Role of Bacteria in Colitis-Associated Colon Cancer

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DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most common form of cancer in men and women in the United States and the second leading cause of cancer-related death. Chronic intestinal inflammation has been identified as an important risk factor for the development of colorectal cancer and consequently individuals suffering from inflammatory bowel diseases (IBD) are at high risk. The role of the microbiota in the development of CRC has not been clearly defined. To date, research has largely focused on the role of innate sensors and associated host responses in the development of colorectal cancer. While studying innate sensors in the host is informative, establishing the role of the microbiome in the development of CRC will require a more direct approach that perturbs the microbial community and measures the consequences for both microbes and host. The objective of the present application is to determine how selective group of commensal bacteria promote development of CRC in Il10-/- mice. We hypothesize that specific bacterial entities promote the development of CRC through expression of microbial genotoxic products, resulting in enhanced host genomic instability and formation of neoplastic lesions. We have formulated this hypothesis based on our preliminary findings showing that specific bacterial taxa expand in tumor-bearing mice, whereas these were not detected in tumor-free mice. Furthermore, although colitis severity at the histological and molecular level is similar between Escherichia coli NC101 (E. coli) and Enterococcus faecalis (E. faecalis) monoassociated Il10-/- mice, tumor numbers were strongly enhanced in the E. coli NC101 group compared to E. faecalis. Finally, we identified the pks genomic island in E.coli NC-101, which encodes a set of polyketide-synthetase genes that have been shown to produce a genotoxic product, colibactin. This genomic island induces cell cycle arrest and histone2AX serine 139 phosphorylation (?H2AX). We plan to test our central hypothesis and fulfill the overall objective of this application with the following specific aims. 1) Identify the impact of inflammation on microbial community structure and function and 2) Determine the mechanisms of E.coli NC101- mediated development of colorectal cancer. At the completion of these studies, we expect to have identified the microbial communities associated with the development of CRC and determined microbial gene products that enhanced susceptibility to this pathology. Since CRC is the second leading cause of cancer death in the U.S. and is a major complication of long standing ulcerative colitis and Crohn's colitis, our findings will be important because they will identify novel pathways that can be targeted to prevent/treat inflammation-induced CRC. In addition, the basic knowledge gained from metagenomic studies is expected to move the general field of CRC research forward.