Grant Details
Grant Number: |
1R01CA135379-01A1 Interpret this number |
Primary Investigator: |
O'Keefe, Stephen |
Organization: |
University Of Pittsburgh At Pittsburgh |
Project Title: |
Diet and Gastrointestinal Cancer Risk in African Americans and Rural Africans |
Fiscal Year: |
2009 |
Abstract
DESCRIPTION (provided by applicant): Geographical variations in cancer incidence can be attributed to environmental causes in general, and to diet, in particular. We are concerned that the reason why African Americans (AAs) have the highest incidence (c1:70,000 of the population) and death rate from colon cancer in the USA is due to dietary factors as native Africans, who consume a very different diet, hardly ever get the disease (<1: 100,000). Studies of ours in the 2 communities, supported by a wealth of experimental evidence, have suggested that the explanation may lie in the high dietary intake of red meat by AAs which increases microbiota populations of sulfur-reducing bacteria (SRBs), which produce cytotoxic and genotoxic hydrogen sulfide as a terminal product. This leads has been shown experimentally to lead to chronic mucosal inflammation and hyperproliferation, a state that increases cancer risk. In contrast, Africans are protected by high populations of methanogens which thrive in high carbohydrate, meat-free conditions and produce the non-toxic terminal product, methane. Our studies have also showed higher populations of secondary bile salt producing bacteria in AAs which are stimulated by high animal fat diets to produce carcinogenic secondary bile salts. In contrast, a high resistant starch diet stimulates mucosal-protective Lactobacillus species were, indeed, found to be more common in Africans. These observations have lead to our hypothesis that the risk of developing cancer of the colon is determined by the interaction between diet and resident microbiota, which influences the level of chronic inflammation and epithelial proliferation - and therefore cancer risk - in the colonic mucosa. In the present proposal, we plan to substantiate this hypothesis by studying 20 healthy middle aged subjects from the population of AAs in the Pittsburgh area and compare them to the same number of Africans before and 2 weeks after dietary switch. Specifically, we will change the AA diet to a high resistant starch, low meat diet and the African diet to a high red meat, low carbohydrate "westernized" diet. If our hypothesis is supported, we will expect to observe in the AA group an increase in methanogenesis and a reduction in colonic SRBs and hydrogen sulfide production, resulting in a reduction in mucosal inflammation and colonic epithelial proliferation, our primary biomarker of cancer risk. In contrast, we will expect to find increased SRB population growth in Africans with suppression of methanogenesis. Microarray analysis of mucosal gene expression, followed up by RT- PCR confirmation will be employed to identify novel pathways that may explain the mechanisms that link diet, bacterial metabolism, inflammation, and hyper-proliferation. Our findings will provide insight into how the diet can be manipulated to modify microbiota to promote mucosal health, and therefore reduce colon cancer risk, diminish health care costs related to diagnosis and treatment, and decrease the unacceptably high present morbidity and mortality from this disease in African Americans. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer death in the USA, and compared to other U.S. racial groups African-Americans have the highest incidence (70 per 100,000 of the population) and mortality. These statistics contrast sharply from those reported in native Africans where incidence rates are <1 per 100,000. Our previous studies have suggested the difference can be attributed to the relatively higher meat and animal fat intake by African Americans and the higher resistant starch intake by Africans.
Publications
Interactions between the environmental and human microbiota in the preservation of health and genesis of disease: symposium report.
Authors: Ramaboli M.
, Nesengani L.
, Katsidzira L.
, Haller D.
, Kinross J.
, Ocvirk S.
, O'Keefe S.J.D.
, African Microbiome International Consortium
.
Source: Current Opinion In Gastroenterology, 2022-03-01 00:00:00.0; 38(2), p. 146-155.
PMID: 35098936
Related Citations
Dietary fat, bile acid metabolism and colorectal cancer.
Authors: Ocvirk S.
, O'Keefe S.J.D.
.
Source: Seminars In Cancer Biology, 2020-10-16 00:00:00.0; , .
EPub date: 2020-10-16 00:00:00.0.
PMID: 33069873
Related Citations
Diet and the Human Gut Microbiome: An International Review.
