PROJECT SUMMARY/ABSTRACT Major Depressive Disorder (MDD) is a common disorder whose etiology remains unclear and likely multifactorial. Serotonin reuptake inhibitors (SSRIs), fail to fully reduce the burden of disease, highlighting need for additional studies into the pathogenesis of MDD. Alterations in gut microbiota composition (termed “dysbiosis”) leading to altered signaling along the route of communication between the gut and the brain (termed the gut -microbiota- brain axis) represents a novel modifiable target associated with MDD. While several studies have linked dysbiosis to MDD, our understanding of how these changes contribute to altered signaling along this gut-microbiota-brain axis and depressive symptoms remains limited. This proposal aims to determine how changes in the activity of an understudied pathway of tryptophan metabolism (the indole pathway) by the gut microbiota contributes to the pathophysiology of MDD. Using stool and blood samples from a well characterized cohort of unmedicated MDD subjects along with healthy controls and samples from these same unmedicated subjects after 8 weeks of antidepressant treatment, the candidate will address two aims. First, using a shotgun metagenomics approach, changes in the capacity of the gut microbiota to produce metabolites of the indole pathway associated with MDD will be assessed. This will be related to changes in serum levels of indoles, activation of the aryl hydrocarbon receptor, and the ability to modulate the activity of microglia. Next, these parameters will be assessed after antidepressant treatment to identify changes associated with successful treatment. This study is novel given its use of unmedicated, well characterized MDD subjects and our assessment of gut microbiome community structure/function within the same individual after treatment (which has never been done previously). The candidate will leverage a number of approaches including 1) metagenomics 2) metabolomics 3) in vitro assays and 4) bacterial genetics to interrogate mechanisms of gut-brain axis signaling involved in the pathophysiology of MDD. This proposal presents a five-year research career development program designed to provide a foundation for future research endeavors as an independent physician -investigator researcher. The candidate is currently a Child and Adolescent Psychiatry Fellow (in a three-year research fellowship) at UCSF. This proposal builds on the candidate's previous experience studying host-pathogen interactions and the role of Lactobacillus species in health and disease. This proposal will integrate new domains of expertise by his mentors, including the study of the role of dysbiosis of complex microbial communities in the etiology of disease, neurodevelopment and the neurobiological basis of depression, and design/implementation of clinical studies by his mentors, Dr. Wolkowitz, Dr. Mellon, and Dr. Lynch. These skills fill critical gaps in the candidate's knowledge and the plan outlin...