155 results on '"Zilbauer M"'
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2. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease (Nature Communications, (2020), 11, 1, (995), 10.1038/s41467-019-14275-y)
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Serra E. G., Schwerd T., Moutsianas L., Cavounidis A., Fachal L., Pandey S., Kammermeier J., Croft N. M., Posovszky C., Rodrigues A., Russell R. K., Barakat F., Auth M. K. H., Heuschkel R., Zilbauer M., Fyderek K., Braegger C., Travis S. P., Satsangi J., Parkes M., Thapar N., Ferry H., Matte J. C., Gilmour K. C., Wedrychowicz A., Sullivan P., Moore C., Sambrook J., Ouwehand W., Roberts D., Danesh J., Baeumler T. A., Fulga T. A., Carrami E. M., Ahmed A., Wilson R., Barrett J. C., Elkadri A., Griffiths A. M., Zurek M., Strisciuglio C., Elawad M., Lo B., Arancibia-Carcamo C., Bailey A., Barnes E., Bird-Lieberman E. L., Brain O., Braden B., Collier J., East J., Howarth L., Keshav S., Klenerman P., Leedham S., Palmer R., Powrie F., Simmons A., Walker M., Tolkien Z., Kaptoge S., Allen D., Mehenny S., Mant J., Di Angelantonio E., Thompson S. G., Yilmaz B., Juillerat P., Geuking M., Wiest R., Macpherson A. J., Bravo F. D., Brugger L., Carstens O., Bigler U. G., Heimgartner B., Rusticeanu M., Schmid-Uebelhart S., Strebel B., Tatu A., Tutuian R., Oyas O., Ramon C., Stelling J., Franc Y., Fournier N., Pittet V. E. H., Burnand B., Egger M., Golay D., Marot A., Musso L., Rossel J. -B., Seematter V., Sommer J., Vulliamy R., Michetti P., Maillard M. H., Keller C., Nydegger A., Schoepfe A., Archanioti E., Ezri J., Fraga M., Schoepfer A., Muller C., Rogler G., Biedermann L., Blattmann M., Burk S., Dora B., Fried M., Misselwitz B., Mullhaupt B., Obialo N., Pohl D., Raschle N., Scharl M., Vavricka S., Von Kanel R., Zeitz J., Abdelrahman K., Ademi G., Borovicka J., Brand S., Frei R., Haarer J., Knellwolf-Grieger C., Krieger-Grubel C., Kunzler P., Meyenberger C., Meyer P., Rohrich N., Sawatzki M., Schelling M., Semadeni G. -M., Sulz M., Zimmermann D., Aepli P., Criblez D. H., Hess C., Richterich J. -P., Spalinger J., Staudenmann D., Stulz A., Wohrle S., Thomas A., Anderegg C., Kohler H., Kusche R., Antonino A. -T., Arrigoni E., Bengoa J. M., Cunningham S., de Saussure P., Girard L., de Jong D. B., Basturk P., Brunner S., Degen L., Hruz P., Bakker C. K. -D., Niess J., Balsiger B., Haldemann J., Saner G., Seibold F., Bauerfeind P., Becocci A., Belli D., Binek J., Hengstler P., Boehm S., Boldanov T., Buhr P., Koller R., Rueger V., Senning A., Burri E., Buyse S., Cao D. -T., D'Angelo F., Delarive J., Doerig C., Hessler R., Preissler C., Rentsch R., Risti B., Ritz M. A., Steuerwald M., Vogtlin J., Sagmeister M., Sauter B., Schibli S., Sokollik C., Schlauri H., Schnegg J. -F., Seirafi M., Spangenberger H., Stadler P., Staub P., Stenz V., Tempia-Caliera M., Thorens J., Truninger K., Urfer P., Viani F., Vouillamoz D., Zander S., Wyli T., Jostins L., Kennedy N. A., Ahmad T., Lamb C. A., Edwards C., Hart A., Hawkey C., Mansfield J. C., Mowat C., Newman W. G., Tremelling M., Lee J. C., Prescott N. J., Mathew C. G., Lees C. W., McGovern D. P. B., Targan S. R., Botwin G., Mengesha E., Fleshner P., Landers C., Li D., Rioux J. D., Bitton A., Cote-Daigneault J., Daly M. J., Xavier R., Morris K., Boucher G., Cho J. H., Abraham C., Merad M., Sands B., Peter I., Hao K., Itan Y., Duerr R. H., Konnikova L., Schwartz M. B., Proksell S., Johnston E., Miladinova V., Chen W., Brant S. R., Datta L., Silverberg M. S., Schumm L. P., Birch S., Giri M., Gettler K., Sharma Y., Stevens C., Lazarev M., Haritunians T., Snapper S. B., Shah N., Muise A. M., Wilson D. C., Uhlig H. H., Anderson C. A., Serra, E. G., Schwerd, T., Moutsianas, L., Cavounidis, A., Fachal, L., Pandey, S., Kammermeier, J., Croft, N. M., Posovszky, C., Rodrigues, A., Russell, R. K., Barakat, F., Auth, M. K. H., Heuschkel, R., Zilbauer, M., Fyderek, K., Braegger, C., Travis, S. P., Satsangi, J., Parkes, M., Thapar, N., Ferry, H., Matte, J. C., Gilmour, K. C., Wedrychowicz, A., Sullivan, P., Moore, C., Sambrook, J., Ouwehand, W., Roberts, D., Danesh, J., Baeumler, T. A., Fulga, T. A., Carrami, E. M., Ahmed, A., Wilson, R., Barrett, J. C., Elkadri, A., Griffiths, A. M., Zurek, M., Strisciuglio, C., Elawad, M., Lo, B., Arancibia-Carcamo, C., Bailey, A., Barnes, E., Bird-Lieberman, E. L., Brain, O., Braden, B., Collier, J., East, J., Howarth, L., Keshav, S., Klenerman, P., Leedham, S., Palmer, R., Powrie, F., Simmons, A., Walker, M., Tolkien, Z., Kaptoge, S., Allen, D., Mehenny, S., Mant, J., Di