Host-microbe interactions: How commensal immunogenicity shapes gut homeostasis and inflammation

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Dokumentart: PhDThesis
Date: 2021-08-05
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Frick, Julia-Stefanie (Prof. Dr.)
Day of Oral Examination: 2021-06-02
DDC Classifikation: 500 - Natural sciences and mathematics
610 - Medicine and health
Keywords: Mikroflora , Immunsystem
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The impact of the gut microbiota on the host’s states of health and disease is indisputably large. Besides contributing to the host’s physiological functions by digesting nutrients, providing vitamins and pathogen resistance, the gut microbiota educates and modulates immune responses. In healthy individuals, the microbiota is composed of a broad variety of different commensals that exhibit different immunogenicity and that reside within the host in a state of immune homeostasis. However, many immune-mediated or autoimmune diseases, e.g. inflammatory bowel disease (IBD), are associated with a shift in the normal microbiota termed dysbiosis. Gut immune responses can be influenced even by single bacterial strains. For instance, the model symbiont Bacteroides vulgatus exerts protective, anti-inflammatory functions in mouse models of experimental colitis, whereas the model pathobiont Escherichia coli rather promotes intestinal inflammation. An important link between the microbiota and the host’s innate and adaptive immune system is represented by dendritic cells (DCs). These front-line antigen presenting cells at mucosal surfaces respond to the commensals by appropriate differentiation and maturation. Depending on their developed phenotype and created cytokine milieu, DCs mediate T cell differentiation towards a regulatory, antiinflammatory or a pro-inflammatory T helper cell subset. In this thesis, one of the most immunogenic bacterial antigens, lipopolysaccharide (LPS), is demonstrated to be the main mediator of immunogenicity of the mentioned model commensals. Due to its weak agonistic activity, LPS isolated from B. vulgatus is even able to ameliorate intestinal inflammation in a mouse model of experimental colitis, similar to administration of living B. vulgatus. This effect was associated with the induction of tolerogenic DCs, which contribute to intestinal homeostasis - in contrast to the fully mature DCs induced by E. coli, which promote inflammation. The transcription factor IκBζ is essential for the induction of an IL-17 secreting T helper cell subset, the Th17 cells, and was hypothesized to play a role in the commensal-specific DC effects. Th17 cells can be protective in mucosal infections under physiological conditions but are also associated with the pathology of autoimmune diseases and are increased in IBD. Here, it is demonstrated that the strong immunogenic E. coli promotes a significantly higher IκBζ expression in DCs, contributing to differentiation of pathologic Th17 cells, whereas B. vulgatus only induces low IκBζ expression in DCs and triggers differentiation of protective T helper cell subsets. However, E. coli also induces development of a regulatory B cell phenotype which counteracts on the strong immune response and can suppress inflammation in a mouse model of experimental colitis in dependence of the host’s immune competence.

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