Arbeitsgruppe für Molekulare Gastroenterologie

Principle Investigator: Stefanie Derer-Petersen, Ph.D. senior scientist

Our research group investigates underlying mechanisms of inflammation-driven diseases of the gastrointestinal tract such as Crohn's disease (CD), ulcerative colitis (UC) and colorectal cancer (CRC). These diseases are currently incurable and share a common pathophysiological feature: a disruption of the interaction between intestinal epithelial cells, immune cells and the intestinal microbiota, which is associated with a loss of function of the intestinal barrier. Due to the re-mitigating chronic inflammatory processes, inflammatory bowel disease patients (CD & UC) have an increased risk of developing inflammation-driven carcinomas in the gastrointestinal tract.

In detail, we demonstrated that CD patients display a hy­per­ac­tive B-cell com­partment reflected by an excessive production of autoantibodies against Sac­cha­ro­myces ce­re­vi­si­ae or glycoprotein 2 (GP2). Our group further identified CD-associated au­to­an­ti­bo­dies against the intestinal M-cell ex­pres­­sed FimH receptor GP2 variant 4 to in­hi­bit induction of adaptive im­munity against adherent-invasive flagellated bacteria such as Sal­mo­nel­la typhimurium. How­ever, underlying mechanisms of an imbalanced B-cell compartment in CD patients still remain to be elusive. Preliminary data of our group revealed CD patients in remission to display a defect in colonic plasma cell differentiation, leading to enhanced generation of plasmablasts  and in a long-term view to an impairment of an effective mucosal adaptive immunity.

Proliferation and differentiation of cells have to be tightly balanced, while the metabolic switch from cytosolic aerobic glycolysis to the mitochondrial oxidative phosphorylation system (OXPHOS) is known to influence the transition of proliferating precursors into post-mitotic differentiated cells such as plasma cells or goblet cells. Our group recently identified two specific caspase-1 cleavage sites at asparagine residues 77 and 229 in the multifunctional protein p32/gC1qR/HABP1, a mitochondria localized protein that is indispensable in the maintenance of mitochondrial OXPHOS. Processing of p32 by active caspase-1 resulted in the loss of its N-terminal mitochondrial leader, loss of OXPHOS activity and a shift towards aerobic glycolysis that enabled increased cell proliferation after cell activation. Furthermore, we described loss of OXPHOS activity to be associated with IBD as well as with CRC.

Hence, our goal is to provide novel insights into how daily and constitutive interaction of the gut with diet-delivered nutrients or compounds improve its integrity or trigger intestinal inflammation that may boost tumor development in an individual manner. Our overriding goal is to decipher underlying molecular mechanisms of IBD as well as rising incidences of colorectal carcinoma patients at younger ages to develop tailored preventive strategies.

To understand how the gut responds to individual dietary habits on the molecular level in the context of inflammation-driven carcinogenesis, we connect functional and metabolic data from cell biology with phenotypic and clinical data collected from human studies, intestinal 3D-organoid cultures or from animal models of acute or chronic intestinal inflammation as well as of inflammation-driven colorectal carcinogenesis. Our lab has long-standing experience in immunohistochemistry, fluorescence microscopy, flow cytometry, molecular cell biology, spatial single-cell proteomics/transcriptomics and metabolic analyses of intestinal cells.

Prof. Dr. Derer-Petersen is trained in ecotrophology with the focus on nutritional science. She performed her Ph.D. thesis in the field of effector functions of distinct therapeutic TNF-a directed antibodies in IBD (Institute of Clinical Molecular Biology, Christian-Albrechts-University in Kiel) and received her Ph.D. in molecular biology in 2009. As a post-doctoral fellow, she moved into the research field of “on­cology & hematology” at the University Hospital Schleswig-Holstein (UKSH) Campus Kiel (Division of Stem Cell Transplantation and Immunotherapy), where she has been specialized on oncogenic KRAS mutations as well as on effector mechanisms of therapeutic antibodies in the context of CRC. Here, she was also trained in designing, engineering, generating and functional characterizing antibodies of different isotypes. In 2015, she joined the Campus Lübeck of the UKSH. Since 2016, she is heading the laboratory and the group “Molecular Gastroenterology” in the Insti­tute of Nutritional Medicine. The main objective of her group is to unravel underlying molecular mechansims of the pa-thogenesis of IBD and inflammation-driven CRC. She recently defined the term Nutri-Inflammation to highlight the potential of nutrition to constantly promote intestinal inflammation and hence lifestyle-associated colorectal cancer.