The trillions of bacteria that inhabit the gastrointestinal tract, known collectively as the gut microbiome, are essential for both health and the normal functioning of the intestine. A growing literature now suggests that disruptive changes to this community are strongly associated with the development of colorectal cancer. However, it is unclear whether these disruptive changes directly contribute to disease or if they are just a consequence of colorectal cancer (CRC). Furthermore, the gut microbiome has not been explored as a potential non-invasive screen for CRC. Our hypothesis is that abnormalities in the gut microbiome can be utilized as a biomarker for detection of CRC at its earliest stages. Additionally, we postulate that these changes potentiate tumor development in the colon. To test these hypotheses, we first characterized the gut microbiome associated with human patients from three clinical groups representing three essential stages in CRC development: healthy, adenoma, and carcinoma. We demonstrated that a specific set of bacterial populations are associated with adenomas and carcinomas. The abundance of these bacterial populations was used to improve our ability to differentiate between healthy and diseased subjects and presents a viable screening tool for the earliest stages of CRC development. Next, we demonstrated using a mouse model of inflammation-driven colon cancer that there are dramatic, continual alterations in the gut microbiome during the development of tumors. By colonizing germ-free mice with the gut microbiome from tumor-bearing mice, we determined that these changes are directly responsible for increased tumor development. Using an antibiotic cocktail, we were able to demonstrate that manipulation of this microbial community can dramatically reduce tumor burden in mice. By varying the composition of this antibiotic cocktail we generated a broad spectrum of microbial communities with varying carcinogenic capacities. This method of manipulating the gut microbiome allowed us to identify potentially protective and carcinogenic bacterial populations for further mechanistic studies. Our results demonstrate that changes to the gut microbiome can serve as an effective non-invasive screen for the early detection of colorectal cancer and that interventions that target these changes may be an effective strategy for preventing the development of colorectal cancer.PhDMicrobiology & ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107125/1/zackular_1.pd
