Intestinale Forschung (AG Zeissig)

Research in the laboratory focuses on the immunological mechanisms of inflammation and tumor development in the intestine and the liver, with particular interest in host-microbial interactions in the pathogenesis of these diseases.

Chronic inflammation is a risk factor for the development of cancer and many prominent examples of this association exist in the gastrointestinal tract. This includes associations between inflammatory bowel disease (IBD) and colorectal cancer (CRC), Helicobacter pylori infection and gastric cancer, Hepatitis B and C virus infections and hepatocellular cancer (HCC) as well as MASLD and HCC. Of note, in many of these examples, inflammation is clinically inapparent, restricted to the respective tissue and dependent on microbial organisms. In line with these principles, we could demonstrate that not only sporadic CRCs but also adenomas, as their benign predecessor lesions, are associated with disruption of the intestinal barrier and translocation of bacteria into host tissue (Peuker and Zeissig, Nat. Med. 2016). This is associated with microbiota-dependent activation of inflammatory pathways in the intestinal epithelium, such as the pathway of calcineurin and nuclear factor of activated T cells (NFAT), which promotes tumor growth through support of tumor stem cell survival and proliferation. We could further demonstrate that, in addition to epithelial cells, myeloid cells in the tumor stroma sense microbial components, thereby orchestrating epithelial and T cell responses (Peuker and Zeissig, Immunity 2022).

In ongoing work, we investigate pathways of microbial regulation of CRC development and progression. Furthermore, we explore whether similar processes of microbiota-dependent cancer progression are operative along the gut-liver axis and extend to hepatocellular cancer (HCC).

In a national consortium, coordinated by Dr. Zeissig and funded by the federal ministry of education and research (BMBF), we explore host-microbial interactions in the pathogenesis and prevention of early-onset CRC (EO-CRC). Specifically, we investigate interactions between the microbiome and environmental factors, including diet, which contribute to the development in early-onset CRC and its rise in incidence observed in past decades. Furthermore, we explore whether stool-based microbiome signatures can be employed for the detection of EO-CRC and for the stratification of individuals at risk of EO-CRC such as obese individuals and those with hereditary risk factors. The goal of our work is to develop strategies for microbiome-based targeting in EO-CRC prevention.

For more information, please refer to: https://mikrobiota-darmkrebs.de

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic intestinal inflammation. Intestinal inflammation in IBD results from a complex and incompletely understood interplay of genetic and environmental factors. We and others have identified monogenic, Mendelian forms of IBD, in which defects in a single gene are sufficient to promote intestinal inflammation with high penetrance (Zeissig Y, Gut 2014; Zeissig S, Gut 2014). One of the most common Mendelian forms of IBD results from mutations in the X-linked inhibitor of apoptosis protein (XIAP). Individuals with XIAP mutations exhibit high but incomplete penetrance of IBD and therefore provide an excellent approach to study host-environmental interactions in IBD pathogenesis. Consistent with this notion, we have shown that patients with loss-of-function mutations in XIAP exhibit loss of Paneth cells in the small intestine, which is associated with impaired secretion of antimicrobial peptides, defects in microbial control, and susceptibility to microbiota-dependent intestinal inflammation (Strigli, Gopalakrishnan, Zeissig, Sci Immunol 2021). Current work focuses on the specific microbial triggers of gut inflammation in XIAP deficiency and the development of strategies that target host-microbial interactions in disease prevention and treatment. Furthermore, in a federally funded project (BMBF “HYDRO-UC”), we develop hydrogels as local therapies for the treatment of intestinal inflammation in IBD.

Sebastian Schmidt (MD/PhD thesis)

Prof. Dr. med. Sebastian Zeissig (Group leader)
Tel.: +49 (0)3834 86-7230

Dr. med. Kenneth Peuker (Postdoc; Head of laboratory)
Tel.: +49 (0)3834 86-80478