This K23 application describes a five year mentored training program. The application has two main objectives. First, it will provide the PI with protected time to complete an integrated research and training program guided by multidisciplinary team of mentors. This will include use of high throughput technologies, basic molecular biology techniques, bioinformatics and systems biology approach to study intestinal microbiomics, metabolomics, and interactions of alcohol and obesity related to liver disease. The PI will also complete formal coursework leading to a Masters in Clinical and Translational Research. In addition, the research utilizes an established network of community treatment programs, providing a unique opportunity for the PI to put new knowledge into actual practice. Taken together, this rigorous training program will provide the PI with information and experience integral to his transition from mentored scientist to independent research physician. The second objective is to investigate the effect of alcohol on obesity related liver disease. The PI will focus on the hypothesis that In obese subjects, alcohol consumption alters the circulating profile of metabolites of intestinal microbial origin. Specific differentially expresse intestinal microbiome- derived metabolites promote development of fatty liver disease by directly activating disease related pathways (steatosis, inflammation, apoptosis etc.) and/or indirectly by activation of inflammatory cells. The proposed research has two specific aims: (1) to phenotype the intestinal metabonome in lean and obese subjects with varying amounts and patterns of alcohol consumption, and (2) to define how regular alcohol intake increases the development and severity of fatty liver disease in obese subjects. The research will interface directly with coe elements of the PI's training plan and is expected to demonstrate that alcohol consumption in obese subjects will alter the profile of intestinal microbiome and systemic metabolome that will modulate hepatic transcriptome and activate disease pathways over and above those seen in obesity. The activation of these pathways can promote liver disease in obese patients with alcohol use. These results will provide novel insights into (1) understanding mechanisms of how alcohol and obesity interact to promote liver disease, (2) development of biomarkers to identify those at risk or have developed liver disease, and (3) identification of specific targets for therapy. The proposed research will address the biologically and behaviorally complex interaction of alcohol and obesity as they relate to liver disease. This is directly aligned with te priorities of the NIH and contribute to their efforts to encourage and support growth of translational scientists, committed to bridging the gap between basic and clinical/community research and treatment. PUBLIC HEALTH RELEVANCE: The economic and social costs of obesity and problem drinking are formidable and both of these are major public health problems that can lead to end stage liver disease. The proposed research investigates the role of intestinal microbiome and its metabolites as a potential link in how alcohol promotes and accelerates liver damage in obese individuals. Study aims are directly aligned with the NIH strategic plan, with a focus on translational research and opportunities to bridge basic science with clinical and community-based research.