Authors: Wilson A.S.
, Koller K.R.
, Ramaboli M.C.
, Nesengani L.T.
, Ocvirk S.
, Chen C.
, Flanagan C.A.
, Sapp F.R.
, Merritt Z.T.
, Bhatti F.
, et al.
.
Source: Digestive Diseases And Sciences, 2020 Mar; 65(3), p. 723-740.
PMID: 32060812
Related Citations
A prospective cohort analysis of gut microbial co-metabolism in Alaska Native and rural African people at high and low risk of colorectal cancer.
Authors: Ocvirk S.
, Wilson A.S.
, Posma J.M.
, Li J.V.
, Koller K.R.
, Day G.M.
, Flanagan C.A.
, Otto J.E.
, Sacco P.E.
, Sacco F.D.
, et al.
.
Source: The American Journal Of Clinical Nutrition, 2020-02-01 00:00:00.0; 111(2), p. 406-419.
PMID: 31851298
Related Citations
The association between dietary fibre deficiency and high-income lifestyle-associated diseases: Burkitt's hypothesis revisited.
Authors: O'Keefe S.J.
.
Source: The Lancet. Gastroenterology & Hepatology, 2019 Dec; 4(12), p. 984-996.
PMID: 31696832
Related Citations
International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis.
Authors: Scott A.J.
, Alexander J.L.
, Merrifield C.A.
, Cunningham D.
, Jobin C.
, Brown R.
, Alverdy J.
, O'Keefe S.J.
, Gaskins H.R.
, Teare J.
, et al.
.
Source: Gut, 2019 09; 68(9), p. 1624-1632.
EPub date: 2019-05-15 00:00:00.0.
PMID: 31092590
Related Citations
Plant-based foods and the microbiome in the preservation of health and prevention of disease.
Authors: O'Keefe S.J.D.
.
Source: The American Journal Of Clinical Nutrition, 2019-08-01 00:00:00.0; 110(2), p. 265-266.
PMID: 31268135
Related Citations
Switching to a fibre-rich and low-fat diet increases colonic folate contents among African Americans.
Authors: Chan Y.M.
, Aufreiter S.
, O'Keefe S.J.
, O'Connor D.L.
.
Source: Applied Physiology, Nutrition, And Metabolism = Physiologie Appliquee, Nutrition Et Metabolisme, 2019 Feb; 44(2), p. 127-132.
EPub date: 2018-07-11 00:00:00.0.
PMID: 29996064
Related Citations
Differences in Fecal Gut Microbiota, Short-Chain Fatty Acids and Bile Acids Link Colorectal Cancer Risk to Dietary Changes Associated with Urbanization Among Zimbabweans.
Authors: Katsidzira L.
, Ocvirk S.
, Wilson A.
, Li J.
, Mahachi C.B.
, Soni D.
, DeLany J.
, Nicholson J.K.
, Zoetendal E.G.
, O'Keefe S.J.D.
.
Source: Nutrition And Cancer, 2019; 71(8), p. 1313-1324.
EPub date: 2019-04-22 00:00:00.0.
PMID: 31007075
Related Citations
The Need to Reassess Dietary Fiber Requirements in Healthy and Critically Ill Patients.
Authors: O'Keefe S.J.D.
.
Source: Gastroenterology Clinics Of North America, 2018 Mar; 47(1), p. 219-229.
PMID: 29413014
Related Citations
Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet - Gut Microbiota Interactions.
Authors: Ocvirk S.
, O'Keefe S.J.
.
Source: Current Nutrition Reports, 2017 Dec; 6(4), p. 315-322.
EPub date: 2017-11-03 00:00:00.0.
PMID: 29430336
Related Citations
Diet, microorganisms and their metabolites, and colon cancer.
Authors: O'Keefe S.J.
.
Source: Nature Reviews. Gastroenterology & Hepatology, 2016 Dec; 13(12), p. 691-706.
EPub date: 2016-11-16 00:00:00.0.
PMID: 27848961
Related Citations
Diet, microbiota, and dysbiosis: a 'recipe' for colorectal cancer.
