The study of gut microbiota (intestinal microbes) in the human body has become a new frontier for medical discovery. Emerging evidence highlights gut microbiota as a metabolically active 'organ'and novel source of risk factors for cardiovascular disease. Recently, using metabolomics approaches, Stanley Hazen and colleagues (collaborators on the proposed study) have identified several gut microbiota-dependent metabolites from dietary components such as choline and red meat that contribute to the pathogenesis of atherosclerosis and are linked to cardiovascular events in humans. This competing renewal grant aims to test new hypotheses on the basis of these highly promising preliminary findings, and to provide novel insights into the role of gut flora metabolites in the development of coronary heart disease (CHD). We propose a cost-efficient investigation in the Nurses'Health Study (NHS) cohort that will use archived fasting blood specimens from participants collected at two time points approximately 10 years apart. In a nested case-control study including 425 incident CHD cases and 425 matched controls, we will examine: 1) whether plasma concentrations of gut microbiota-dependent metabolites (trimethylamine N-oxide [TMAO], choline, and L-carnitine) are associated with subsequent CHD risk;2) whether 10-year changes in, or cumulative exposure to, these metabolites predict incident CHD;3) whether gut microbiota metabolites mediate the cardiovascular risks associated with specific dietary factors such as choline and red meat;and 4) whether blood lipids and inflammatory markers mediate the association between gut flora metabolites and CHD risk. Our study has major strengths including a prospective and highly cost-efficient design, long-term follow-up, repeated collection of blood samples, well-documented incident CHD cases, leveraging of a wide array of previously measured cardio-metabolic biomarkers in our plasma samples, and longitudinal information on diet and lifestyle. This competing renewal builds upon our long-standing research in NHS on risk factors for CHD in women (resulting in 286 publications over the past 30 years) and extends our work to the study of novel risk factors derived from gut microbiota. The findings of our proposed project may elucidate new etiologic pathways for atherothrombotic vascular disease, as well as provide novel prevention options and therapeutic strategies for cardiovascular diseases (including diet/lifestyle, probiotic, and targeted pharmacologic approaches). Thus, the proposed study has the potential for major clinical and public health impact.

Public Health Relevance

New research suggests that gut microbiota metabolites may represent novel risk factors for cardiovascular disease. Findings from our prospective study of plasma levels of these microbial metabolites, their 10-years changes and interrelationships with specific dietary factors (red meat and choline), traditional risk factors (lipids and inflammation markers), and coronary heart disease (CHD) in the Nurses'Health Study (NHS) may lead to new insights into the pathogenesis of CHD and suggest new strategies for CHD prevention and treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Aviles-Santa, Larissa
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Brigham and Women's Hospital
United States
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Patel, Ravi B; Moorthy, M V; Chiuve, Stephanie E et al. (2017) Hemoglobin A1c levels and risk of sudden cardiac death: A nested case-control study. Heart Rhythm 14:72-78
Justice, Anne E (see original citation for additional authors) (2017) Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits. Nat Commun 8:14977
Sotos-Prieto, Mercedes; Bhupathiraju, Shilpa N; Mattei, Josiemer et al. (2017) Association of Changes in Diet Quality with Total and Cause-Specific Mortality. N Engl J Med 377:143-153
Wang, Tiange; Huang, Tao; Heianza, Yoriko et al. (2017) Genetic Susceptibility, Change in Physical Activity, and Long-term Weight Gain. Diabetes 66:2704-2712
Huang, Tao; Zheng, Yan; Hruby, Adela et al. (2017) Dietary Protein Modifies the Effect of the MC4R Genotype on 2-Year Changes in Appetite and Food Craving: The POUNDS Lost Trial. J Nutr 147:439-444
Chang, Shun-Chiao; Glymour, Maria; Cornelis, Marilyn et al. (2017) Social Integration and Reduced Risk of Coronary Heart Disease in Women: The Role of Lifestyle Behaviors. Circ Res 120:1927-1937
Guasch-Ferré, Marta; Liu, Xiaoran; Malik, Vasanti S et al. (2017) Nut Consumption and Risk of Cardiovascular Disease. J Am Coll Cardiol 70:2519-2532
Heianza, Yoriko; Sun, Dianjianyi; Wang, Tiange et al. (2017) Starch Digestion-Related Amylase Genetic Variant Affects 2-Year Changes in Adiposity in Response to Weight-Loss Diets: The POUNDS Lost Trial. Diabetes 66:2416-2423
Lv, Jun; Yu, Canqing; Guo, Yu et al. (2017) Gallstone Disease and the Risk of Type 2 Diabetes. Sci Rep 7:15853
Qi, Lu; Ma, Wenjie; Heianza, Yoriko et al. (2017) Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease. Arterioscler Thromb Vasc Biol 37:2204-2212

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