UC San Diego

With advances in high-throughput sequencing technology and decreasing costs, microbiome science has permeated all fields of biological research, enriching our understanding of the essential roles microbes play in host biology. However, with this added information comes added complexity; teasing out the effects of thousands of microbes on host biology amongst variations in host genetics, diet, microbial exposures, xenobiotic exposures, and other factors is exceedingly challenging. Murine models, which allow for control of many confounding factors, have been crucial for unraveling the complexity of host-microbe interactions. They allow for targeted exploration of microbiome dysbiosis, and the resulting downstream health consequences. In this dissertation, we sought to leverage the utility of the murine model to understand (a) how the microbiome influences the chemistry of the whole-organism and (b) how does this change with microbial dysbiosis. Chapters 1 & 2 serve as background and motivation for this work. Conducting a microbiome study, from experimental planning to analysis, warrants special considerations to generate accurate and useful results. Chapter 1 discusses these considerations and common pitfalls, summarizing how to study the microbiome. Chapter 2 highlights an example of why host-microbe interactions are important to study, investigating how microbiome dysbiosis affects drug metabolism. Chapter 3 focuses on work utilizing a 3-D mouse model to understand the whole-organism impact of the microbiome. In 3.1, we compare the metabolomes of germ-free to specific-pathogen-free (SPF) mice at 96 different sample sites across 29 organs to understand how microbes influence the chemistry of an entire mammal. In 3.2, we use a similar 3-D mouse model to investigate how antibiotics, a common agent of dysbiosis, alter the microbiome and metabolome across a whole-organism. Chapter 4 utilizes a murine model to focus on pathogen-induced dysbiosis in one specific body site, the vaginal tract, and how a urogenital pathogen interacts with commensal flora. Overall, this dissertation highlights how host-associated microbiomes have far ranging impacts across the entire organism, and, how agents of dysbiosis can impact host chemistry and commensal microbial communities.