Early microbiome changes and its antigenic potential in individuals at high-risk for inflammatory bowel diseases

Research group P1

Introduction

The interaction of lifestyle and environmental factors with the well-studied predisposing genetic susceptibility is currently thought to trigger inflammatory bowel diseases (IBDs). Due to its mere size, its prominent presence at the inflamed intestinal sites, and its metabolic and immunological importance, the gut microbiome has been identified as a major disease-relevant intermediate phenotype and a potential driving factor of IBD development and its clinical course. IBDs develop progressively, i.e. microbial changes (dysbiosis) can be detected years before the onset of IBD with relatives of IBD patients being at particular risk for developing the disease through genetic and environmental proximity. It is assumed that dysregulated or inappropriate T cell reactions against otherwise harmless members of the microbiome play a central role for disease pathogenesis and/or chronification. However, which microbes are the targets of pathogenic T cell reactions and how these reactions develop is currently unknown. Patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies and information on the magnitude and importance of early changes in the microbiome and the human immune system is still lacking.

Aims

We will perform standardized metagenomic analyses of biosamples from different time points and analyze potential disease-associated alterations of the T cell reaction against candidate microbes from members of our KINDRED (family) cohort for IBD (see Biobank Popgen for more details on the cohort).

We here aim:

  • to identify genetic and non-genetic factors that shape the gut microbiome in IBD patients and their first-degree relatives,
  • to analyze the function of the gut microbiome in IBD patients and their first-degree relatives over time,
  • to identify disease-associated metabolites, microbial signatures, and patterns thereof, and
  • to identify early changes in the immunological responses against candidate microbes.
Fig. 1: Main objecties and aims of project 1 – Identify molecular / cellular signatures that predict the clinical onset of IBD

Outlook

This project holds the potential to identify molecular signatures, microbial and metabolic biomarkers, or even antigens that predict and explain the clinical onset and disease course of IBD. We will accurately describe pre-clinical changes in the microbiome of high-risk individuals to improve the etiological understanding of subclinical disease forms. Direct analyses of the T cell reaction against selected candidate microbes will enable us to investigate the missing link between microbial dysbiosis and altered immune reactions. In a potential second RU funding phase our findings could be followed up by targeted intervention studies in at-risk individuals of the KINDRED cohort, additional integration and analyses of new onset cases, and by working further on the HLA-antigen and TCR candidates in order to identify novel targets for treatment.


Project-related publications

P1

Autoantigen-specific CD4<sup>+</sup> T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases.

Carina Saggau, Petra Bacher, Daniela Esser, Mahdi Rasa, Silja Meise, Nicola Mohr, Nora Kohlstedt, Andreas Hutloff, Sarah-Sophie Schacht, Justina Dargvainiene, Gabriela Rios Martini, Klarissa H Stürner, Ina Schröder, Robert Markewitz, Johannes Hartl, Maria Hastermann, Ankelien Duchow, Patrick Schindler, Mareike Becker, Carolin Bautista, Judith Gottfreund, Jörn Walter, Julia K Polansky, Mingxing Yang, Reza Naghavian, Mareike Wendorff, Ev-Marie Schuster, Andreas Dahl, Andreas Petzold, Susanne Reinhardt, Andre Franke, Marek Wieczorek, Lea Henschel, Daniel Berger, Guido Heine, Maike Holtsche, Vivien Häußler, Christian Peters, Enno Schmidt, Simon Fillatreau, Dirk H Busch, Klaus-Peter Wandinger, Kilian Schober, Roland Martin, Friedemann Paul, Frank Leypoldt, Alexander Scheffold

Immunity (Cambridge, Mass.)
2024
P1

Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn’s disease.

Gabriela Rios Martini, Ekaterina Tikhonova, Elisa Rosati, Meghan Bialt DeCelie, Laura Katharina Sievers, Florian Tran, Matthias Lessing, Arne Bergfeld, Sophia Hinz, Susanna Nikolaus, Julia Kümpers, Anna Matysiak, Philipp Hofmann, Carina Saggau, Stephan Schneiders, Ann-Kristin Kamps, Gunnar Jacobs, Wolfgang Lieb, Jochen Maul, Britta Siegmund, Barbara Seegers, Holger Hinrichsen, Hans-Heinrich Oberg, Daniela Wesch, Stefan Bereswill, Markus M Heimesaat, Jan Rupp, Olaf Kniemeyer, Axel A Brakhage, Sascha Brunke, Bernhard Hube, Konrad Aden, Andre Franke, Iliyan D Iliev, Alexander Scheffold, Stefan Schreiber, Petra Bacher

Nature medicine
2023
P1

Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation.

