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要旨:
Blood groups were discovered more than one hundred years ago, but their evolutionary- and biological role is still not fully understood. Blood-group-related glycan structures can serve as attachment sites and nutrient sources for intestinal bacteria, thus, changes in the glycan repertoire may result in changes in bacterial community structure and functionality. However, environmental differences such as diet, hygiene, or the environment from which the bacterial community is recruited also exert strong influences on community structure. This variation, introduced by genetic or environmental factors, may also influence the development- and susceptibility to diseases. This thesis is dedicated to the analysis of microbial community characteristics with respect to (i) environmental variables (i.e. geography) and (ii) variation in blood-group-related antigens in the gastrointestinal tract and their possible contribution to disease development.
In the first chapter of this thesis I investigate the differences of the active and stagnant microbial communities between human populations (Germany, Lithuania, and India) in healthy- and diseased subjects (Crohn Disease, Ulcerative Colitis). This allowed me to identify universal- and population-specific patterns of microbial communities and dysbiosis, specifically among the active microbial community members. My results indicate biogeographic patterns in mucosa associated microbial communities and population-specific disease signatures, which may entail specific treatment strategies in the future.
Chapters II and III aim to explore the impact of variation in the Crohn Disease risk locus FUT2 (α-1,2-fucosyltransferase) and inflammatory diseases on the microbial communities. To investigate the influence of host-specific glycan composition on the microbial community I took different approaches, using human sample material (colonic biopsies, bile samples) and mouse models. This allowed me to investigate changes in the ecology of the host associated microbial communities, through genetic, environmental, and pathological influences. The FUT2 gene shows widespread sequence variation in human populations and is required for expression of ABO blood group antigens in all bodily secretions and mucosal surfaces. Several highly conserved mutations have been identified in different human populations, which eliminate blood group expression in excretory tissues (so called “nonsecretor” mutations). These mutations have been associated with decreased susceptibility to several infectious agents, but increased susceptibility to inflammatory bowel diseases. I could show how this variation in blood group expression translates into changes of the composition and diversity of microbial communities, potentially influencing susceptibility to chronic inflammation in the gastrointestinal tract (Chapter II). Furthermore, ecological processes like initial colonization, succession, and their intricate interaction with host genetic traits are of crucial importance to understand host-microbiome interactions and
represent potential drivers in the development of community imbalances or disease (Chapter III).
In chapter IV I investigate the role of interactions between the blood-group-related gene B4galnt2 (β-1,4-N-Acetylgalactosaminyltransferase 2) and the intestinal microbiota in susceptibility to the enteric pathogen Salmonella enterica ssp. ser. Typhimurium. Naturally occurring cis-regulatory variation at B4galnt2 leads to a tissue-specific switch from gut epithelial expression to expression in the vascular endothelium and results in a bleeding diathesis. The maintenance of such variation could be related to a trade-off scenario between resistance to enteric pathogens (absence of certain glycans in the gut) and prolonged bleeding after injury. I identified microbial community factors present in mice without gut epithelial B4galnt2 expression, which are responsible for a higher community resilience and lower susceptibility to Salmonella infection.
In summary, these findings provide strong evidence for the influence of blood-group-related antigens and the environment on the microbial communities with potential fitness consequences for the host. The balance between adaptation to local microbial communities, pathogen resistance, and loss of potentially beneficial bacterial symbionts and functions might thus contribute to the patterns of long-term-balancing selection in genes like FUT2 and B4galnt2. These results may lead to future population- and genotype-specific measures for treatment and prevention of inflammatory bowel diseases.