Angelantonio, E., Thompson, S. G., Yilmaz, B., Juillerat, P., Geuking, M., Wiest, R., Macpherson, A. J., Bravo, F. D., Brugger, L., Carstens, O., Bigler, U. G., Heimgartner, B., Rusticeanu, M., Schmid-Uebelhart, S., Strebel, B., Tatu, A., Tutuian, R., Oyas, O., Ramon, C., Stelling, J., Franc, Y., Fournier, N., Pittet, V. E. H., Burnand, B., Egger, M., Golay, D., Marot, A., Musso, L., Rossel, J. -B., Seematter, V., Sommer, J., Vulliamy, R., Michetti, P., Maillard, M. H., Keller, C., Nydegger, A., Schoepfe, A., Archanioti, E., Ezri, J., Fraga, M., Schoepfer, A., Muller, C., Rogler, G., Biedermann, L., Blattmann, M., Burk, S., Dora, B., Fried, M., Misselwitz, B., Mullhaupt, B., Obialo, N., Pohl, D., Raschle, N., Scharl, M., Vavricka, S., Von Kanel, R., Zeitz, J., Abdelrahman, K., Ademi, G., Borovicka, J., Brand, S., Frei, R., Haarer, J., Knellwolf-Grieger, C., Krieger-Grubel, C., Kunzler, P., Meyenberger, C., Meyer, P., Rohrich, N., Sawatzki, M., Schelling, M., Semadeni, G. -M., Sulz, M., Zimmermann, D., Aepli, P., Criblez, D. H., Hess, C., Richterich, J. -P., Spalinger, J., Staudenmann, D., Stulz, A., Wohrle, S., Thomas, A., Anderegg, C., Kohler, H., Kusche, R., Antonino, A. -T., Arrigoni, E., Bengoa, J. M., Cunningham, S., de Saussure, P., Girard, L., de Jong, D. B., Basturk, P., Brunner, S., Degen, L., Hruz, P., Bakker, C. K. -D., Niess, J., Balsiger, B., Haldemann, J., Saner, G., Seibold, F., Bauerfeind, P., Becocci, A., Belli, D., Binek, J., Hengstler, P., Boehm, S., Boldanov, T., Buhr, P., Koller, R., Rueger, V., Senning, A., Burri, E., Buyse, S., Cao, D. -T., D'Angelo, F., Delarive, J., Doerig, C., Hessler, R., Preissler, C., Rentsch, R., Risti, B., Ritz, M. A., Steuerwald, M., Vogtlin, J., Sagmeister, M., Sauter, B., Schibli, S., Sokollik, C., Schlauri, H., Schnegg, J. -F., Seirafi, M., Spangenberger, H., Stadler, P., Staub, P., Stenz, V., Tempia-Caliera, M., Thorens, J., Truninger, K., Urfer, P., Viani, F., Vouillamoz, D., Zander, S., Wyli, T., Jostins, L., Kennedy, N. A., Ahmad, T., Lamb, C. A., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Tremelling, M., Lee, J. C., Prescott, N. J., Mathew, C. G., Lees, C. W., Mcgovern, D. P. B., Targan, S. R., Botwin, G., Mengesha, E., Fleshner, P., Landers, C., Li, D., Rioux, J. D., Bitton, A., Cote-Daigneault, J., Daly, M. J., Xavier, R., Morris, K., Boucher, G., Cho, J. H., Abraham, C., Merad, M., Sands, B., Peter, I., Hao, K., Itan, Y., Duerr, R. H., Konnikova, L., Schwartz, M. B., Proksell, S., Johnston, E., Miladinova, V., Chen, W., Brant, S. R., Datta, L., Silverberg, M. S., Schumm, L. P., Birch, S., Giri, M., Gettler, K., Sharma, Y., Stevens, C., Lazarev, M., Haritunians, T., Snapper, S. B., Shah, N., Muise, A. M., Wilson, D. C., Uhlig, H. H., and Anderson, C. A.
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- 2022
3. Colitis-associated sclerosing cholangitis in children: A single centre experience
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Noble-Jamieson, G., Heuschkel, R.B., Torrente, F., Hadzic, N., and Zilbauer, M.
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- 2013
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4. Assessing DNA methylation in the developing human intestinal epithelium: potential link to inflammatory bowel disease
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Kraiczy, J, Nayak, K, Ross, A, Raine, T, Mak, T N, Gasparetto, M, Cario, E, Rakyan, V, Heuschkel, R, and Zilbauer, M
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- 2016
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5. Use of small bowel MRI enteroclysis in the management of paediatric IBD
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Sanka, S., Gomez, A., Set, P., Rimareva, N., Davies, R.J., Rolfe, P., Noble-Jamieson, G., Torrente, F., Heuschkel, R., and Zilbauer, M.
