Professor Matthias Zilbauer

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Professor Matthias Zilbauer

Intestinal stem cell biology

Clinical Professor of Paediatric Gastroenterology

Email: mz304@cam.ac.uk     |     Departmental affiliation: University Department of Paediatrics, Department of Paediatric Gastroenterology, Hepatology and Nutrition (Cambridge University Hospitals)

Research

Plain English: The intestinal epithelium forms the most inner layer of the human intestine. In addition to playing an important role in helping to digest and absorb nutrients and water, the epithelium also provides a crucial barrier that protects us from potentially harmful bacteria or toxins contained in our daily diet. Impaired function of the epithelium can lead to disease for example chronic gut inflammation (Crohn’s Disease and Ulcerative Colitis). Such chronic inflammatory bowel diseases increasingly affect small children and have a devastating impact on their lives. Although we do not understand why more and more people are diagnosed with these conditions, it seems clear that changes in our environmental play a key role. That is why the Zilbauer Group are studying the potential role of ‘epigenetic mechanisms’ in gut diseases. These ‘epigenetic mechanisms’ can switch genes on or off and thereby allow our cells to adapt to changes in our environment. This is important to allow our body to function, but it can also lead to disease if something goes wrong.

If we understand the epigenetic changes in the gut epithelium of patients suffering from gut diseases we can find ways to ‘reset’ the epigenome or use medications to prevent the consequences causing damage to the gut.

Research Focus: The Zilbauer Group's main research interest lies in the field of human intestinal epithelial stem cell biology during development, health and related diseases such as Inflammatory Bowel Diseases (IBD) and Necrotising Enterocolitis (NEC). A particular focus lies on the role of role of epigenetic mechanisms (i.e. DNA methylation) in regulating gene expression and cellular function of the human intestinal epithelium and the implication of epigenetic (re)programming on development and disease pathogenesis. 

As one of the main experimental models, they use human mucosa derived intestinal epithelial organoids. Over the past 8 years, they have generated a large living biobank containing >1000 frozen organoid lines that form the basis for future translational research efforts. In addition to organoids derived from intestinal mucosal samples, induced pluripotent stem cells (iPSCs) can be differentiated into intestinal epithelium.

Current projects focus on the development of clinical biomarkers to guide treatment of children diagnosed with Inflammatory Bowel Diseases, test novel treatments targeting the intestinal epithelium using our organoid model and further develop 2D and 3D culture systems which allow complex co-culture of the intestinal epithelium with other cell types (e.g. immune and stromal cells) as well as the intestinal microbiota.

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Figure 1: Use of human intestinal epithelial organoids as translational research tools for the development of novel treatment approaches.

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Figure 2: Brightfield images of Human Intestinal Epithelial Organoids (IEOs) derived from A) Terminal Ileum B) Duodenum C) Sigmoid Colon. D) Fluorescent image of organoid derived from Terminal Ileum and stained for Nuclei (blue), LGR5 (green) and E-cadherin (red)

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Zilbauer Group photo 

Key publications

• Culture-Associated DNA Methylation Changes Impact on Cellular Function of Human Intestinal Organoids.

  Edgar RD, Perrone F, Foster AR, Payne F, Lewis S, Nayak KM, Kraiczy J, Cenier A, Torrente F, Salvestrini C, Heuschkel R, Hensel KO, Harris R, Jones DL, Zerbino DR, Zilbauer M. Cell Mol Gastroenterol Hepatol. 2022;14(6):1295-1310. doi: 10.1016/j.jcmgh.2022.08.008. Epub 2022 Aug 28.

• Cells of the human intestinal tract mapped across space and time.

  Elmentaite R, Kumasaka N, Roberts K, Fleming A, Dann E, King HW, Kleshchevnikov V, Dabrowska M, Pritchard S, Bolt L, Vieira SF, Mamanova L, Huang N, Perrone F, Goh Kai'En I, Lisgo SN, Katan M, Leonard S, Oliver TRW, Hook CE, Nayak K, Campos LS, Domínguez Conde C, Stephenson E, Engelbert J, Botting RA, Polanski K, van Dongen S, Patel M, Morgan MD, Marioni JC, Bayraktar OA, Meyer KB, He X, Barker RA, Uhlig HH, Mahbubani KT, Saeb-Parsy K, Zilbauer M, Clatworthy MR, Haniffa M, James KR, Teichmann SA.Nature. 2021 Sep;597(7875):250-255. doi: 10.1038/s41586-021-03852-1. Epub 2021 Sep 8.