Sara Federici, Sharon Kredo-Russo, Rafael Valdés-Mas, Denise Kviatcovsky, Eyal Weinstock, Yulia Matiuhin, Yael Silberberg, Koji Atarashi, Munehiro Furuichi, Akihiko Oka, Bo Liu, Morine Fibelman, Iddo Nadav Weiner, Efrat Khabra, Nyssa Cullin, Noa Ben-Yishai, Dana Inbar, Hava Ben-David, Julian Nicenboim, Noga Kowalsman, Wolfgang Lieb, Edith Kario, Tal Cohen, Yael Friedman Geffen, Lior Zelcbuch, Ariel Cohen, Urania Rappo, Inbar Gahali-Sass, Myriam Golembo, Vered Lev, Mally Dori-Bachash, Hagit Shapiro, Claudia Moresi, Amanda Cuevas-Sierra, Gayatree Mohapatra, Lara Kern, Danping Zheng, Samuel Philip Nobs, Jotham Suez, Noa Stettner, Alon Harmelin, Naomi Zak, Sailaja Puttagunta, Merav Bassan, Kenya Honda, Harry Sokol, Corinna Bang, Andre Franke, Christoph Schramm, Nitsan Maharshak, Ryan Balfour Sartor, Rotem Sorek, Eran Elinav

P1

A novel unconventional T cell population enriched in Crohn’s disease.

Elisa Rosati, Gabriela Rios Martini, Mikhail V Pogorelyy, Anastasia A Minervina, Frauke Degenhardt, Mareike Wendorff, Soner Sari, Gabriele Mayr, Antonella Fazio, Christel Marie Dowds, Charlotte Hauser, Florian Tran, Witigo von Schönfels, Julius Pochhammer, Maria A Salnikova, Charlot Jaeckel, Johannes Boy Gigla, Sanaz Sedghpour Sabet, Matthias Hübenthal, Esther Schiminsky, Stefan Schreiber, Philip C Rosenstiel, Alexander Scheffold, Paul G Thomas, Wolfgang Lieb, Bernd Bokemeyer, Maria Witte, Konrad Aden, Alexander Hendricks, Clemens Schafmayer, Jan-Hendrick Egberts, Ilgar Z Mamedov, Petra Bacher, Andre Franke

Gut : journal of the British Society of Gastroenterology
2022
P1

Detailed transcriptional landscape of peripheral blood points to increased neutrophil activation in treatment-naïve inflammatory bowel disease.

Simonas Juzenas, Matthias Hübenthal, Carl Mårten Lindqvist, Robert Kruse, Tim Alexander Steiert, Frauke Degenhardt, Dominik Schulte, Susanna Nikolaus, Sebastian Zeissig, Daniel Bergemalm, Sven Almer, Henrik Hjortswang, Francesca Bresso, Nina Strüning, Juozas Kupcinskas, Andreas Keller, Wolfgang Lieb, Philip Rosenstiel, Stefan Schreiber, Mauro D’Amato, Jonas Halfvarson, Georg Hemmrich-Stanisak, Andre Franke

Journal of Crohn's & colitis : international journal devoted to inflammatory bowel diseases
2022
P1

Reporting guidelines for human microbiome research: the STORMS checklist.