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- 2012
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6. Cells of the human intestinal tract mapped across space and time
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Elmentaite, R, primary, Kumasaka, N, additional, King, HW, additional, Roberts, K, additional, Dabrowska, M, additional, Pritchard, S, additional, Bolt, L, additional, Vieira, SF, additional, Mamanova, L, additional, Huang, N, additional, Goh Kai’En, I, additional, Stephenson, E, additional, Engelbert, J, additional, Botting, RA, additional, Fleming, A, additional, Dann, E, additional, Lisgo, SN, additional, Katan, M, additional, Leonard, S, additional, Oliver, TRW, additional, Hook, CE, additional, Nayak, K, additional, Perrone, F, additional, Campos, LS, additional, Dominguez-Conde, C, additional, Polanski, K, additional, Van Dongen, S, additional, Patel, M, additional, Morgan, MD, additional, Marioni, JC, additional, Bayraktar, OA, additional, Meyer, KB, additional, Zilbauer, M, additional, Uhlig, H, additional, Clatworthy, MR, additional, Mahbubani, KT, additional, Saeb Parsy, K, additional, Haniffa, M, additional, James, KR, additional, and Teichmann, SA, additional
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- 2021
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7. G62 A questionnaire survey of adherence to European guidelines for the diagnosis of coeliac disease in asymptomatic children with type 1 diabetes mellitus
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Atherton, RR, Zilbauer, M, and Heuschkel, R
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- 2014
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8. Tissue transglutaminase antibody levels predict IgA deficiency
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Shahnaz, A, Maguire, G, Parker, R, Heuschkel, R B, and Zilbauer, M
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- 2013
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9. CD8+ T-cell transcription and DNA methylation show age specific differences and lack correlation with clinical outcome in pediatric Inflammatory Bowel Disease
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Gasparetto, M, primary, Payne, F, additional, Nayak, K, additional, Kraiczy, J, additional, Glemas, C, additional, Philip-McKenzie, Y, additional, Ross, A, additional, Edgar, RD, additional, Zerbino, D, additional, Salvestrini, C, additional, Torrente, F, additional, Sarkies, P, additional, Heuschkel, R, additional, and Zilbauer, M, additional
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- 2020
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10. Mutation frequency of NS5A in patients vertically infected with HCV genotype 1 predicts sustained virological response to peginterferon alfa-2b and ribavirin combination therapy
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Jenke, A. C. W., Moser, S., Orth, V., Zilbauer, M., Gerner, P., and Wirth, S.
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- 2009
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11. The role of human beta-defensins during Campylobacter jejuni infection
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Zilbauer, M., Dorrell, N., George, J. T., Boughan, P. K., and Bajaj-Elliott, M.
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- 2004
12. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids
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Sampaziotis, F, Justin, AW, Tysoe, OC, Sawiak, S, Cardoso-De-Brito, M, Ortmann, D, Yangou, L, Ross, A, Bargher, J, Bertero, A, Zonneveld, MCF, Pawlowski, M, Madrigal, P, Georgakopoulos, N, Pirmadjid, N, Zilbauer, M, Sinha, S, Hannan, NRF, Vallier, L, Sampaziotis, Fotios [0000-0003-0812-7586], Sawiak, Stephen [0000-0003-4210-9816], Madrigal, Pedro [0000-0003-1959-8199], Georgakopoulos, Nikitas [0000-0002-1879-6583], Zilbauer, Matthias [0000-0002-7272-0547], Sinha, Sanjay [0000-0001-5900-1209], Vallier, Ludovic [0000-0002-3848-2602], and Apollo - University of Cambridge Repository
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tissue engineering ,regenerative medicine - Abstract
The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids $\textit{in vivo}$ and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded $\textit{in vitro}$.
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- 2017
13. Clinical outcomes of a dietitian and nurse led coeliac clinic for children
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Alterio, T., primary, Gasparetto, M., additional, Milroy, H., additional, Zilbauer, M., additional, and Heuschkel, R., additional
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- 2017
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14. Early onset inflammatory bowel disease: phenotype and burden of disease. Abstracts of the 9th Congress of ECCO
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Gasparetto, M, Guariso, Graziella, Torrente, F, Brennan, M, Heuschkel, R, and Zilbauer, M.
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- 2014
15. Delineation of the Innate and Adaptive T-Cell Immune Outcome in the Human Host in Response to Campylobacter jejuni Infection
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Edwards, L. A., Nistala, K., Mills, D. C., Stephenson, H. N., Zilbauer, M., Wren, B. W., Dorrell, N., Lindley, K. J., Wedderburn, L. R., and Bajaj-Elliott, M.
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INFLAMMATORY-BOWEL-DISEASE, NATURAL-KILLER-CELLS, DENDRITIC CELLS, CYTOKINE PRODUCTION, INTESTINAL-MUCOSA, ESCHERICHIA-COLI, INTERLEUKIN 22, IN-VITRO, PATHOGENESIS, BETA-DEFENSIN-2 - Abstract
Background: Campylobacter jejuni is the most prevalent cause of bacterial gastroenteritis worldwide. Despite the significant health burden this infection presents, molecular understanding of C. jejuni-mediated disease pathogenesis remains poorly defined. Here, we report the characterisation of the early, innate immune response to C. jejuni using an ex-vivo human gut model of infection. Secondly, impact of bacterial-driven dendritic cell activation on T-cell mediated immunity was also sought.Methodology: Healthy, control paediatric terminal ileum or colonic biopsy tissue was infected with C. jejuni for 8-12 hours. Bacterial colonisation was followed by confocal microscopy and mucosal innate immune responses measured by ELISA. Marked induction of IFN gamma with modest increase in IL-22 and IL-17A was noted. Increased mucosal IL-12, IL-23, IL-1 beta and IL-6 were indicative of a cytokine milieu that may modulate subsequent T-cell mediated immunity. C. jejuni-driven human monocyte-derived dendritic cell activation was followed by analyses of T cell immune responses utilising flow cytometry and ELISA. Significant increase in Th-17, Th-1 and Th-17/Th-1 double-positive cells and corresponding cytokines was observed. The ability of IFN gamma, IL-22 and IL-17 cytokines to exert host defence via modulation of C. jejuni adhesion and invasion to intestinal epithelia was measured by standard gentamicin protection assay.Conclusions: Both innate and adaptive T cell-immunity to C. jejuni infection led to the release of IFN gamma, IL-22 and IL-17A; suggesting a critical role for this cytokine triad in establishing host anti-microbial immunity during the acute and effectors phase of infection. In addition, to their known anti-microbial functions; IL-17A and IL-17F reduced the number of intracellular C. jejuni in intestinal epithelia, highlighting a novel aspect of how IL-17 family members may contribute to protective immunity against C. jejuni.
