Bacterial strains within the same species can exhibit substantial genetic and functional diversity. Bacterial strains possess a variety of mechanisms to interact with and manipulate their host's physiology. The impact of bacterial strains on host physiology can be highly context-dependent and vary from strain to strain. For example, host factors such as genetics, diet, and drugs, can influence the interaction between bacterial strains and the host's physiology, making these interactions even harder to understand. Unlike the concept of a single "core genome" that represents the shared genes within a species, the pangenome encompasses both the core genes shared among strains and the accessory genes that are present only in some strains. In this seminar, I will show how we leverage high-throughput host-microbe genetic, pharmacological and dietary screens to understand how microbes regulate host physiology. In particular, I will show that bacterial phylogenetics at the strain level are a poor predictor of effects on host physiology. Further, we have developed a novel high-throughput microbial-drug-host GWAS strategy to explore how functional variation within pangenomes and their genes can lead to variations in the responses of the host to therapy. By examining the pangenomes of microbial species, we can gain valuable insights into their pathogenicity, ecological roles, and most importantly their regulation of host physiology.