Identifying Gut Microbial Inducers of Biological Aging in the Colon

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA24-029. Colorectal cancer (CRC) can be prevented by identifying and removing precancerous colorectal adenomas during colonoscopy, establishing the value of identifying precancer states in the colon. Emerging data implicate gut microbes and metabolites in the health-to-precancer-to-CRC progression, but the scope of microbiome-inducible precancer states and mediators thereof are not well understood. Our preliminary data, generated in the experiments we had proposed in Aim 3 of Project 3, demonstrate a causative link between the gut microbiome and senescence (an age-related precancer state) in seemingly healthy non-tumor colonic tissues, suggesting that the microbiome can induce precancer states. Our overarching hypothesis is that the microbiome-senescence connection represents the ‘tip of the iceberg’ i.e. that much remains to be discovered. We hypothesize that increased biological age and precancerous states are more prevalent in individuals with CRC-associated microbes, and among these states, subtypes are driven by specific CRC-associated bacteria and metabolites. To test these hypotheses, we will profile a unique collection of 145 paired stool and non-tumor colonic tissue samples collected by the Early Detection Research Network (EDRN), led by new collaborator Dr. Robert Bresalier, an expert in GI cancer biomarkers and early GI cancer detection. We will calculate biological age of the colon (using epigenetic markers in epithelial cells) and associated gene expression (with a central focus on senescence-associated gene expression signatures). We will identify putative microbial drivers of increased biological age and precancer states (through metagenomic sequencing and mass spectrometry, focusing on CRC-associated bacteria and butyrate [previously linked to senescence]). The proposed research will enhance the impact of Project 3 of our parent U54 TBEL Award, which investigates the microbiome in early precancerous colorectal lesions. Identification of intervenable host-microbiome interactions driving precancer states could serve as the basis for biology-backed precision prevention of adenomas and ultimately CRC.