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- 2010
16. G366(P) Impedance monitoring in paediatric gastro-oesophageal reflux disease: an evaluation of its use and clinical value
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Crook, P, primary, Ross, A, additional, Heuschkel, R, additional, and Zilbauer, M, additional
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- 2015
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17. P-039: Assessing phenotype and disease prognosis in early onset IBD. Retrospective data from 2 tertiary centres in the United Kingdom and Italy
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Gasparetto, M., primary, Guariso, G., additional, Torrente, F., additional, Brennan, M., additional, Heuschkel, R., additional, and Zilbauer, M., additional
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- 2014
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18. P231 Early onset inflammatory bowel disease: phenotype and burden of disease. Experience at Cambridge University Hospitals – United Kingdom
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Gasparetto, M., primary, Guariso, G., additional, Torrente, F., additional, Brennan, M., additional, Heuschkel, R., additional, and Zilbauer, M., additional
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- 2014
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19. Outcome measures in paediatric IBD: Data from a tertiary level center in UK
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Gatti, S., primary, Brennan, M., additional, Torrente, F., additional, Zilbauer, M., additional, and Heuschkel, R., additional
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- 2013
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20. Epidemiology of vitamin D deficiency in children with inflammatory bowel disease presenting to a tertiary care center in the UK
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Gatti, S., primary, Penagini, F., additional, Torrente, F., additional, Noble-Jamieson, G., additional, Zilbauer, M., additional, and Heuschkel, R., additional
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- 2013
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21. Effect of cell separation on gene expression and DNA methylation profiles in intestinal epithelial cells
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Molitor, M, primary, Postberg, J, additional, Orth, V, additional, Zilbauer, M, additional, and Jenke, AC, additional
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- 2013
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22. Intestinal alpha-defensin expression in pediatric inflammatory bowel disease1
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Zilbauer, M., primary, Jenke, A., additional, Wenzel, G., additional, Goedde, D., additional, Postberg, J., additional, Phillips, A. D., additional, Lucas, M., additional, Noble-Jamieson, G., additional, Torrente, F., additional, Salvestrini, C., additional, Heuschkel, R., additional, and Wirth, S., additional
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- 2011
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23. Fructose Malabsorption in Children with Recurrent Abdominal Pain: Positive Effects of Dietary Treatment
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Wintermeyer, P., primary, Baur, M., additional, Pilic, D., additional, Schmidt-Choudhury, A., additional, Zilbauer, M., additional, and Wirth, S., additional
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- 2011
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24. CAMPYLOBACTER JEJUNI CAPSULAR POLYSACCHARIDE AND INTESTINAL INNATE IMMUNITY
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Zilbauer, M, primary, Dorrell, N, additional, Boughan, P, additional, Wren, B, additional, Klein, N, additional, and Bajaj-Elliott, M, additional
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- 2005
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25. P0063 PP THE ROLE OF HUMAN BETA‐DEFENSINS DURING CAMPYLOBACTER JEJUNI INFECTION
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Zilbauer, M., primary, Dorrell, N., additional, George, J. T., additional, Boughan, P. K., additional, and Bajaj‐Elliott, M., additional
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- 2004
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26. Zöliakie: Mosaiksteine der Pathogenese
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Zilbauer, M., primary and Zimmer, K.-P., additional
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- 2002
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27. Intussusception: incidence and treatment-insights from the nationwide german surveillance.
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Jenke AC, Klaaen-Mielke R, Zilbauer M, Heininger U, Trampisch H, and Wirth S
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- 2011
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28. Defining eosinophilic colitis in children: insights from a retrospective case series.
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Behjati S, Zilbauer M, Heuschkel R, Phillips A, Salvestrini C, Torrente F, and Bates AW
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- 2009
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29. Differential expression of mucosal trefoil factors and mucins in pediatric inflammatory bowel diseases
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Ac, Jenke, Boland V, Jan Postberg, Vogel S, Gödde D, Zilbauer M, Heuschkel R, Wirth S, and Ko, Hensel
30. Making Research Flourish Through ESPGHAN: A Position Paper From the ESPGHAN Special Interest Group for Basic and Translational Research
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Philip Robinson, Bálint Tél, Caterina Strisciuglio, Matthias Zilbauer, Andreas Jenke, Jan Novak, Federica Giachero, Marco Gasparetto, Kostantinos Gerasimidis, Amit Assa, Gasparetto, M., Strisciuglio, C., Assa, A., Gerasimidis, K., Giachero, F., Novak, J., Robinson, P., Tel, B., Zilbauer, M., and Jenke, A.
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Status quo ,Research areas ,media_common.quotation_subject ,Translational research ,basic science ,Translational Research, Biomedical ,Basic research ,Paediatric gastroenterology ,Medicine ,Humans ,survey ,Child ,Societies, Medical ,media_common ,search ,business.industry ,questionnaire ,Gastroenterology ,Special Interest Group ,Public Opinion ,Pediatrics, Perinatology and Child Health ,Position paper ,Engineering ethics ,Working group ,business ,Child Nutritional Physiological Phenomena - Abstract
Recent research breakthroughs have emerged from applied basic research throughout all scientific areas, including adult and paediatric gastroenterology, hepatology and nutrition (PGHAN). The research landscape within the European Society of Paediatric Gastroenterology and Nutrition (ESPGHAN) is also inevitably changing from clinical research to studies involving applied laboratory research. This position paper aims to depict the current status quo of basic science and translational research within ESPGHAN, and to delineate how the society could invest in research in the present and future time. The paper also explores which research areas in the field of PGHAN represent the current and future priorities, and what type of support is needed across the ESPGHAN working groups (WGs) and special interest groups (SIGs) to fulfil their research goals.
