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Grant Details

Grant Number: 5U01CA261961-02 Interpret this number
Primary Investigator: Song, Mingyang
Organization: Harvard School Of Public Health
Project Title: The Gut Microbiome, Lifestyle, and Colorectal Neoplasia
Fiscal Year: 2023


Abstract

PROJECT SUMMARY / ABSTRACT Colorectal adenoma is the precursor for the vast majority of colorectal cancers (CRCs). We and others have shown that lifestyle factors play an important role in the colorectal adenoma-carcinoma sequence. Western diet and obesity have been associated with increased risk of colorectal neoplasia, whereas physical activity and regular use of aspirin has been associated with lower risk. Emerging evidence indicates that gut microbes are pivotal in integrating environmental cues with host physiology and metabolism, and disturbances in the gut microbiota have been linked to colorectal neoplasia and other chronic conditions. Although a role for microbiota in carcinogenesis is gaining acceptance, available human data are largely cross-sectional and do not lend themselves to interrogation of whether microbes are intrinsically oncogenic (i.e. “drivers”) or a consequence of tumorigenesis (i.e. “passengers”). Thus, there is a high unmet need to conduct a large, prospective study to examine the network of interactions between the gut microbiota and their associated metabolites, lifestyle factors, and colorectal neoplasia within diverse populations. We propose to characterize the gut microbiota leveraging stool samples currently being collected from women and men enrolled in the ongoing Nurses’ Health Study (NHS)II (n=25,000) and the Southern Community Cohort Study (SCCS) (n=8,500). Participants have been followed since 1989 (NHSII) and 2002 (SCCS) and have provided validated, updated assessments of diet, lifestyle, medication use, and diagnoses of chronic diseases with high follow-up. After stool collection, we will continue to follow these cohorts and document the incidence of adenoma. We will test the hypothesis that lifestyle factors linked with CRC are associated with a higher abundance of immunomodulatory and tumor- permissive gut microbes and a depletion of microbes that protect against tumorigenesis. In turn, these gut microbiome patterns and their associated metabolites will be associated with risk of adenoma on follow-up colonoscopy. To provide additional evidence of causality, we will examine if the gut microbial features in baseline stool samples linked to adenoma will be stable in stool samples collected after adenoma development and is associated with gut microbial features and expression of human host genes and pathways in adenoma tissue. By leveraging ongoing, already funded stool collections within a cohort of predominantly white women (NHS II) and a cohort of women and men with a high proportion of African-Americans (65%) and the socioeconomically disadvantaged (SCCS), our proposal is highly cost-efficient and will offer rigorous and reproducible results relevant to diverse populations. Our established multidisciplinary team proposes the next critical step in understanding the intricate relationship between the gut microbiota, lifestyle factors and colorectal neoplasia in diverse populations. This investigation will illuminate significant insights into the etiopathogenesis of CRC and launch novel research into CRC prevention through gut microbiota-targeted diagnostics and therapeutics.



