - Gut
VL  - 66
IS  - 2
PB  - Bmj Publishing Group
PY  - 2015
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Surgical interventions that prevent nutrient exposure to the duodenum are among the most successful treatments for obesity and diabetes. However, these interventions are highly invasive, irreversible and often carry significant risk. The duodenal-endoluminal sleeve (DES) is a flexible tube that acts as a barrier to nutrient-tissue interaction along the duodenum. We implanted this device in Zucker Diabetic Fatty (ZDF) rats to gain greater understanding of duodenal nutrient exclusion on glucose homeostasis. DESIGN: ZDF rats were randomised to four groups: Naive, sham ad libitum, sham pair-fed, and DES implanted. Food intake, body weight (BW) and body composition were measured for 28 days postoperatively. Glucose, lipid and bile acid metabolism were evaluated, as well as histological assessment of the upper intestine. RESULTS: DES implantation induced a sustained decrease in BW throughout the study that was matched by pair-fed sham animals. Decreased BW resulted from loss of fat, but not lean mass. DES rats were also found to be more glucose tolerant than either ad libitum-fed or pair-fed sham controls, suggesting fat mass independent metabolic benefits. DES also reduced circulating triglyceride and glycerol levels while increasing circulating bile acids. Interestingly, DES stimulated a considerable increase in villus length throughout the upper intestine, which may contribute to metabolic improvements. CONCLUSIONS: Our preclinical results validate DES as a promising therapeutic approach to diabetes and obesity, which offers reversibility, low risk, low invasiveness and triple benefits including fat mass loss, glucose and lipid metabolism improvement which mechanistically may involve increased villus growth in the upper gut.
AU  - Habegger, K.M.*
AU  - Al-Massadi, O.*
AU  - Heppner, K.M.*
AU  - Myronovych, A.*
AU  - Holland, J.*
AU  - Berger, J.*
AU  - Yi, C.-X.
AU  - Gao, Y.*
AU  - Lehti, M.*
AU  - Ottaway, N.*
AU  - Amburgy, S.*
AU  - Raver, C.*
AU  - Müller, T.D.
AU  - Pfluger, P.T.
AU  - Kohli, R.*
AU  - Perez-Tilve, D.*
AU  - Seeley, R.J.*
AU  - Tschöp, M.H.
C1  - 27817
C2  - 32824
CY  - London
SP  - 1238-1246
TI  - Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia.
JO  - Gut
VL  - 63
IS  - 8
PB  - BMJ Publishing
PY  - 2014
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - ObjectiveHepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated.MethodsUsing quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearest-template prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182.ResultsThe identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8(+) T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor α, interferon γ) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death.ConclusionA 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.
AU  - Chew, V.*
AU  - Chen, J.*
AU  - Lee, D.*
AU  - Loh, E.*
AU  - Lee, J.*
AU  - Lim, K.H.*
AU  - Weber, A.*
AU  - Slankamenac, K.*
AU  - Poon, R.T.*
AU  - Yang, H.*
AU  - Ooi, L.L.*
AU  - Toh, H.C.*
AU  - Heikenwälder, M.
AU  - Ng, I.O.*
AU  - Nardin, A.*
AU  - Abastado, J.-P.*
C1  - 6874
C2  - 29377
SP  - 427-438
TI  - Chemokine-driven lymphocyte infiltration: An early intratumoural event determining long-term survival in resectable hepatocellular carcinoma.
JO  - Gut
VL  - 61
IS  - 3
PB  - BMJ Publishing Group Ltd & British Society of Gastroenterology
PY  - 2012
SN  - 0017-5749
ER  - 

TY  - JOUR
AB  - Background: Although histone deacetylase inhibitors (HDACi) are promising cancer therapeutics regulating proliferation, differentiation and apoptosis, molecular pathways engaged by specific HDAC isoenzymes in cancer are ill defined. Results: In this study we demonstrate that HDAC2 is highly expressed in pancreatic ductal adenocarcinoma (PDAC), especially in undifferentiated tumours. We show that HDAC2, but not HDAC1, confers resistance towards the topoisomerase II inhibitor etoposide in PDAC cells. Correspondingly, the class I selective HDACi valproic acid (VPA) synergises with etoposide to induce apoptosis of PDAC cells. Transcriptome profiling of HDAC2-depleted PDAC cells revealed upregulation of the BH3-only protein NOXA. We show that the epigenetically silenced NOXA gene locus is opened after HDAC2 depletion and that NOXA upregulation is sufficient to sensitise PDAC cells towards etoposide-induced apoptosis. Conclusions: In summary, our data characterise a novel molecular mechanism that links the epigenetic regulator HDAC2 to the regulation of the pro-apoptotic BH3-only protein NOXA in PDAC. Targeting HDAC2 will therefore be a promising strategy to overcome therapeutic resistance of PDAC against chemotherapeutics that induce DNA damage.
AU  - Fritsche, P.*
AU  - Seidler, B.*
AU  - Schüler, S.*
AU  - Schnieke, A.*
AU  - Göttlicher, M.
AU  - Schmid, R.M.*
AU  - Saur, D.*
AU  - Schneider, G.*
C1  - 1605
C2  - 26895
CY  - London
SP  - 1399-1409
TI  - HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA.
JO  - Gut
VL  - 58
IS  - 10
PB  - B M J Publishing Group
PY  - 2009
SN  - 0017-5749
ER  - 

TY  - JOUR
AU  - Koletzko, S.*
AU  - Jesch, I.*
AU  - Faus-Kessler, T.
AU  - Briner, J.*
AU  - Meier-Ruge, W.*
AU  - Müntfering, H.*
AU  - Coerdt, W.*
AU  - Wessel, L.*
AU  - Keller, K.M.*
AU  - Nützenadel, W.*
C1  - 21146
C2  - 19187
SP  - 853-861
TI  - Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: A prospective multicentre sstudy on interobserver variation and clinical outcome.
JO  - Gut
VL  - 44
PY  - 1999
SN  - 0017-5749
ER  -