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- 2021
31. Disease-associated DNA methylation signatures in esophageal biopsies of children diagnosed with Eosinophilic Esophagitis
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Caterina Strisciuglio, Matthias Zilbauer, Komal Nayak, Felicity Payne, Marialuisa Andreozzi, Erasmo Miele, Alessandra Vitale, Zilbauer, Matthias [0000-0002-7272-0547], Apollo - University of Cambridge Repository, Strisciuglio, Caterina, Payne, Felicity, Nayak, Komal, Andreozzi, Marialuisa, Vitale, Alessandra, Miele, Erasmo, Zilbauer, Matthias, Strisciuglio, C., Payne, F., Nayak, K., Andreozzi, M., Vitale, A., Miele, E., and Zilbauer, M.
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Male ,medicine.medical_specialty ,Adolescent ,Biopsy ,Short Report ,Disease ,Gastroenterology ,Esophagus ,Internal medicine ,Genetics ,medicine ,Humans ,Epigenetics ,Prospective Studies ,Eosinophilic esophagitis ,Child ,Molecular Biology ,Genetics (clinical) ,Histological examination ,DNA methylation ,Mucosal biopsy ,medicine.diagnostic_test ,business.industry ,Epigenetic ,Eosinophilic Esophagitis ,Eosinophil ,medicine.disease ,Dysphagia ,medicine.anatomical_structure ,Italy ,Child, Preschool ,Female ,Epigenetic Biomarkers ,medicine.symptom ,business ,Eosinophilic Esophagiti ,Developmental Biology ,Genome-Wide Association Study - Abstract
Funder: European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), Eosinophilic esophagitis (EoE) is a leading cause of dysphagia and food impaction in children and adults. The diagnosis relies on histological examination of esophageal mucosal biopsies and requires the presence of > 15 eosinophils per high-powered field. Potential pitfalls include the impact of biopsy sectioning as well as regional variations of eosinophil density. We performed genome-wide DNA methylation analyses on 30 esophageal biopsies obtained from children diagnosed with EoE (n = 7) and matched controls (n = 13) at the time of diagnosis as well as following first-line treatment. Analyses revealed striking disease-associated differences in mucosal DNA methylation profiles in children diagnosed with EoE, highlighting the potential for these epigenetic signatures to be developed into clinically applicable biomarkers.
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- 2021
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32. Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.
- Author
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Dennison TW, Edgar RD, Payne F, Nayak KM, Ross ADB, Cenier A, Glemas C, Giachero F, Foster AR, Harris R, Kraiczy J, Salvestrini C, Stavrou G, Torrente F, Brook K, Trayers C, Elmentaite R, Youssef G, Tél B, Winton DJ, Skoufou-Papoutsaki N, Adler S, Bufler P, Azabdaftari A, Jenke A, G N, Thomas N, Miele E, Al-Mohammad A, Guarda G, Kugathasan S, Venkateswaran S, Clatworthy MR, Castro-Dopico T, Suchanek O, Strisciuglio C, Gasparetto M, Lee S, Xu X, Bello E, Han N, Zerbino DR, Teichmann SA, Nys J, Heuschkel R, Perrone F, and Zilbauer M
- Subjects
- Humans, Mice, Animals, Female, Male, Mice, Knockout, Biological Specimen Banks, Adult, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I metabolism, Disease Models, Animal, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Crohn Disease genetics, Crohn Disease pathology, Crohn Disease metabolism, Organoids metabolism, Organoids pathology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Epigenesis, Genetic, DNA Methylation
- Abstract
Objective: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis., Design: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model., Results: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature., Conclusions: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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33. Tissue Organoid Cultures Metabolize Dietary Carcinogens Proficiently and Are Effective Models for DNA Adduct Formation.
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Caipa Garcia AL, Kucab JE, Al-Serori H, Beck RSS, Bellamri M, Turesky RJ, Groopman JD, Francies HE, Garnett MJ, Huch M, Drost J, Zilbauer M, Arlt VM, and Phillips DH
- Subjects
- Humans, Carcinogens toxicity, Carcinogens metabolism, Liver metabolism, Organoids metabolism, DNA Adducts, Neoplasms
- Abstract
Human tissue three-dimensional (3D) organoid cultures have the potential to reproduce in vitro the physiological properties and cellular architecture of the organs from which they are derived. The ability of organoid cultures derived from human stomach, liver, kidney, and colon to metabolically activate three dietary carcinogens, aflatoxin B
1 (AFB1 ), aristolochic acid I (AAI), and 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP), was investigated. In each case, the response of a target tissue (liver for AFB1 ; kidney for AAI; colon for PhIP) was compared with that of a nontarget tissue (gastric). After treatment cell viabilities were measured, DNA damage response (DDR) was determined by Western blotting for p-p53, p21, p-CHK2, and γ-H2AX, and DNA adduct formation was quantified by mass spectrometry. Induction of the key xenobiotic-metabolizing enzymes (XMEs) CYP1A1, CYP1A2, CYP3A4, and NQO1 was assessed by qRT-PCR. We found that organoids from different tissues can activate AAI, AFB1 , and PhIP. In some cases, this metabolic potential varied between tissues and between different cultures of the same tissue. Similarly, variations in the levels of expression of XMEs were observed. At comparable levels of cytotoxicity, organoids derived from tissues that are considered targets for these carcinogens had higher levels of adduct formation than a nontarget tissue.- Published
- 2024
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34. In Vitro Models for Investigating Intestinal Host-Pathogen Interactions.
