The microbiota is imperative for the development of our immune system and thus critical for human health. Studies have identified a few specific members of the gut microbial community that have explicit functions in aiding immune system education, however these studies have been piecemeal. Unanswered questions remain regarding how both bacterial-bacterial interactions and bacterial-host interactions affect immune system development. I hypothesize that within microbial community bacterial-bacterial relations alter bacterial-host interactions that initiate and maintain a healthy immune system. I propose to apply a systems biology approach to examine host-microbe ecology in the simplified system of gnotobiotic zebrafish. The zebrafish is a well-established model for gnotobiotic studies, and possesses many advantages for examining bacterial-host interactions. Most importantly, their gut microbiota is well defined and cultureable, allowing a systematic, comprehensive examination of each species'individual role in immune response education.
Specific aims : (1) Test the hypothesis that the immune response to a gut microbial community is different than the sum of the individual immune responses to each member. (2) Determine whether secreted bacterial products contribute to the induction of the innate immune response. (3) Identify Aeromonas veronii genes differentially required for survival within a microbial community compared to an A. veronii single species community. Research Design: To compare immune responses to single bacterial species with immune responses to microbial communities I will examine gut neutrophil infiltration and host transcriptomes in gnotobiotic studies with one or two-member communities. To examine whether secreted products are necessary and sufficient to induce innate immunity, I will examine gut neutrophil infiltration and innate immune gene induction in response to an A. veronii secretion system mutant and to A. veronii cell free supernatent. Finally, to identify A. veronii genes differentially required for survival in a microbal community I will employ the A.veronii transposon library developed in the Guillemin lab. I will focus on genes necessary for colonization that differ between a mono- association of A. veronii and a co-association with A. veronii and a second zebrafish gut microbe. This systematic approach will address the question of how collective activities of microbial communities educate the immune system. This data is vital for interpretation of Human Microbiome Project data, construction of probiotics, and application of microbiota manipulations as a therapeutic approach to treat disease.
Bacteria that live in our bodies significantly influence human health and disease. Thus, people commonly take probiotics to promote health, and now, scientists suggest that manipulating the types of bacteria in our bodies will be a way to treat diseases like inflammatory bowel disease, diabetes, and obesity. However, because bacteria have beneficial effects, changing the bacteria in our bodies can have widespread consequences. My goal is to characterize normal bacteria-host interactions that are influenced by the context of the bacterial community. These data will allow microbiota-manipulating therapies to be carried out specifically and without unintended consequences.