Project Summary Childhood trauma dramatically increases the risk of adult psychiatric illness and significantly alters symptom complexity and treatment outcomes. Discovering causal factors and novel interventions could have a dramatic impact on treating psychiatric illness. Over the past decade, there has been a growing appreciation for the role of the gut microbiota in normal brain development and behavior and of critical modulatory effects of the gut microbiota on mental health. Interactions of microbiota with stress-related hormonal, immune, and inflammatory processes in the brain are particularly well supported. Thus, there is intense interest in understanding how interactions among stress, microbiome, and brain (the “stress-biome-brain” axis; SBB) contribute to a significant impact on mental health. We will address the hypothesis that adolescent trauma-induced alterations in the microbiome contribute to the neurobiological and behavioral disruptions seen in adulthood. First, we will characterize stress-biome-brain axis dynamics in mice following recurrent trauma. Mice exposed to recurrent predation stress or to control conditions will be assessed for changes in the gut microbiota, hippocampal gene expression, and behavior. We will use these data to construct multi-level models and predict causal interactions among stress, microbiome, brain, and behavior. Next, we will test the hypothesis that changes in the gut microbiota induced by childhood trauma have causal effects in the brain. We will perform fecal transplants from trauma-exposed mice into naïve mice and measure changes in brain gene expression. These experiments will be performed in a germ-free mouse facility in mice with a small specified number of species, for precise control of microbial content. In addition, we will test strategies for perturbation of the microbial community and to assess behavioral outcomes in the germ-free facility. The data generated will set the stage for precision perturbation studies of the microbiota and its effects on behavior and for future translational studies.