The Gut Microbiome, Lifestyle, and Colorectal Neoplasia

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PROJECT SUMMARY / ABSTRACT Colorectal adenoma is the precursor for the vast majority of colorectal cancers (CRCs). We and others have shown that lifestyle factors play an important role in the colorectal adenoma-carcinoma sequence. Western diet and obesity have been associated with increased risk of colorectal neoplasia, whereas physical activity and regular use of aspirin has been associated with lower risk. Emerging evidence indicates that gut microbes are pivotal in integrating environmental cues with host physiology and metabolism, and disturbances in the gut microbiota have been linked to colorectal neoplasia and other chronic conditions. Although a role for microbiota in carcinogenesis is gaining acceptance, available human data are largely cross-sectional and do not lend themselves to interrogation of whether microbes are intrinsically oncogenic (i.e. “drivers”) or a consequence of tumorigenesis (i.e. “passengers”). Thus, there is a high unmet need to conduct a large, prospective study to examine the network of interactions between the gut microbiota and their associated metabolites, lifestyle factors, and colorectal neoplasia within diverse populations. We propose to characterize the gut microbiota leveraging stool samples currently being collected from women and men enrolled in the ongoing Nurses’ Health Study (NHS)II (n=25,000) and the Southern Community Cohort Study (SCCS) (n=8,500). Participants have been followed since 1989 (NHSII) and 2002 (SCCS) and have provided validated, updated assessments of diet, lifestyle, medication use, and diagnoses of chronic diseases with high follow-up. After stool collection, we will continue to follow these cohorts and document the incidence of adenoma. We will test the hypothesis that lifestyle factors linked with CRC are associated with a higher abundance of immunomodulatory and tumor- permissive gut microbes and a depletion of microbes that protect against tumorigenesis. In turn, these gut microbiome patterns and their associated metabolites will be associated with risk of adenoma on follow-up colonoscopy. To provide additional evidence of causality, we will examine if the gut microbial features in baseline stool samples linked to adenoma will be stable in stool samples collected after adenoma development and is associated with gut microbial features and expression of human host genes and pathways in adenoma tissue. By leveraging ongoing, already funded stool collections within a cohort of predominantly white women (NHS II) and a cohort of women and men with a high proportion of African-Americans (65%) and the socioeconomically disadvantaged (SCCS), our proposal is highly cost-efficient and will offer rigorous and reproducible results relevant to diverse populations. Our established multidisciplinary team proposes the next critical step in understanding the intricate relationship between the gut microbiota, lifestyle factors and colorectal neoplasia in diverse populations. This investigation will illuminate significant insights into the etiopathogenesis of CRC and launch novel research into CRC prevention through gut microbiota-targeted diagnostics and therapeutics.