We seek to understand how the intestinal microbiome contributes to vertebrate physiology and disease. To that end, we leverage complementary zebrafish and mouse models to study the integrative physiology of host-microbiome interactions. This work has identified novel and conserved mechanisms by which intestinal bacteria regulate dietary fat metabolism and systemic innate immunity. We also apply genomic approaches in these animal models to understand the transcriptional regulatory pathways utilized by the intestinal epithelium to mediate host responses to the microbiome. Using this approach, we have identified mechanisms of transcriptional and chromatin regulation that have been conserved during vertebrate evolution and also contribute to modern human diseases such as the inflammatory bowel diseases, obesity, and diabetes. To further advance our understanding of obesity pathophysiology, we developed the zebrafish as a model system for studying adipose tissues and identifying new environmental and genetic regulators of adiposity. We are also engaged in translational research in humans and animal models to define microbial and metabolic determinants of obesity and efficacy of weight loss intervention. Grounded in comparative and integrative physiology, our research program has been effective in discovering ancient mechanisms of host-microbiome interaction that are conserved across animal taxa and contribute to the etiology of modern human diseases. These insights are advancing our understanding of host-microbiome relationships in vertebrate physiology and identifying novel therapeutic targets for human diseases ranging from inflammatory bowel disease to obesity to neurological disorders.