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.

Public Health Relevance

Colorectal cancer is the third leading cause of cancer death in men and women in the United States. An average of about 6 people die every hour of colorectal cancer and approximately 150,000 new cases are diagnosed annually. Colitis-associated colorectal cancer (CAC) represents a major form of cancer and a serious medical complication for patients suffering from inflammatory bowel disease (IBD). The economic burden for inflammatory bowel diseases (IBD) treatment is significant with annual costs in the United States estimated to be $6.3 billion. Despite this health and socio-economical burden, limited therapeutic options are currently available to prevent/treat colorectal cancer. This project investigates the role of bacteria on development of CAC through the use of metagenomic, gnotobiotic and microbial genetic approaches. Our hypothesis is that specific bacterial entities promote development of CRC through expression of microbial genotoxic products, resulting in enhanced host genomic instability and formation of neoplastic lesions. This project will lead to the generation of novel paradigm regarding CAC and potentially identify new cancer biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK073338-05A1
Application #
8308078
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Grey, Michael J
Project Start
2007-04-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$367,921
Indirect Cost
$118,662
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Tomkovich, Sarah; Jobin, Christian (2016) Microbiota and host immune responses: a love-hate relationship. Immunology 147:1-10
Mottawea, Walid; Chiang, Cheng-Kang; Mühlbauer, Marcus et al. (2016) Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease. Nat Commun 7:13419
Bruner, S D; Jobin, C (2016) Intestinal Microbiota in Inflammatory Bowel Disease and Carcinogenesis: Implication for Therapeutics. Clin Pharmacol Ther 99:585-7
Yang, Ye; Jobin, Christian (2015) Professor Arlette Darfeuille-Michaud: the discovery of adherent-invasive Escherichia coli. J Crohns Colitis 9:373-5
Thomas, Ryan M; Jobin, Christian (2015) The Microbiome and Cancer: Is the 'Oncobiome' Mirage Real? Trends Cancer 1:24-35
Ohland, Christina L; Jobin, Christian (2015) Microbial activities and intestinal homeostasis: A delicate balance between health and disease. Cell Mol Gastroenterol Hepatol 1:28-40
Neumann, Philipp-Alexander; Koch, Stefan; Hilgarth, Roland S et al. (2014) Gut commensal bacteria and regional Wnt gene expression in the proximal versus distal colon. Am J Pathol 184:592-9
Sun, Xiaolun; Jobin, Christian (2014) Nucleotide-binding oligomerization domain-containing protein 2 controls host response to Campylobacter jejuni in Il10-/- mice. J Infect Dis 210:1145-54
Perez-Chanona, Ernesto; Jobin, Christian (2014) From promotion to management: the wide impact of bacteria on cancer and its treatment. Bioessays 36:658-64
Arthur, Janelle C; Gharaibeh, Raad Z; Mühlbauer, Marcus et al. (2014) Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer. Nat Commun 5:4724

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