PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) related hepatocellular carcinoma (HCC) is a growing public health problem, and the burden is disproportionately carried by racial and ethnic minority populations. There is an urgent need to gain a better understanding of the underlying biological mechanisms responsible for why some people with NAFLD are more prone to developing HCC, and the causes for disparities in NAFLD related HCC. Experimental data show that the composition and products of the gut microbiome, many of which have established relationship with obesity and/or a high fat diet, are carcinogenic to the liver. Our preliminary data suggest that there are ethnic differences in microbial composition in a cirrhotic population at high risk for HCC, and that certain metabolites can differentiate cirrhotics with HCC from those without HCC. In the proposed case-control study, we will examine the contributions of race/ethnicity, fecal microbiome, fecal metabolome, and host factors (e.g. specific dietary factors and markers of body and liver fat composition) to NAFLD related HCC. Importantly, we have constructed a multi-disciplinary and collaborative research team with the required scientific expertise in microbiology, informatics, statistics, cancer epidemiology, and NAFLD biology; and the right clinical partnerships to succeed with the targeted patient recruitment required to address the specific aims. We will recruit 225 study participants with NAFLD and with HCC (N=75) and without HCC (N=150), over 1.25 months. Participants will be recruited from two neighboring clinical centers that care for a large proportion of Hispanics and African Americans in Los Angeles, two groups that are at the highest risk for HCC and stand to gain the most from the proposed research. Study participants will provide fecal, urine, and blood specimens; epidemiological data; clinical data; and nutritional data. Over the last 6 months of the project, we will perform laboratory testing and statistical modeling. We will use a combination of mixed effects logistic regression models, and integrative analytic approaches, to understand the contribution of our laboratory, epidemiological, and clinical data to NAFLD-HCC. The information gained from this study may open prospects for therapeutic interventions that could delay or avert HCC in these vulnerable at-risk populations.