How intestinal commensals affect the immune system and the outcome of inflammatory disorders: novel molecular insights

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Dokumentart: PhDThesis
Date: 2017
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Frick, Julia-Stefanie (Prof. Dr.)
Day of Oral Examination: 2017-02-03
DDC Classifikation: 570 - Life sciences; biology
610 - Medicine and health
Keywords: Darm , Mikrobiologie , Immunologie
Other Keywords: Chronisch entzündliche Darmerkrankungen
inflammatory bowel diseases
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The gut is considered to be the biggest immunological organ in mammals and the composition of the intestinal microbiota is therefore assumed to have widespread effects on the immune system of its host. During past years, more and more insights were gained concerning the correlation of intestinal microbiota composition and onset and progress of various autoimmune diseases, i.e. Inflammatory Bowel Diseases (IBD). Nevertheless, insights in defined molecular mechanisms underlying these observations are rare. However, a deeper knowledge of these mechanisms is necessary for proper drug development for gut-associated and immune system-related pathologies. With this work, knowledge gaps concerning molecular events of the interplay between commensal gut bacteria and the host immune system shall be closed. In this context, we focused on how different intestinal commensals, symbionts and pathobionts, differentially influence the host immune system. Briefly summarized, B. vulgatus mpk, a Gram negative model symbiont of the intestinal microbiota, was able to prevent from induction of intestinal inflammation in a mouse model for experimental colitis. This effect was not restricted to prevention, as even already established colonic inflammation was reduced by oral administration of this bacterium, resulting in complete healing of damaged colonic tissue. Furthermore, isolated lipopolysaccharide from B. vulgatus mpk, providing a unique core oligosaccharide structure, was able to mimic both observed bacteria-mediated therapeutic effects. Additionally and for the first time, a symbiotic commensal such as B. vulgatus mpk was demonstrated to prevent from cathepsin S activity upregulation in host dendritic cells by a regulation mechanism involving the endogenous protein cystatin C. Cathepsin S activity regulation is a decisive criterion for the prevention of pathological CD4+ T cell mediated immune responses. Since many autoimmune diseases were already demonstrated to be associated with cathepsin S activity dysregulation, our observation might explain why and how the microbiota composition influences the progress of autoimmune diseases in various mouse models. We furthermore showed that cathepsin S activity regulation in dendritic cells is part of DC semi-maturation. Semi-mature DCs provide a a tolerant and tolerogenic phenotype contributing to (re-)establishment of intestinal homeostasis and prevention of pathological inflammation. Taken together, we hereby offer novel therapeutic approaches for the treatment of inflammatory bowel disease in specific and autoimmune diseases in general. First, lipopolysaccharides of symbiotic commensals might act as therapeutic agents and insights gained from the structural analysis of B. vulgatus mpk LPS might help to chemically design novel inflammation-silencing drugs. Second, B. vulgatus mpk was shown to prevent from pathological cathepsin S activitiy increase, making this bacterium an attractive alternative to chemical cathepsin S inhibitors which are widely considered to be promising drugs for the treatment of autoimmune diseases.

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