The Role of Oral Genotoxic Bacteria in the Development of Colon Cancer
Abstract
Scientific Objective and Rationale Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. An approximately 150,000 new cases are diagnosed annually and about 6 people die every hour by CRC. Cleary, therapeutic options are needed, particularly for the prevention and early detection of CRC. It is widely accepted that bacteria reside in the gut play essential roles in the pathogenesis of CRC. Recent studies demonstrated that bacteria accumulated in CRC patients are not common gut bacteria. Instead, bacteria, which are known as oral residents, accumulated in the gut of CRC patients. Also, a recent large cohort study showed that patients with oral diseases are at high risk for CRC. Thus, it is conceivable that oral inflammation results in the abnormal gut colonization by oral bacteria. The gut colonization by oral bacteria may contribute to the development of CRC. To address this hypothesis, we used animal models of CRC in combination with an animal oral inflammation model and discovered that oral inflammation promotes CRC development. We also found that oral inflammation results in an expansion of oral bacteria that causes DNA damages to the host cells (a hallmark of tumor-promoting bacteria). Of note, amassed oral DNA-damaging bacteria can translocate to the gut. Consistent with our mouse experiments, human CRC patients with oral inflammation showed the colonization of DNA-damaging bacteria in both oral cavity (saliva) and the gut (stool). In this proposal, we will aim to elucidate more detailed mechanisms by which oral DNA-damaging bacteria contribute to CRC development. In Aim1, we will examine the mechanism of how oral bacteria compete with gut resident bacteria and stably colonize the gut. In Aim2, we will identify partner bacteria that help the gut colonization by oral bacteria. In Aim3, we will examine the impact of human CRC-derived oral DNA-damaging bacteria on the development of CRC in mice. Ultimate applicability of the research and PI’s career goals in cancer research: Although the majority of mechanistic studies on CRC examine the pathological events occurring within the gut (“intra-intestinal” pathology), this project will focus on the involvement of “extra-intestinal” pathology such as oral diseases in the CRC development. Thus, this approach will lead to the generation of novel paradigm regarding CRC development and provide new insight into the prevention and early detection of CRC. Our preliminary data show the significant positive correlation between the burden of oral and gut genotoxic bacteria in CRC patients. Thus, in the foreseeable future, it is likely that (a) the early detection of genotoxic bacteria in the mouth (e.g., saliva) can be utilized as a non-invasive method for identifying individuals at increased risk for CRC. Moreover, (b) optimal oral hygiene (reducing genotoxic bacteria in the oral cavity) can also reduce the risk of CRC. As mentioned above, since CRC is the one of the most common cancers, the completion of this project will benefit not only for both deployed and non-deployed personnel, their dependents, Veterans, and other military beneficiaries (i.e., family members of retirees), but also for the non-military general population in the United States. My long-term goals are to link integrate basic scientific discoveries from multidisciplinary fields to early diagnosis and/or prevention of gastrointestinal diseases such as CRC. Under the mentorship from well-recognized scientists (Prof. Eric Fearon and Dr. Nobuhiko Kamada) in multidisciplinary fields including cancer biology, microbiology, and immunology, I am going to learn how to efficiently and properly connect the dots (preliminary findings) for developing future CRC intervention. I firmly believe that this US Department of Defense Career Development Award program will facilitate my career development and prepare me to make valuable scientific contributions that will result in novel early di
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010547
Entities
People
- Sho Kitamoto
Organizations
- United States Army
- University of Michigan