How does the intestinal microbiota influence chronic inflammation and cancer?
Approximately 10% of the German population suffers from chronic inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease. In many patients with chronic inflammatory diseases, the composition of the intestinal flora (intestinal microbiota) is altered compared to healthy people (dysbiosis). Several studies have shown that these alterations can correlate with the clinical course of disease, response to therapy, and the risk of developing cancer. However, causal relationships between components of the intestinal microbiota and disease/clinical response are largely unknown. Supported by the Dr. Rolf M. Schwiete Foundation, we try to identify pathogenic and protective components of the microbiota and unravel the dialogue between such bacteria and the immune system to gain insight into the role of the microbiota in the development and chronification of inflammation.
Together with the group of Prof. Susann Müller from the Helmholtz Institute for Environmental Research in Leipzig, we have recently developed a method for assessing the composition of the intestinal microbiota by flow cytometry. This “microbiota cytometry” discriminates single bacteria based on DNA content, light scatter properties, and, in addition, on mucosal antibody coating, to specifically identify bacteria which have come in contact with and are seen by the immune system. Microbiota cytometry allows us to simply and rapidly compare the composition of the microbiota between individuals, healthy versus diseased, at multiple time points and identify and isolate by cell sorting bacterial populations of interest for taxonomic and functional analyses. Together with our clinical partners at the gastroenterology department of the Charité Universitätsmedizin Berlin, we are looking at defined cohorts of patients with inflammatory bowel diseases, i.e. patients with Crohn’s disease and ulcerative colitis, as well as patients with spondylarthropathies and rheumatoid arthritis with the aim of identifying bacteria that have a positive or negative influence on the clinical course of the disease, or on concomitant diseases such as cancer, and on the response to therapy.
To increase the resolution of the microbiota flow cytometry analysis for the identification of specific bacterial taxons, we are developing multi-parameter microbiota cytometry using monoclonal bacteria-specific antibodies in close collaboration with the group of Andrey Kruglov (Chronic Inflammation Group).
In our studies we have already identified potentially pro-inflammatory bacteria which determine the capacity of pro-inflammatory T helper lymphocytes to induce intestinal inflammation in a pre-clinical model of colitis. We have also identified a bacterium with potential anti-inflammatory properties, due to its ability to induce the expression of TGF-β. TGF-β is an important anti-inflammatory cytokine and also promotes the production of IgA antibodies in the gut. IgA antibodies are an important component of the intestinal barrier and control the composition of the intestinal microbiota by directly binding to bacteria. Thus, the bacteria could have therapeutic potential in inflammatory bowel diseases as an inducer of TGF-β and IgA antibodies to dampen inflammation and strengthen the intestinal barrier.
It is our overall goal to gain a molecular understanding of how selective bacterial species contribute to the induction and maintenance of chronic inflammatory diseases and develop innovative therapeutic approaches through the specific manipulation of the intestinal microbiota.
Dr. rer. nat. habil. Hyun-Dong Chang
Dr. Alexander Beller
Dr. Pawel Durek
Dr. Ute Hoffmann
Lisa Budzinski, M.Sc.
Victoria von Goetze, M.Sc.
Kevin Heiking, M.Sc.
Aayushi Shah, M.Sc.
Tanisha Momtaz, B. Sc.
Georgia Lattanzi, B.Sc.
- Dr. Petra Bacher, IKMB – Christian-Albrechts-Universität zu Kiel, Germany
- Dr. Charlotte Esser, Leibniz Forschungsinstitut für Umweltmedizin Düsseldorf, Germany
- Dr. Ahmed Hegazy, Charité Universitätsmedizin Berlin, Medizinische Klinik I, Germany
- Andrey Kruglov, DRFZ, Germany
- Anja Kühl, Charité Universitätsmedizin Berlin, Medizinische Klinik I, Germany
- Mir-Farzin Mashreghi, DRFZ, Germany
- Dr. Susann Müller, Helmholtz Institut für Umweltforschung, Leipzig, Germany
- Dr. Denis Poddubnyy, Charité Universitätsmedizin Berlin, Medizinische Klinik I, Germany
- Anne Regierer, DRFZ, Germany
- Dr. Chiara Romagnani, Charité Universitätsmedizin Berlin, Medizinische Klinik I, Germany
- Dr. Dagmar Scheel-Toellner, Universität Birmingham, Germany
- Maren Schmiester, Charité Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Germany
- Dr. Alexander Scheffold, Christian-Albrechts-Universität zu Kiel, Germany
- Dr. Britta Siegmund, Charité Universitätsmedizin Berlin, Medizinische Klinik I, Germany
- Rene Toes and Dr. Ulrich Scherer, Leiden University Medical Centre, The Netherlands
- Carl Weidinger, Charité Universitätsmedizin Berlin, Medizinische Klinik I, Germany
- Jakob Zimmermann, Universität Bern, Germany
- Cossarizza A, Chang HD, Radbruch A et al Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur J Immunol. 2017 Oct;47(10):1584-1797. doi: 10.1002/eji.201646632.
- Zimmermann J, Durek P, Kühl AA, Schattenberg F, Maschmeyer P, Siracusa F, Lehmann K, Westendorf K, Weber M, Riedel R, Müller S, Radbruch A, Chang HD. The intestinal microbiota determines the colitis-inducing potential of T-bet-deficient Th cells in mice. Eur J Immunol. 2018 Jan;48(1):161-167. doi: 10.1002/eji.201747100.
- Chang HD, Tokoyoda K, Radbruch A. Immunological memories of the bone marrow. Immunol Rev. 2018 May;283(1):86-98. doi: 10.1111/imr.12656. Review.
- Christian Neumann, Jonas Blume, Urmi Roy, Peggy P. Teh, Ajithkumar Vasanthakumar, Alexander Beller, Yang Liao, Frederik Heinrich, Teresita L. Arenzana, Jason A. Hackney, Celine Eidenschenk, Eric J. C. Gálvez, Christina Stehle, Gitta A. Heinz, Patrick Maschmeyer, Tom Sidwell, Yifang Hu, Derk Amsen, Chiara Romagnani, Hyun-Dong Chang, Andrey Kruglov, Mir-Farzin Mashreghi, Wei Shi, Till Strowig, Sascha Rutz, Axel Kallies and Alexander Scheffold; c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis; Nature Immunology 2019
- Rolf M. Schwiete Stiftung
- TRR130 Teilprojekt 16 (Radbruch/Chang): Deciphering the Survival Code of Memory Plasma Cells and Memory B Cells
- TRR241 Teilprojekt B03 (Radbruch/Chang): The intestinal epithelial cells in the dialogue between microbiota and the immune system
- Rheumastiftung: Molecular adaptations of pathogenic memory T Helper cells in rheumatic inflammations
- Pfizer: JAK/STAT inhibitors as a potential therapeutic treatment to specifically deplete plasma cells in the inflammatory niche of rheumatoid arthritis patients (WI221601)
- RTCure: WP3 (Project leader Chang/Radbruch)