Chloe Mirzayi, Audrey Renson, Fatima Zohra, Shaimaa Elsafoury, Ludwig Geistlinger, Lora J Kasselman, Kelly Eckenrode, Janneke van de Wijgert, Amy Loughman, Francine Z Marques, David A MacIntyre, Manimozhiyan Arumugam, Rimsha Azhar, Francesco Beghini, Kirk Bergstrom, Ami Bhatt, Jordan E Bisanz, Jonathan Braun, Hector Corrada Bravo, Gregory A Buck, Frederic Bushman, David Casero, Gerard Clarke, Maria Carmen Collado, Paul D Cotter, John F Cryan, Ryan T Demmer, Suzanne Devkota, Eran Elinav, Juan S Escobar, Jennifer Fettweis, Robert D Finn, Anthony A Fodor, Sofia Forslund, Andre Franke, Cesare Furlanello, Jack Gilbert, Elizabeth Grice, Benjamin Haibe-Kains, Scott Handley, Pamela Herd, Susan Holmes, Jonathan P Jacobs, Lisa Karstens, Rob Knight, Dan Knights, Omry Koren, Douglas S Kwon, Morgan Langille, Brianna Lindsay, Dermot McGovern, Alice C McHardy, Shannon McWeeney, Noel T Mueller, Luigi Nezi, Matthew Olm, Noah Palm, Edoardo Pasolli, Jeroen Raes, Matthew R Redinbo, Malte Rühlemann, R Balfour Sartor, Patrick D Schloss, Lynn Schriml, Eran Segal, Michelle Shardell, Thomas Sharpton, Ekaterina Smirnova, Harry Sokol, Justin L Sonnenburg, Sujatha Srinivasan, Louise B Thingholm, Peter J Turnbaugh, Vaibhav Upadhyay, Ramona L Walls, Paul Wilmes, Takuji Yamada, Georg Zeller, Mingyu Zhang, Ni Zhao, Liping Zhao, Wenjun Bao, Aedin Culhane, Viswanath Devanarayan, Joaquin Dopazo, Xiaohui Fan, Matthias Fischer, Wendell Jones, Rebecca Kusko, Christopher E Mason, Tim R Mercer, Susanna-Assunta Sansone, Andreas Scherer, Leming Shi, Shraddha Thakkar, Weida Tong, Russ Wolfinger, Christopher Hunter, Nicola Segata, Curtis Huttenhower, Jennifer B Dowd, Heidi E Jones, Levi Waldron

Nature medicine
2021
P1

Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations.

Frauke Degenhardt, Gabriele Mayr, Mareike Wendorff, Gabrielle Boucher, Eva Ellinghaus, David Ellinghaus, Hesham ElAbd, Elisa Rosati, Matthias Hübenthal, Simonas Juzenas, Shifteh Abedian, Homayon Vahedi, B K Thelma, Suk-Kyun Yang, Byong Duk Ye, Jae Hee Cheon, Lisa Wu Datta, Naser Ebrahim Daryani, Pierre Ellul, Motohiro Esaki, Yuta Fuyuno, Dermot P B McGovern, Talin Haritunians, Myhunghee Hong, Garima Juyal, Eun Suk Jung, Michiaki Kubo, Subra Kugathasan, Tobias L Lenz, Stephen Leslie, Reza Malekzadeh, Vandana Midha, Allan Motyer, Siew C Ng, David T Okou, Soumya Raychaudhuri, John Schembri, Stefan Schreiber, Kyuyoung Song, Ajit Sood, Atsushi Takahashi, Esther A Torres, Junji Umeno, Behrooz Z Alizadeh, Rinse K Weersma, Sunny H Wong, Keiko Yamazaki, Tom H Karlsen, John D Rioux, Steven R Brant, Andre Franke

Human molecular genetics
2021
P1

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans.

Petra Bacher, Thordis Hohnstein, Eva Beerbaum, Marie Röcker, Matthew G Blango, Svenja Kaufmann, Jobst Röhmel, Patience Eschenhagen, Claudia Grehn, Kathrin Seidel, Volker Rickerts, Laura Lozza, Ulrik Stervbo, Mikalai Nienen, Nina Babel, Julia Milleck, Mario Assenmacher, Oliver A Cornely, Maren Ziegler, Hilmar Wisplinghoff, Guido Heine, Margitta Worm, Britta Siegmund, Jochen Maul, Petra Creutz, Christoph Tabeling, Christoph Ruwwe-Glösenkamp, Leif E Sander, Christoph Knosalla, Sascha Brunke, Bernhard Hube, Olaf Kniemeyer, Axel A Brakhage, Carsten Schwarz, Alexander Scheffold


Researchers

Johanna Saalfrank

Doctoral Researcher, Associated Scientist
Institute of Clinical Molecular Biology (IKMB) / Kiel University (CAU), Kiel University (CAU), University Medical Center Schleswig-Holstein (UKSH)
P1 (Phase 1),
P1 (Phase 2)

Other important members of P1

  • Dr. rer nat. Malte Rühlemann
  • Dr. rer nat. Louise Thingholm
  • Ilona Urbach
  • Ines Spitzer
  • NGS lab technicians
  • Michaela Hilgert

Participating Institutes