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Grant Details

Grant Number: 5R01CA136887-04 Interpret this number
Primary Investigator: Keku, Temitope
Organization: Univ Of North Carolina Chapel Hill
Project Title: Intestinal Microbiota, Diet and Risk of Colorectal Adenomas
Fiscal Year: 2012
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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

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Publications

Gut microbiome and colorectal adenomas.
Authors: Dulal S, Keku TO
Source: Cancer J, 2014 May-Jun;20(3), p. 225-31.
PMID: 24855012
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Altered tissue metabolites correlate with microbial dysbiosis in colorectal adenomas.
Authors: Nugent JL, McCoy AN, Addamo CJ, Jia W, Sandler RS, Keku TO
Source: J Proteome Res, 2014 Apr 4;13(4), p. 1921-9.
EPub date: 2014 Mar 21.
PMID: 24601673
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Plasma insulin, glucose, IGF-I, IGF-II, and IGFBP-3 and risk of recurrent colorectal adenomas.
Authors: Kang M, Peery AF, Locklear C, Galanko JA, Sandler RS, Keku TO
Source: J Gastroenterol Hepatol Res, 2013 Apr 14;2(4), p. 531-535.
PMID: 24533351
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Fusobacterium spp. and colorectal cancer: cause or consequence?
Authors: Keku TO, McCoy AN, Azcarate-Peril AM
Source: Trends Microbiol, 2013 Oct;21(10), p. 506-8.
EPub date: 2013 Sep 9.
PMID: 24029382
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Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas.
Authors: Kang M, Edmundson P, Araujo-Perez F, McCoy AN, Galanko J, Keku TO
Source: BMC Cancer, 2013 Feb 26;13, p. 91.
EPub date: 2013 Feb 26.
PMID: 23442743
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Fusobacterium is associated with colorectal adenomas.
Authors: McCoy AN, Araújo-Pérez F, Azcárate-Peril A, Yeh JJ, Sandler RS, Keku TO
Source: PLoS One, 2013;8(1), p. e53653.
EPub date: 2013 Jan 15.
PMID: 23335968
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Differences in microbial signatures between rectal mucosal biopsies and rectal swabs.
Authors: Araújo-Pérez F, McCoy AN, Okechukwu C, Carroll IM, Smith KM, Jeremiah K, Sandler RS, Asher GN, Keku TO
Source: Gut Microbes, 2012 Nov-Dec;3(6), p. 530-5.
EPub date: 2012 Oct 11.
PMID: 23060016
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Intestinal inflammation targets cancer-inducing activity of the microbiota.
Authors: Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB, Rhodes JM, Stintzi A, Simpson KW, Hansen JJ, Keku TO, Fodor AA, Jobin C
Source: Science, 2012 Oct 5;338(6103), p. 120-3.
EPub date: 2012 Aug 16.
PMID: 22903521
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Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans.
Authors: Sanapareddy N, Legge RM, Jovov B, McCoy A, Burcal L, Araujo-Perez F, Randall TA, Galanko J, Benson A, Sandler RS, Rawls JF, Abdo Z, Fodor AA, Keku TO
Source: ISME J, 2012 Oct;6(10), p. 1858-68.
EPub date: 2012 May 24.
PMID: 22622349
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Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas.
Authors: Shen XJ, Rawls JF, Randall T, Burcal L, Mpande CN, Jenkins N, Jovov B, Abdo Z, Sandler RS, Keku TO
Source: Gut Microbes, 2010 May-Jun;1(3), p. 138-47.
EPub date: 2010 May 13.
PMID: 20740058
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