Interaction between microbiota, antimicrobial defense and differentiation factors in Inflammatory Bowel Disease

• Applicant: Professor Dr. Jan Wehkamp
• Subject Area: Gastroenterology ; Nutritional Sciences
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237716477

Inflammatory bowel diseases (IBD) are to date incurable and characterized be recurring and severe inflammations of the intestinal tract. Even though there is an ongoing dispute about basic and general disease mechanisms, a major role of an imbalanced microbial-epithelial interaction at the intestinal barrier is commonly accepted among clinicians and researchers. In this regard, our group focusses on a potentially disturbed epithelial differentiation. In our research approaches we and consecutively also others have found disturbances in an important Wnt pathway transcription factors (TCF7L2 also known as TCF4) in patients with small intestinal Crohn’s Disease (CD), a subgroup of IBD. Following studies also pinpointed a Wnt coreceptor (LRP6) in a similar context. The Wnt pathway is of major importance in maintaining proliferation, regeneration and paradoxically also directed differentiation of epithelia in the gastrointestinal tract. In particular, Paneth cell maturation and function is controlled by the β-catenin dependent branch of the pathway. Paneth cells are normally specifically found on the bottom of crypts right next to the stem cells in the small intestine. They are specialized producers of antimicrobial peptides which they store in granules and release upon stimulation of pattern recognition receptors. Their most abundant products, HD5 and HD6, are transcriptionally controlled by the Wnt pathway and exhibit a primary decrease in ileal CD. HD5 and HD6 as well as other Paneth cell AMPs are crucial in fending off pathogenic threats but also in controlling the relationship towards intestinal commensals. Their reduced expression in patients represents an interesting possibility for the development of targeted therapy approaches, but further studies are indispensable to gain a better understanding of the complicated system and the involved networks. We therefore plan to analyze the role of microbiota in the context of Wnt controlled antimicrobial defense, as well as to identify potential additional factors which might underlie the imbalanced host-microbiota interactions at the epithelial barrier in patients.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1656: Intestinal Microbiota - A Microbial Ecosystem at the Edge between Immune Homeostasis and Inflammation
• Participating Person: Professor Dr. Eduard F. Stange