PROJECT SUMMARY In the United States, colorectal cancer (CRC) mortality is markedly higher in African-American (AA) patients than any other racial or ethnic group. Treatment options, socioeconomic status (SES), comorbidities, and tumor characteristics contribute to survival disparities. Tumor characteristics focused on metabolism and microbiology have been rarely studied in relation to CRC mortality and racial/ethnic group, and thus requires further investigation. Metabolites are substrates and products of metabolism required by tumor cells for gene regulation, growth, and immune responses. They can modulate the metabolism and efficacy of chemotherapeutic drugs, therefore are linked to CRC treatment response and mortality rates. Differences in lifestyle factors (i.e., diet, physical activity), social determinants of health, and environmental exposures exist between racial/ethnic groups and affect metabolite production in CRC. In addition, the colon microbiome is a major modulator of metabolites and has been implicated in CRC. Given that metabolites are susceptible to modulation by lifestyle factors that differ between racial/ethnic groups, and tumor characteristics contribute to disparities in CRC mortality, we hypothesize that differences in CRC metabolites and microbiome between racial/ethnic groups account for disparities in clinical outcomes. Our objective is to address the lack of knowledge in this area by performing a discovery metabolomics approach to identify salient features of CRC metabolism inherent to race. We will also examine how the microbiome and metabolome change during the continuum of CRC care, associate with treatment responses, and are affected by SES. In specific aim 1, we will use untargeted metabolomics, metabolic pathway analysis, and molecular networking approaches to identify CRC tumor tissue metabolites specific to AAs, with stratification by sex, stage, and SES. This will generate the first ever metabolic signatures of CRC in AAs and will include exogenous metabolites derived from environmental exposures and the microbiome. For specific aim 2, we will identify the impact of surgery and chemotherapeutic treatments on the CRC stool microbiome. We will identify microbiota unique to AA patients and determine if factors related to SES including diet, physical activity, and body mass index may confound this association. We will ultimately determine how the response to treatment differs between AA and non-Hispanic white patients to better understand mechanisms of increased mortality in AAs with CRC. The immediate outcomes of this proposal are: 1) generation of the first metabolic signature of CRC by race, 2) identification of novel microbial and environmental metabolites of CRC by race, 3) the first characterization of microbiome and metabolite changes at crucial time points along the continuum of CRC care (e.g., diagnosis, surgery, chemotherapy) and associations to SES. This data will generate new hypotheses regarding tumor...