A central question in behavioral biology is how environmental and genetic factors shape behavioral traits, allowing for substantial individuality. Homeostatic behaviors like feeding and food preferences are prime examples of genetic predispositions interacting with the food environment to produce diverse feeding habits. However, these programs are further modified by host-associated microbes, suggesting the overall systems controlling behavioral phenotype is far more complex than first anticipated. The critical questions that remain to be addressed are: to what extent do host-microbe interactions contribute to individual differences in behavior? Specifically, how does gene regulation of behavior operate in the context of host-microbe symbiosis? Implicit in this question is the hypothesis that perturbation of host-microbe symbiosis results in aberrant behavioral outcomes in certain individuals or populations, a topic fundamental to human health yet unsolved. The goal of my research program is to define how behaviors are shaped by host-microbe interactions. My lab studies foraging and food choice behaviors in the fly Drosophila melanogaster, using a gnotobiotic system I developed that permits precise configuration of the fly microbiome. I hypothesize that feeding behavior and food preferences are the product of host genetics-microbiome interactions, which determine, in part, an individual’s long-term health. Our recent data show that foraging and diet selection preferences vary by the microbiome, and altering the microbiome triggers transcriptional changes in specific cell clusters within the fly brain, involving genes predicted to affect behavior. In this five-year plan, I will leverage fly genetics and state- of-the-art genomics and metabolomics tools to identify the gene regulatory networks and mechanisms underlying microbial modulation of host behavior. Expected outcomes include comprehensive gut endocrine signaling and inter-organ communication maps at single-cell transcriptome scale and metabolite-gene interactions networks. The causal effects of microbiome-responsive genes, neuropeptides, and metabolites on host feeding behavior and food preferences will be revealed. Since we know little about how the interplay of host genetics and microbiome contribute to complex behavior, my research has the potential to advance fundamental knowledge in behavioral genetics but also to identify genes or processes that may function similarly in Drosophila and mammals as targets to treat behavioral disorders, such as eating disorders and obesity.