Authors: Vipperla K.
, O'Keefe S.J.
.
Source: Food & Function, 2016 Apr; 7(4), p. 1731-40.
PMID: 26840037
Related Citations
Fat, fibre and cancer risk in African Americans and rural Africans.
Authors: O'Keefe S.J.
, Li J.V.
, Lahti L.
, Ou J.
, Carbonero F.
, Mohammed K.
, Posma J.M.
, Kinross J.
, Wahl E.
, Ruder E.
, et al.
.
Source: Nature Communications, 2015-04-28 00:00:00.0; 6, p. 6342.
EPub date: 2015-04-28 00:00:00.0.
PMID: 25919227
Related Citations
The use of metabolomics in population-based research.
Authors: Su L.J.
, Fiehn O.
, Maruvada P.
, Moore S.C.
, O'Keefe S.J.
, Wishart D.S.
, Zanetti K.A.
.
Source: Advances In Nutrition (bethesda, Md.), 2014 Nov; 5(6), p. 785-8.
PMID: 25398741
Related Citations
Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans.
Authors: Ou J.
, Carbonero F.
, Zoetendal E.G.
, DeLany J.P.
, Wang M.
, Newton K.
, Gaskins H.R.
, O'Keefe S.J.
.
Source: The American Journal Of Clinical Nutrition, 2013 Jul; 98(1), p. 111-20.
PMID: 23719549
Related Citations
The microbiota and its metabolites in colonic mucosal health and cancer risk.
Authors: Vipperla K.
, O'Keefe S.J.
.
Source: Nutrition In Clinical Practice : Official Publication Of The American Society For Parenteral And Enteral Nutrition, 2012 Oct; 27(5), p. 624-35.
EPub date: 2012-08-06 00:00:00.0.
PMID: 22868282
Related Citations
Contributions of the microbial hydrogen economy to colonic homeostasis.
Authors: Carbonero F.
, Benefiel A.C.
, Gaskins H.R.
.
Source: Nature Reviews. Gastroenterology & Hepatology, 2012 Sep; 9(9), p. 504-18.
PMID: 22585131
Related Citations
Hydrogenotrophic microbiota distinguish native Africans from African and European Americans.
Authors: Nava G.M.
, Carbonero F.
, Ou J.
, Benefiel A.C.
, O'Keefe S.J.
, Gaskins H.R.
.
Source: Environmental Microbiology Reports, 2012 Jun; 4(3), p. 307-15.
PMID: 23760794
Related Citations
Association Between Low Colonic Short-chain Fatty Acids And High Bile Acids In High Colon Cancer Risk Populations
Authors: Ou,J.
, DeLany,J.P.
, Zhang,M.
, Sharma,S.
, O'Keefe,S.J.
.
Source: Nutrition And Cancer, 2012; 64(1), p. 34-40.
PMID: 22136517
Related Citations
Effect of fiber supplementation on the microbiota in critically ill patients.
Authors: O'Keefe S.J.
, Ou J.
, Delany J.P.
, Curry S.
, Zoetendal E.
, Gaskins H.R.
, Gunn S.
.
Source: World Journal Of Gastrointestinal Pathophysiology, 2011-12-15 00:00:00.0; 2(6), p. 138-45.
PMID: 22180847
Related Citations
Microbial DNA extraction from intestinal biopsies is improved by avoiding mechanical cell disruption.
Authors: Carbonero F.
, Nava G.M.
, Benefiel A.C.
, Greenberg E.
, Gaskins H.R.
.
Source: Journal Of Microbiological Methods, 2011 Oct; 87(1), p. 125-7.
PMID: 21820015
Related Citations
Products Of The Colonic Microbiota Mediate The Effects Of Diet On Colon Cancer Risk
Authors: O'Keefe,S.J.
, Ou,J.
, Aufreiter,S.
, O'Connor,D.
, Sharma,S.
, Sepulveda,J.
, Fukuwatari,T.
, Shibata,K.
, Mawhinney,T.
.
Source: The Journal Of Nutrition, 2009 Nov; 139(11), p. 2044-8.
PMID: 19741203
Related Citations