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McCoy R, Oldroyd S, Yang W, Wang K, Hoven D, Bulmer D, Zilbauer M, and Owens RM
- Subjects
- Host-Pathogen Interactions, Organoids, Intestines
- Abstract
Infectious diseases are increasingly recognized as a major threat worldwide due to the rise of antimicrobial resistance and the emergence of novel pathogens. In vitro models that can adequately mimic in vivo gastrointestinal physiology are in high demand to elucidate mechanisms behind pathogen infectivity, and to aid the design of effective preventive and therapeutic interventions. There exists a trade-off between simple and high throughput models and those that are more complex and physiologically relevant. The complexity of the model used shall be guided by the biological question to be addressed. This review provides an overview of the structure and function of the intestine and the models that are developed to emulate this. Conventional models are discussed in addition to emerging models which employ engineering principles to equip them with necessary advanced monitoring capabilities for intestinal host-pathogen interrogation. Limitations of current models and future perspectives on the field are presented., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
- Published
- 2024
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35. Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals.
- Author
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Gerasimidis K, Russell RK, Giachero F, Gkikas K, Tel B, Assa A, Bronsky J, de Ridder L, Hojsak I, Jenke A, Norsa L, Sigall-Boneh R, Sila S, Wine E, Zilbauer M, Strisciuglio C, and Gasparetto M
- Subjects
- Humans, Child, Translational Research, Biomedical, Public Opinion, Remission Induction, Allied Health Personnel, Inflammatory Bowel Diseases therapy, Crohn Disease therapy
- Abstract
Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food-based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre- and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single-nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non-colonic CD, mild-to-moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required., (© 2023 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
- Published
- 2024
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36. Dysregulation of the Environmental Sensor Aryl Hydrocarbon Receptor Affects Differentiation of Human Colon Organoids.
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Liebert A, Shapiro M, Maradana MR, Li Y, Powell N, Zilbauer M, and Stockinger B
- Subjects
- Humans, Receptors, Aryl Hydrocarbon genetics, Colon
- Published
- 2024
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37. Probing milk extracellular vesicles for intestinal delivery of RNA therapies.
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Zhang Y, Belaid M, Luo X, Daci A, Limani R, Mantaj J, Zilbauer M, Nayak K, and Vllasaliu D
- Subjects
- Humans, Rats, Animals, Caco-2 Cells, Milk, RNA, Small Interfering pharmacology, Intestinal Mucosa, Nanoparticles, Inflammatory Bowel Diseases drug therapy, Nucleic Acids
- Abstract
Background: Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa., Results: Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D 'apical-out' and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model., Conclusions: Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application., (© 2023. The Author(s).)
- Published
- 2023
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38. Efficient genetic editing of human intestinal organoids using ribonucleoprotein-based CRISPR.
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Skoufou-Papoutsaki N, Adler S, D'Santos P, Mannion L, Mehmed S, Kemp R, Smith A, Perrone F, Nayak K, Russell A, Zilbauer M, and Winton DJ
- Subjects
- Humans, Gene Editing methods, Organoids metabolism, CRISPR-Cas Systems genetics, Clustered Regularly Interspaced Short Palindromic Repeats genetics, Ribonucleoproteins metabolism
- Abstract
Organoids, combined with genetic editing strategies, have the potential to offer rapid and efficient investigation of gene function in many models of human disease. However, to date, the editing efficiency of organoids with the use of non-viral electroporation methods has only been up to 30%, with implications for the subsequent need for selection, including turnaround time and exhaustion or adaptation of the organoid population. Here, we describe an efficient method for intestinal organoid editing using a ribonucleoprotein-based CRISPR approach. Editing efficiencies of up to 98% in target genes were robustly achieved across different gut anatomical locations and developmental timepoints from multiple patient samples with no observed off-target editing. The method allowed us to study the effect of loss of the tumour suppressor gene PTEN in normal human intestinal cells. Analysis of PTEN-deficient organoids defined phenotypes that likely relate to its tumour suppressive function in vivo, such as a proliferative advantage and increased organoid budding. Transcriptional profiling revealed differential expression of genes in pathways commonly known to be associated with PTEN loss, including mTORC1 activation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)
- Published
- 2023
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39. Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity.
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Kröhn L, Azabdaftari A, Heuberger J, Hudert C, Zilbauer M, Breiderhoff T, and Bufler P
- Subjects
- Humans, Mice, Animals, Immunity, Innate, Cytokines metabolism, RNA, Messenger metabolism, Interleukin-1 genetics, Interleukin-1 metabolism, Tumor Necrosis Factor-alpha metabolism, Intestinal Mucosa
- Abstract
Background and Aims: Intestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids., Methods: Murine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors., Results: Expression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids., Conclusions: We speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Kröhn, Azabdaftari, Heuberger, Hudert, Zilbauer, Breiderhoff and Bufler.)
- Published
- 2023
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40. A Roadmap for the Human Gut Cell Atlas.
