The intestinal microbiome contribution to colon cancer and senescence

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Project Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Colorectal cancer (CRC) is correlated with age (unmodifiable risk factor) and has been linked to the gut microbiome (potentially modifiable risk factor). Our preliminary data suggest that the microbiome may drive age-related changes in the colon such as senescence. We therefore hypothesize that age-related changes in the intestinal microbiome functionally alter colon homeostasis and its microenvironment, thereby promoting the formation of neoplastic lesions. We further hypothesize that increased cellular senescence in the colon stroma functionally connects the microbiome with tumor formation. In Aim 1, we will colonize tumor-prone gnotobiotic Fabp1-Cre+ mT/mG+ Pik3ca*+ ApcMin/+ mice with microbiomes from young and old human donors to determine whether “geriatric” microbiomes promote the formation of colonic tumors. In Aim 2, we will colonize germ-free wild-type mice with microbiomes from young and old human donors to determine whether “geriatric” microbiomes induce cellular senescence in the colonic stroma. Our studies will lay the foundations to develop microbiome-based strategies (concretely manifesting as dietary modifications or transplant-based interventions) for colorectal cancer prevention and improvement of health span.