Colonic bile acid metabolism and responses in African Americans and non-Hispanic Whites - African Americans (AA) have among the highest colorectal cancer (CRC) incidence and mortality in the US. Environmental factors influenced by social factors, especially high fat diets, are known to increase CRC risk, but how these factors contribute to CRC risk differences is largely unknown. Bile acids (BA), produced in response to dietary fat, are converted by the gut microbiome to secondary BA, especially deoxycholic acid (DCA) and lithocholic acid (LCA), that can be carcinogenic in the human colon. Previous studies suggested differences in BA concentration and metabolism between AA and non-Hispanic Whites (NHW), but these preliminary findings require rigorous validation and further investigation. Colonic responses to BA could also differ between populations and modulate CRC risk. We developed an innovative experimental framework using colonic organoids to study host-environment interactions in colonic tumorigenesis that has been successfully applied to identify cancer-related, inter-ethnic responses to relevant environmental factors. In this proposal, we will study 3 aspects of BA metabolism to determine if there is a connection to CRC risk and observed differences in CRC between heterogenous groups. As an R21 proposal, the goal is to test the hypothesis of population differences in one or more of these factors that, if found, would then be studied through mechanistically-focused investigations in the future. Specifically, we will: 1) Compare serum BA composition in self-identified AAs and NHWs leveraging a prospective study called COMPASS, 2) perform microbiome profiling in tissue and stool from AAs and NHWs with specific attention to pathways involved in BA conversion, and 3) test for differences in transcriptional and cellular responses to DCA and/or LCA in colonic organoids from individuals of African and European descent. Importantly, we will control for relevant covariates such as age, sex, diet and social factors. If one or more of these hypotheses is confirmed, our results will provide critical preliminary data to support a future proposal to dissect underlying mechanisms of observed differences in BA metabolism and colonic responses between populations and how these could impact CRC risk. This study has potential for high impact to elucidate the interrelated roles of diet, BA metabolism and colonic responses in CRC that could translate into future “precision prevention” trials and new biomarkers of CRC risk especially in AAs who experience unequal burden of disease.