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  Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn's Disease.

  Elmentaite R, Ross ADB, Roberts K, James KR, Ortmann D, Gomes T, Nayak K, Tuck L, Pritchard S, Bayraktar OA, Heuschkel R, Vallier L, Teichmann SA, Zilbauer M.Dev Cell. 2020 Dec 21;55(6):771-783.e5. doi: 10.1016/j.devcel.2020.11.010. Epub 2020 Dec 7.

• High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells.

  Beumer J, Puschhof J, Bauzá-Martinez J, Martínez-Silgado A, Elmentaite R, James KR, Ross A, Hendriks D, Artegiani B, Busslinger GA, Ponsioen B, Andersson-Rolf A, Saftien A, Boot C, Kretzschmar K, Geurts MH, Bar-Ephraim YE, Pleguezuelos-Manzano C, Post Y, Begthel H, van der Linden F, Lopez-Iglesias C, van de Wetering WJ, van der Linden R, Peters PJ, Heck AJR, Goedhart J, Snippert H, Zilbauer M, Teichmann SA, Wu W, Clevers H.Cell. 2020 Aug 20;182(4):1062-1064. doi: 10.1016/j.cell.2020.08.005.

• Transcription and DNA Methylation Patterns of Blood-Derived CD8⁺ T Cells Are Associated With Age and Inflammatory Bowel Disease But Do Not Predict Prognosis.

  Gasparetto M, Payne F, Nayak K, Kraiczy J, Glemas C, Philip-McKenzie Y, Ross A, Edgar RD, Zerbino DR, Salvestrini C, Torrente F, Ventham NT, Kalla R, Satsangi J, Sarkies P, Heuschkel R, Zilbauer M. Gastroenterology. 2021 Jan;160(1):232-244.e7. doi: 10.1053/j.gastro.2020.08.017. Epub 2020 Aug 16.

• The landscape of somatic mutation in normal colorectal epithelial cells.

  Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA, Moore L, Georgakopoulos N, Torrente F, Noorani A, Goddard M, Robinson P, Coorens THH, O'Neill L, Alder C, Wang J, Fitzgerald RC, Zilbauer M, Coleman N, Saeb-Parsy K, Martincorena I, Campbell PJ, Stratton MR.Nature. 2019 Oct;574(7779):532-537. doi: 10.1038/s41586-019-1672-7. Epub 2019 Oct 23.PMID: 31645730

• Genome-Wide Epigenetic and Transcriptomic Characterization of Human-Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids.

  Kraiczy J, Ross ADB, Forbester JL, Dougan G, Vallier L, Zilbauer M. Cell Mol Gastroenterol Hepatol. 2019;7(2):285-288. doi: 10.1016/j.jcmgh.2018.10.008. Epub 2018 Oct 23.

• DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development.

  Kraiczy J, Nayak KM, Howell KJ, Ross A, Forbester J, Salvestrini C, Mustata R, Perkins S, Andersson-Rolf A, Leenen E, Liebert A, Vallier L, Rosenstiel PC, Stegle O, Dougan G, Heuschkel R, Koo BK, Zilbauer M. Gut. 2019 Jan;68(1):49-61. doi: 10.1136/gutjnl-2017-314817. Epub 2017 Nov 15

• DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome.

  Howell KJ, Kraiczy J, Nayak KM, Gasparetto M, Ross A, Lee C, Mak TN, Koo BK, Kumar N, Lawley T, Sinha A, Rosenstiel P, Heuschkel R, Stegle O, Zilbauer M. Gastroenterology. 2018 Feb;154(3):585-598. doi: 10.1053/j.gastro.2017.10.007. Epub 2017 Oct 12.