Defining Small Intestinal Microbial Landscapes To Improve Therapeutics For Gastrointestinal Disease

Project Summary: Defining Small Intestinal Microbial Landscapes To Improve Therapeutics For Gastrointestinal Disease Disease Relevance: Irritable Bowel Syndrome (IBS) is a chronic disorder characterized by altered bowel function (consistency and/or frequency) in additional to abdominal pain, effecting 7-16% of the US population and associated with an $1 billion of direct health care costs annually. This proposal seeks to better understand IBS and to develop more effective treatments for IBS. Candidate and Career Development Plan: My long-term goal is to become a fully independent physician scientist through leadership of a cutting-edge research program in human microbiota analysis and its association with clinical data complemented using a variety of tools (molecular genetics, metabolomics, gnotobiotic mouse models) to clarify mechanisms of action that will enable development of improved microbiota directed therapeutics for GI disease. Through my clinical training I am poised to become an expert in diagnosing and treating IBS, and through my previous research training am well equipped with the skills to perform high-resolution human and mouse immunology. To fully actualize my career goals of becoming an expert in microbiota-host interactions in IBS I will need to gain skills beyond my current knowledge base. This award will support the needed additional training in microbiota analysis, methods of clinical research, bacterial isolation and culturing, and gnotobiotic mouse models. Research Plan: The overarching research goal of this proposal is to move beyond feces, to define the site-specific microbial ecology of the human small intestine in IBS. We will construct a longitudinal map of intestinal microbiota and metabolites in humans with a swallowed, microbiota sampling capsule device. I have successfully employed this approach in healthy humans and the proposed research will expand sample collection to include IBS patient samples analyzed with microbiota sequencing, novel microbiota-focused metabolomics (Aim 1), and bacterial isolation and functional testing (Aim 2), with complementary studies in gnotobiotic mice (Aim 3) to define fundamental aspects of host- microbe interactions in the small intestine. Mentorship Team: To achieve these Aims, I have assembled a world class mentorship team with expertise in translational human microbiome studies (Justin Sonnenburg, primary mentor), isolation and study of bacteria from the human microbiome (KC Huang, co-mentor), and the treatment and study of IBS (Linda Nguyen, co-mentor). Environment and Institutional Commitment: Stanford University is a world leader in human microbiome studies and treating Gastroenterological(GI) disease. I will have access to mentorship, collaborators, and a breadth of resources that will provide an exceptional training environment. My mentorship team and the leadership within the Stanford Department of Medicine are committed to ensuring my success. The scientific training, skill acquisition, and career development under this award will allow me to become a fully independent physician scientist and leader in the translational microbiota science of GI disease.