Colorectal Cancer and Racial Disparity: Gut Microbiome as a Potential Regulator

Introduction: Although the incidence and mortality from colorectal cancer (CRC) is greater in African Americans (AAs) than Caucasian Americans (CAs), little is known about the underlying biochemical mechanisms for this racial disparity. We have previously reported that patients with >3 adenomas exhibit a marked increase in CSCs in the colon. Although the regulatory mechanisms for this increase in CSCs are poorly understood, we have suggested a role for secondary bile acids in the intestine, specifically deoxycholic (DCA) and lithocolic (LCA) acids, bio-transformed by gut microbiota, in regulating the process. We hypothesize that the differences in the gut microbiome between AAs and CAs, resulting in changes in intestinal secondary bile acids, are responsible for racial disparity in CRC. Methods: Colonic effluent (washings collected during colonoscopy) from patients aged 40-80 undergoing outpatient colonoscopy were collected and analyzed for DCA, LCA levels(mass spectrometry) microbiome, CD44, CD166 and other stem cell markers( qRT-PCR). Results: Levels of DCA and LCA in colonic effluent from AAS were found to be higher than in CAs. Similarly, AAs, who exhibited a significantly higher number of adenomas in the colon than CAs, also showed an increase in Enterobacteria and reduction in Bifidobacteria, known to be proinflammatory and anti-inflammatory respectively. These changes in AAs were associated with increased CSCs (specifically CD44+CD1166- phenotype), activation of EGFR, increased expression of B-catenin, CCAT2 and HOTAIR and also dysregulation of the oncomiR miR21 and the tumor suppressor miR 145 (both of which are regulated by CCAT2) in the colonic mucosa. Interestingly, we also found both DCA and LCA to induce stemness in normal human colonic epithelial cells HCoEpiC, as evidenced by increased colonosphere formation, induction of several CSC markers, and activation of EGFR and increased expression of MMP2 and c-Myc and also Muscarinic Receptor 3(M3R). Conclusion: Our observations, not only suggest that alterations in specific gut micro-organisms result in increase in secondary bile acids in AAs and hence, provide a basis for racial disparity in colorectal cancer, but also suggest the possible mechanisms involved in induction of stemness in colonic epithelial cells, hence opening up fronts for future research.