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Zilbauer M, James KR, Kaur M, Pott S, Li Z, Burger A, Thiagarajah JR, Burclaff J, Jahnsen FL, Perrone F, Ross AD, Matteoli G, Stakenborg N, Sujino T, Moor A, Bartolome-Casado R, Bækkevold ES, Zhou R, Xie B, Lau KS, Din S, Magness ST, Yao Q, Beyaz S, Arends M, Denadai-Souza A, Coburn LA, Gaublomme JT, Baldock R, Papatheodorou I, Ordovas-Montanes J, Boeckxstaens G, Hupalowska A, Teichmann SA, Regev A, Xavier RJ, Simmons A, Snyder MP, and Wilson KT
- Subjects
- Humans, Forecasting, Organoids, Gastrointestinal Tract
- Abstract
The number of studies investigating the human gastrointestinal tract using various single-cell profiling methods has increased substantially in the past few years. Although this increase provides a unique opportunity for the generation of the first comprehensive Human Gut Cell Atlas (HGCA), there remains a range of major challenges ahead. Above all, the ultimate success will largely depend on a structured and coordinated approach that aligns global efforts undertaken by a large number of research groups. In this Roadmap, we discuss a comprehensive forward-thinking direction for the generation of the HGCA on behalf of the Gut Biological Network of the Human Cell Atlas. Based on the consensus opinion of experts from across the globe, we outline the main requirements for the first complete HGCA by summarizing existing data sets and highlighting anatomical regions and/or tissues with limited coverage. We provide recommendations for future studies and discuss key methodologies and the importance of integrating the healthy gut atlas with related diseases and gut organoids. Importantly, we critically overview the computational tools available and provide recommendations to overcome key challenges., (© 2023. Springer Nature Limited.)
- Published
- 2023
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41. Validation of IBD-associated Whole-blood DNA Methylation Changes-Where Do We Go From Here?
- Author
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Ross ADB and Zilbauer M
- Subjects
- Humans, DNA Methylation, Epigenome, Epigenesis, Genetic, Inflammatory Bowel Diseases genetics, Colitis, Ulcerative genetics
- Published
- 2023
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42. APOBEC mutagenesis is a common process in normal human small intestine.
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Wang Y, Robinson PS, Coorens THH, Moore L, Lee-Six H, Noorani A, Sanders MA, Jung H, Katainen R, Heuschkel R, Brunton-Sim R, Weston R, Read D, Nobbs B, Fitzgerald RC, Saeb-Parsy K, Martincorena I, Campbell PJ, Rushbrook S, Zilbauer M, Buczacki SJA, and Stratton MR
- Subjects
- Child, Humans, Child, Preschool, Mutagenesis genetics, RNA, Messenger genetics, APOBEC-1 Deaminase genetics, Intestine, Small, Apolipoproteins B genetics, Cytidine Deaminase genetics
- Abstract
APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA., (© 2023. The Author(s).)
- Published
- 2023
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43. Metabolic Activation of Benzo[ a ]pyrene by Human Tissue Organoid Cultures.
- Author
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Caipa Garcia AL, Kucab JE, Al-Serori H, Beck RSS, Fischer F, Hufnagel M, Hartwig A, Floeder A, Balbo S, Francies H, Garnett M, Huch M, Drost J, Zilbauer M, Arlt VM, and Phillips DH
- Subjects
- Humans, Activation, Metabolic, Cytochrome P-450 CYP1A1 metabolism, Liver metabolism, Benzo(a)pyrene toxicity, DNA Adducts metabolism, Organoids drug effects, Organoids metabolism
- Abstract
Organoids are 3D cultures that to some extent reproduce the structure, composition and function of the mammalian tissues from which they derive, thereby creating in vitro systems with more in vivo-like characteristics than 2D monocultures. Here, the ability of human organoids derived from normal gastric, pancreas, liver, colon and kidney tissues to metabolise the environmental carcinogen benzo[ a ]pyrene (BaP) was investigated. While organoids from the different tissues showed varied cytotoxic responses to BaP, with gastric and colon organoids being the most susceptible, the xenobiotic-metabolising enzyme (XME) genes, CYP1A1 and NQO1 , were highly upregulated in all organoid types, with kidney organoids having the highest levels. Furthermore, the presence of two key metabolites, BaP- t -7,8-dihydrodiol and BaP-tetrol-l-1, was detected in all organoid types, confirming their ability to metabolise BaP. BaP bioactivation was confirmed both by the activation of the DNA damage response pathway (induction of p-p53, pCHK2, p21 and γ-H2AX) and by DNA adduct formation. Overall, pancreatic and undifferentiated liver organoids formed the highest levels of DNA adducts. Colon organoids had the lowest responses in DNA adduct and metabolite formation, as well as XME expression. Additionally, high-throughput RT-qPCR explored differences in gene expression between organoid types after BaP treatment. The results demonstrate the potential usefulness of organoids for studying environmental carcinogenesis and genetic toxicology.
- Published
- 2022
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44. Single-cell atlas of human liver development reveals pathways directing hepatic cell fates.
- Author
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Wesley BT, Ross ADB, Muraro D, Miao Z, Saxton S, Tomaz RA, Morell CM, Ridley K, Zacharis ED, Petrus-Reurer S, Kraiczy J, Mahbubani KT, Brown S, Garcia-Bernardo J, Alsinet C, Gaffney D, Horsfall D, Tysoe OC, Botting RA, Stephenson E, Popescu DM, MacParland S, Bader G, McGilvray ID, Ortmann D, Sampaziotis F, Saeb-Parsy K, Haniffa M, Stevens KR, Zilbauer M, Teichmann SA, and Vallier L
- Subjects
- Humans, Cell Differentiation, Organoids, Transcription Factors genetics, Transcription Factors metabolism, Liver metabolism, Hepatocytes metabolism
- Abstract
The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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45. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.
- Author
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Serra EG, Schwerd T, Moutsianas L, Cavounidis A, Fachal L, Pandey S, Kammermeier J, Croft NM, Posovszky C, Rodrigues A, Russell RK, Barakat F, Auth MKH, Heuschkel R, Zilbauer M, Fyderek K, Braegger C, Travis SP, Satsangi J, Parkes M, Thapar N, Ferry H, Matte JC, Gilmour KC, Wedrychowicz A, Sullivan P, Moore C, Sambrook J, Ouwehand W, Roberts D, Danesh J, Baeumler TA, Fulga TA, Carrami EM, Ahmed A, Wilson R, Barrett JC, Elkadri A, Griffiths AM, Snapper SB, Shah N, Muise AM, Wilson DC, Uhlig HH, and Anderson CA
- Published
- 2022
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46. Epigenetics in IBD: a conceptual framework for disease pathogenesis.
