Gut Liver axis: The interrelated role of regulated ‐ necrosis as key driver of gastrointestinal and hepatic inflammation
Final Report Abstract
Immune-based therapies and diagnostics have demonstrated their immense potential in the treatment of immune-mediated inflammatory diseases (IMIDs), including inflammatory bowel disease (IBD), autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and multiple sclerosis (MS). These advances are currently transforming medical practice across various disciplines, enabling highly individualized therapeutic approaches. Understanding the underlying molecular disease mechanisms has thus become increasingly important for both researchers and clinicians. Common features of these diseases include progressive inflammation-driven tissue damage and subsequent organ dysfunction. Our research group focuses on how tissue injury and associated repair mechanisms are modulated by the microenvironment, with particular interest in IMIDs affecting the liver and gut. Our interdisciplinary and translational research approach spans basic cellular and molecular techniques, preclinical models, and clinical validation using human samples, resulting in several clinically relevant findings. In previous work, we demonstrated that regulated cell death-induced mucosal barrier dysfunction is strongly linked to microbial dysbiosis and chronic intestinal inflammation in both experimental colitis models and IBD patients. We further showed that inflammatory cytokines such as TNFα, IFNλ, and IFNγ synergistically trigger cell death and barrier dysfunction in genetically predisposed individuals, perpetuating inflammation. Moreover, we revealed that genetic susceptibility alone can cause mild inflammation, while environmental factors, such as disease-relevant microbial flora, determine the extent and localization of gut inflammation. These insights confirm that both host-dependent mechanisms and the microenvironment are critical in promoting immune-mediated inflammation. We further demonstrated that barrier dysfunction caused by regulated necrosis and dysbiosis is associated with altered mucosal and systemic immune responses, which promote inflammation in distant organs such as the liver and bones. By integrating immunological principles, molecular biology, and microbiology, and translating these findings into the clinic, we uncovered key disease mechanisms of IMIDs. This has opened new avenues for identifying prognostic and therapeutic targets, allowing clinicians to interfere with disease processes on multiple levels, ultimately enabling personalized therapeutic strategies.
Publications
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Environmental Microbial Factors Determine the Pattern of Inflammatory Lesions in a Murine Model of Crohn’s Disease–Like Inflammation. Inflammatory Bowel Diseases, 26(1), 66-79.
Stolzer, Iris; Kaden-Volynets, Valentina; Ruder, Barbara; Letizia, Marilena; Bittel, Miriam; Rausch, Philipp; Basic, Marijana; Bleich, André; Baines, John F.; Neurath, Markus F.; Wirtz, Stefan; Weidinger, Carl; Bischoff, Stephan C.; Becker, Christoph & Günther, Claudia
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Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure. Cell Death & Disease, 10(12).
Bittel, Miriam; Kremer, Andreas E.; Stürzl, Michael; Wirtz, Stefan; Stolzer, Iris; Neurath, Markus F.; Ballon, Gianna & Günther, Claudia
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An IFN-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease. Frontiers in Medicine, 8.
Stolzer, Iris; Dressel, Anja; Chiriac, Mircea T.; Neurath, Markus F. & Günther, Claudia
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Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe‐host‐communication in vivo. Journal of Extracellular Vesicles, 10(12).
Bittel, Miriam; Reichert, Patrick; Sarfati, Ilann; Dressel, Anja; Leikam, Stefanie; Uderhardt, Stefan; Stolzer, Iris; Phu, Tuan Anh; Ng, Martin; Vu, Ngan K.; Tenzer, Stefan; Distler, Ute; Wirtz, Stefan; Rothhammer, Veit; Neurath, Markus F.; Raffai, Robert L.; Günther, Claudia & Momma, Stefan
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STAT1 coordinates intestinal epithelial cell death during gastrointestinal infection upstream of Caspase-8. Mucosal Immunology, 15(1), 130-142.
Stolzer, Iris; Schickedanz, Laura; Chiriac, Mircea T.; López-Posadas, Rocío; Grassl, Guntram A.; Mattner, Jochen; Wirtz, Stefan; Winner, Beate; Neurath, Markus F. & Günther, Claudia
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Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing. International Journal of Molecular Sciences, 24(8), 7402.
Wittner, Leonie; Wagener, Lukas; Wiese, Jakob J.; Stolzer, Iris; Krug, Susanne M.; Naschberger, Elisabeth; Jackstadt, Rene; Beyaert, Rudi; Atreya, Raja; Kühl, Anja A.; Sturm, Gregor; Gonzalez-Acera, Miguel; Patankar, Jay V.; Becker, Christoph; Siegmund, Britta; Trajanoski, Zlatko; Winner, Beate; Neurath, Markus F.; Schumann, Michael & Günther, Claudia
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Gut Pathobiont–Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis–Associated Inflammatory Bowel Disease. Gastroenterology, 167(6), 1183-1197.e16.
Dorner, Heidrun; Stolzer, Iris; Mattner, Jochen; Kaminski, Sophie; Leistl, Sofia; Edrich, Lisa-Maria; Schwendner, Raphael; Hobauer, Julia; Sebald, Adrian; Leikam, Stefanie; Gonzalez, Acera Miguel; Düll, Miriam; Lang, Roland; Seidel, Gerald; Seitz, Tatjana; Hellerbrand, Claus; Fuhrmann, Gregor; Distler, Ute; Tenzer, Stefan ... & Günther, Claudia
