Intestinal Microbiota, Diet and Risk of Colorectal Adenomas
Principal Investigator: Temitope O Keku
Affiliation: University of North Carolina
Abstract: DESCRIPTION (provided by applicant): 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
Funding Period: 2009-05-01 - 2014-02-28
more information: NIH RePORT
- Gut microbiome and colorectal adenomasSantosh Dulal
From the Center for Gastrointestinal Biology and Disease, and Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, and School of Medicine, University of North Carolina at Chapel Hill, NC
Cancer J 20:225-31. 2014..Understanding the microbiome may provide promising new directions towards novel diagnostic tools, biomarkers, and therapeutic interventions for CRC. ..
- Altered tissue metabolites correlate with microbial dysbiosis in colorectal adenomasJulia L Nugent
School of Medicine, University of North Carolina at Chapel Hill, 321 South Columbia Street, Chapel Hill, North Carolina 27599, United States
J Proteome Res 13:1921-9. 2014..These findings suggest that metabolic products of bacteria may be responsible for the development of colorectal adenomas and CRC. ..
- Fusobacterium spp. and colorectal cancer: cause or consequence?Temitope O Keku
Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Electronic address
Trends Microbiol 21:506-8. 2013..Recent studies have implicated overabundance of Fusobacterium in association with colorectal adenomas and cancer. Two articles published in Cell Host & Microbe provide insights into the Fusobacterium-CRC relationship. ..
- Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomasMelissa Kang
Center for Gastrointestinal Biology and Disease, University of North Carolina, 103 Mason Farm Road, 7340 Medical Biomolecular Research Building, CB 7032, 27599 7032, Chapel Hill, NC 27599, USA
BMC Cancer 13:91. 2013..Given the evidence linking inflammation and colorectal cancer, we sought to determine if plasma endotoxin concentrations are associated with indicators of systemic or local inflammation and colorectal adenomas...
- Fusobacterium is associated with colorectal adenomasAmber N McCoy
Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
PLoS ONE 8:e53653. 2013..33, p = 0.06 while it was 0.44, p = 0.01 for Fusobacterium and IL-10. These results support a link between the abundance of Fusobacterium in colonic mucosa and adenomas and suggest a possible role for mucosal inflammation in this process...
- Differences in microbial signatures between rectal mucosal biopsies and rectal swabsFelix Araujo-Perez
Division of Gastroenterology and Hepatology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Gut Microbes 3:530-5. 2012..0001) and Eubacteria (p = 0.0003) in swab samples compared with biopsies. Our findings suggest that rectal swabs and rectal mucosal samples provide different views of the microbiota in the large intestine...
- Intestinal inflammation targets cancer-inducing activity of the microbiotaJanelle C Arthur
Department of Medicine, Pharmacology and Immunology Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Science 338:120-3. 2012..This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities...
- Increased rectal microbial richness is associated with the presence of colorectal adenomas in humansNina Sanapareddy
Department of Bioinformatics and Genomics, University of North Carolina, Charlotte, NC, USA
ISME J 6:1858-68. 2012..This suggests that sequence analysis of the microbiota could be used to identify patients at risk for developing adenomas...
- Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomasXiang Jun Shen
Center for Gastrointestinal Biology and Disease University of North Carolina at Chapel Hill, NC, USA
Gut Microbes 1:138-47. 2010..Extension of these findings could lead to strategies to manipulate the microbiota to prevent colorectal adenomas and cancer as well as to identify individuals at high risk...