- Author
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G N and Zilbauer M
- Abstract
The global incidence and prevalence of paediatric inflammatory bowel disease (IBD) is increasing, with a notable emergence in developing countries with historically low rates. This suggests that environmental and epigenetic factors may play an important role in the pathogenesis and progression of IBD. Epigenetics refers to the study of biological mechanisms that result in a change of phenotype, without an change in the underlying DNA sequence. Epigenetic mechanisms drive many biological processes that occur in health, such as development and ageing, and are also implicated in disease, including cancer and other inflammatory diseases. Importantly, identification of cell-type-specific epigenetic mechanisms could lead to the identification of molecular disease subtypes allowing a personalised treatment approach. In this short review, we provide a summary of epigenetic mechanisms operative in mammals, and their potential involvement in IBD pathogenesis. Furthermore, we discuss key challenges associated with investigating epigenetics in IBD and provide potential strategies to overcome these, such as through the use of 'omics' and organoid technologies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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47. Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults: A Cross-Sectional Study.
- Author
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Mann JP, Jenkins B, Furse S, Snowden SG, Alisi A, Draijer LG, Karnebeek K, Kelly DA, Koot BG, Mosca A, Salvestrini C, van Mourik I, Vreugdenhil A, Zilbauer M, and Koulman A
- Subjects
- Adult, Child, Cross-Sectional Studies, Humans, Lipidomics, Liver pathology, Triglycerides, Cardiovascular Diseases etiology, Non-alcoholic Fatty Liver Disease pathology
- Abstract
Objective: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterised by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease., Methods: We performed untargeted liquid chromatography-mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9500 adults with metabolic phenotyping., Results: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (pC) and triglycerides (TG). Similar trends in pC and TG chain length and saturation were seen in adults with hepatic steatosis; however, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants., Conclusion: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
- Published
- 2022
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48. An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease.
- Author
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Bolton C, Smillie CS, Pandey S, Elmentaite R, Wei G, Argmann C, Aschenbrenner D, James KR, McGovern DPB, Macchi M, Cho J, Shouval DS, Kammermeier J, Koletzko S, Bagalopal K, Capitani M, Cavounidis A, Pires E, Weidinger C, McCullagh J, Arkwright PD, Haller W, Siegmund B, Peters L, Jostins L, Travis SPL, Anderson CA, Snapper S, Klein C, Schadt E, Zilbauer M, Xavier R, Teichmann S, Muise AM, Regev A, and Uhlig HH
- Subjects
- Age of Onset, Antiporters genetics, Cells, Cultured, Classification, Gene Expression Profiling, Genetic Association Studies, Genotype, Glucose-6-Phosphatase genetics, Glucose-6-Phosphate metabolism, Humans, Inflammatory Bowel Diseases metabolism, Macrophages, Metabolomics, Monosaccharide Transport Proteins genetics, Penetrance, Phenotype, Signal Transduction genetics, Inflammatory Bowel Diseases classification, Inflammatory Bowel Diseases genetics
- Abstract
Background & Aims: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis., Methods: To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4)., Results: Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8
+ T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD., Conclusion: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses., (Copyright © 2022 AGA Institute. All rights reserved.)- Published
- 2022
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49. Making Research Flourish Through ESPGHAN: A Position Paper From the ESPGHAN Special Interest Group for Basic and Translational Research.
- Author
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Gasparetto M, Strisciuglio C, Assa A, Gerasimidis K, Giachero F, Novak J, Robinson P, Tél B, Zilbauer M, and Jenke A
- Subjects
- Child, Child Nutritional Physiological Phenomena, Humans, Public Opinion, Societies, Medical, Translational Research, Biomedical, Gastroenterology
- Abstract
Abstract: Recent research breakthroughs have emerged from applied basic research throughout all scientific areas, including adult and paediatric gastroenterology, hepatology and nutrition (PGHAN). The research landscape within the European Society of Paediatric Gastroenterology and Nutrition (ESPGHAN) is also inevitably changing from clinical research to studies involving applied laboratory research. This position paper aims to depict the current status quo of basic science and translational research within ESPGHAN, and to delineate how the society could invest in research in the present and future time. The paper also explores which research areas in the field of PGHAN represent the current and future priorities, and what type of support is needed across the ESPGHAN working groups (WGs) and special interest groups (SIGs) to fulfil their research goals., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
- Published
- 2022
- Full Text
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50. Disease Prognostic Biomarkers in Inflammatory Bowel Diseases-A Reality Check.
- Author
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Zilbauer M and Heuschkel R
- Subjects
- Disease Progression, Humans, Prognosis, Biomarkers analysis, Inflammatory Bowel Diseases pathology
- Abstract
Inflammatory bowel diseases [IBD] such as Crohn's disease [CD] and ulcerative colitis [UC] are complex conditions presenting with a wide range of phenotypes. Given major variation in disease severity and outcomes as well as response to existing therapies, a personalised treatment approach stands the chance of improving the overall disease outcome as well as minimising potentially harmful side effects. However, disease activity or distribution at the point of diagnosis are poor predictors of future disease outcome. Hence, the urgent need to develop biomarkers that could either predict the overall disease course [i.e., disease prognostic biomarkers] or the response to individual therapies [i.e., disease predictive biomarkers]. Despite the widely accepted need for such biomarkers to improve the management of IBD patients, their development has proven to be challenging for a number of reasons. Based on our own experience in this field, we perform a reality check on existing evidence, discuss main challenges, and outline future perspectives., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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