Publications

Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.
Authors: Georgeson P. , Steinfelder R.S. , Harrison T.A. , Pope B.J. , Zaidi S.H. , Qu C. , Lin Y. , Joo J.E. , Mahmood K. , Clendenning M. , et al. .
Source: medRxiv : the preprint server for health sciences, 2024-01-30; , .
EPub date: 2024-01-30.
PMID: 37090539
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Enrichment of Bacteroides fragilis and enterotoxigenic Bacteroides fragilis in CpG island methylator phenotype-high colorectal carcinoma.
Authors: Takashima Y. , Kawamura H. , Okadome K. , Ugai S. , Haruki K. , Arima K. , Mima K. , Akimoto N. , Nowak J.A. , Giannakis M. , et al. .
Source: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2024-01-22; , .
EPub date: 2024-01-22.
PMID: 38266708
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Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts.
Authors: Shi S. , Wang K. , Ugai T. , Giannakis M. , Cazaubiel J. , Chan A.T. , Giovannucci E.L. , Nowak J.A. , Meyerhardt J.A. , Ogino S. , et al. .
Source: British journal of cancer, 2023 Nov; 129(11), p. 1793-1800.
EPub date: 2023-09-30.
PMID: 37775523
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Inflammatory Bowel Disease and Risk of Colorectal Polyps: A Nationwide Population-Based Cohort Study From Sweden.
Authors: Axelrad J.E. , Olén O. , Söderling J. , Roelstraete B. , Khalili H. , Song M. , Faye A. , Eberhardson M. , Halfvarson J. , Ludvigsson J.F. .
Source: Journal of Crohn's & colitis, 2023-10-20; 17(9), p. 1395-1409.
PMID: 36994851
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Flavonoid intake and survival after diagnosis of colorectal cancer: a prospective study in 2 US cohorts.
Authors: Shi S. , Wang K. , Zhong R. , Cassidy A. , Rimm E.B. , Nimptsch K. , Wu K. , Chan A.T. , Giovannucci E.L. , Ogino S. , et al. .
Source: The American journal of clinical nutrition, 2023 Jun; 117(6), p. 1121-1129.
EPub date: 2023-04-01.
PMID: 37011765
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Association of inflammatory bowel disease in first-degree relatives with risk of colorectal cancer: A nationwide case-control study in Sweden.
Authors: Wang K. , Olén O. , Emilsson L. , Khalili H. , Halfvarson J. , Song M. , Ludvigsson J.F. .
Source: International journal of cancer, 2023-06-01; 152(11), p. 2303-2313.
EPub date: 2023-02-20.
PMID: 36760205
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The gut microbiome modifies the associations of short- and long-term physical activity with body weight changes.
Authors: Wang K. , Mehta R.S. , Ma W. , Nguyen L.H. , Wang D.D. , Ghazi A.R. , Yan Y. , Al-Shaar L. , Wang Y. , Hang D. , et al. .
Source: Microbiome, 2023-05-30; 11(1), p. 121.
EPub date: 2023-05-30.
PMID: 37254152
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Use of surveillance colonoscopy among individuals with removal of high-risk polyps according to the US Multi-Society Task Force recommendations.
Authors: Knudsen M.D. , Wang K. , Berstad P. , Polychronidis G. , Vithayathil M. , Song M. .
Source: Cancer, 2023-05-01; 129(9), p. 1394-1401.
EPub date: 2023-02-17.
PMID: 36807015
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Application of Mendelian randomization to explore the causal role of the human gut microbiome in colorectal cancer.
Authors: Hatcher C. , Richenberg G. , Waterson S. , Nguyen L.H. , Joshi A.D. , Carreras-Torres R. , Moreno V. , Chan A.T. , Gunter M. , Lin Y. , et al. .
Source: Scientific reports, 2023-04-12; 13(1), p. 5968.
EPub date: 2023-04-12.
PMID: 37045850
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Optimal dietary patterns for prevention of chronic disease.
Authors: Wang P. , Song M. , Eliassen A.H. , Wang M. , Fung T.T. , Clinton S.K. , Rimm E.B. , Hu F.B. , Willett W.C. , Tabung F.K. , et al. .
Source: Nature medicine, 2023 Mar; 29(3), p. 719-728.
EPub date: 2023-03-13.
PMID: 36914892
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Dietary patterns and risk of colorectal cancer: a comparative analysis.
Authors: Wang P. , Song M. , Eliassen A.H. , Wang M. , Giovannucci E.L. .
Source: International journal of epidemiology, 2023-02-08; 52(1), p. 96-106.
PMID: 36515537
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Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.
Authors: Lu Y. , Zhao Y.C. , Chang-Claude J. , Gruber S.B. , Gsur A. , Offit K. , Vodickova L. , Woods M.O. , Nguyen L.H. , Wade K.H. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2023-02-06; 32(2), p. 281-286.
PMID: 36512731
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Inverse relationship between Fusobacterium nucleatum amount and tumor CD274 (PD-L1) expression in colorectal carcinoma.
Authors: Ugai T. , Shimizu T. , Kawamura H. , Ugai S. , Takashima Y. , Usui G. , Väyrynen J.P. , Okadome K. , Haruki K. , Akimoto N. , et al. .
Source: Clinical & translational immunology, 2023; 12(8), p. e1453.
EPub date: 2023-08-02.
PMID: 37538192
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