Evidence from animal and human studies suggests that intestinal bacteria may contribute to the pathogenesis of colorectal cancer (CRC), a major leading cause of cancer mortality in the United States. Potential mechanisms for the link between gut microbiota and CRC is through diet and inflammation. We propose a model whereby intestinal bacteria play a prominent role in the etiology of CRC through diet, inflammation and metabolism of xenobiotics. We propose to test the hypothesis that adherent bacteria (adherent) are linked with elevated risk of colorectal adenoma and that these bacteria modulate the association between diet, inflammation and colorectal adenomas. We propose that distinct patterns of commensal colonization or presence/absence of specific bacteria species will correlate with adenoma risk.
The specific aims are to 1) determine whether the adherent (mucosa-associated) bacteria community composition and structure (profiles) differ between subjects with adenomas and those without adenomas, 2) evaluate the associations of adherent bacteria profiles and systemic or local markers of inflammation (IL-12, IL-23, IL-4, IL-17, INF(, IL-8, IL-10 and TGF-(;macrophages, NK cells, T cells- CD4+ and CD8+;protein expression of NF-(B (p65) and STAT3) among subjects with and without adenomas, 3) assess the association between adherent bacteria profiles and diet/lifestyle such as fiber, meat intake, obesity (body mass index (BMI), waist-hip-ratio), and NSAID use in relation to colorectal adenomas. Evaluation of the diversity of gut bacteria in relation to disease in humans is limited in part, by the difficulty growing these organisms in culture. Recent advances in molecular methods have made it possible to assess the role of intestinal microbiota in diseases such as colon cancer. To test our hypothesis, we propose to use molecular-phylogenetic methods based on the highly conserved 16S bacteria rRNA gene to assess the contribution of intestinal microbiota to the development of colorectal adenomas. These methods include PCR amplification of the 16S rRNA gene, terminal restriction fragment length polymorphism (TRFLP), generation of bacteria clone libraries and sequencing. This study will use colonic biopsy specimens obtained from 600 patients (300 cases and 300 controls) and risk factor data such as diet and inflammation from a funded ongoing study of colorectal adenomas, the Diet and Health Study (NCI R01 CA 44684). Limited information exists on the role of gut bacteria in the development of adenomas. This study will provide critical insights on the composition and diversity of the microbiota and their association with colorectal adenomas and known risk factors. The findings from this study could lead to the development of strategies to manipulate the intestinal microbiota to prevent colorectal adenomas and cancer as well as identify individuals at high risk.

Public Health Relevance

The goal of this study is to evaluate the composition and structure of bacteria communities that reside on the lining of the large bowel, in relation to colorectal adenomas and known risk factors such as diet and inflammation. The findings from this study could help identify individuals at high risk of adenomas as well as enhance the development of strategies to manipulate the intestinal microbiota to prevent colorectal adenomas and cancer

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136887-04
Application #
8223248
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Reid, Britt C
Project Start
2009-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$297,887
Indirect Cost
$96,612
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
Santoro, M Agostina; Andres, Sarah F; Galanko, Joseph A et al. (2014) Reduced insulin-like growth factor I receptor and altered insulin receptor isoform mRNAs in normal mucosa predict colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 23:2093-100
Nugent, Julia L; McCoy, Amber N; Addamo, Cassandra J et al. (2014) Altered tissue metabolites correlate with microbial dysbiosis in colorectal adenomas. J Proteome Res 13:1921-9
Dulal, Santosh; Keku, Temitope O (2014) Gut microbiome and colorectal adenomas. Cancer J 20:225-31
Kang, Melissa; Edmundson, Patrick; Araujo-Perez, Felix et al. (2013) Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas. BMC Cancer 13:91
Keku, Temitope O; McCoy, Amber N; Azcarate-Peril, Andrea M (2013) Fusobacterium spp. and colorectal cancer: cause or consequence? Trends Microbiol 21:506-8
McCoy, Amber N; Araujo-Perez, Felix; Azcarate-Peril, Andrea et al. (2013) Fusobacterium is associated with colorectal adenomas. PLoS One 8:e53653
Shen, Xiang Jun; Rawls, John F; Randall, Thomas et al. (2010) Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes 1:138-47