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Abstract

The skin is in constant contact with the environment and serves a critical barrier function, yet provides a range of niches to inhabiting microbial communities. A multitude of interactions between the skin microbiota, host and environment contribute to community structure and its potential contribution to changes in health status is well known. Susceptibility to chronic inflammatory diseases is determined by the interaction of immunogenetic and environmental risk factors. In particular, resident microbial communities as environmental factors are the subject of intense scrutiny due to numerous observations of differences in community composition or structure are of primary etiological importance or secondary to the altered inflammatory environment remains largely unknown. Epidermolysis bullosa acquisita (EBA) is a chronic skin blistering disease of autoimmune origin characterized by antibodies to type VII collagen (COL7). This study provides experimental evidence for host gene-microbiota interactions contributing to disease risk in a mouse immunization model of EBA. By using an advanced intercross mouse population, genetic loci contributing to variability in the skin microbiota were simultaneously identified along with susceptibility to EBA and their overlap. QTL mapping of the skin microbiota with susceptibility to EBA demonstrates the involvement of host gene-microbe interactions in disease. Furthermore, treating the abundances of individual bacterial species as covariates with disease lead to the discovery of a novel disease locus. The majority of the identified covariate taxa were characterized by a reduction in abundance being associated with increased disease risk. This provides evidence of a primary role for individual bacterial species abundances in disease susceptibility and underscores their importance in protection from disease. Interestingly, in a parallel study in this thesis, mice that did not develop clinical disease showed a higher diversity in their skin microbial communities before disease induction. This further demonstrates the importance of skin community in predictive of EBA disease outcome. Thus, further characterization of these putative probiotic species or species assemblages offers promising potential for preventative and therapeutic treatment development.