We have accrued new data that suggests a new nutritional basis as a contributory pathway to the development of atherosclerotic heart disease. The overall pathway involves an interplay between dietary intake of lipid (the choline moiety of phosphatidyl choline), intestinal microbiota (gut flora), genetic susceptibility (hepatic expression levels of flavin monooxygenase 3, FMO3), and generation of pro-atherosclerotic metabolites that promote atherosclerotic heart disease and its major adverse complications (myocardial infarction (MI), stroke, and death). Intestinal microbiota ("gut flora"), comprised of trillions of typically non-pathogenic commensal organisms, serve as a filter for our greatest environmental exposure - what we eat. Gut flora play an essential role, aiding in the digestion and absorption of many nutrients. Alterations in gut flora can be associated with changes across a wide range of metabolic pathways. Similarly, alterations in diet influence both the composition of gut flora and plasma levels of metabolites. Animal studies have recently shown that intestinal microbial communities can influence traits, and metabolomic studies of inbred mouse strains have shown that gut microbiota may play an active role in the development of complex dysmetabolic phenotypes, such as susceptibility to insulin resistance and non-alcoholic fatty liver disease. Demonstration of a link between gut flora dependent phospholipid metabolism and atherosclerosis risk through generation of pro-atherosclerotic metabolites has not yet been reported. The overall goal of this proposal is to test the hypothesis that gut flora dependent metabolism of dietary phosphatidylcholine is mechanistically linked to the pathogenesis of cardiovascular disease.
The specific aims are:
Aim 1) Testing the hypothesis that dietary phosphatidylcholine metabolites choline, TMANO and betaine are both diagnostic markers for cardiac risk and mechanistically linked to development of atherosclerosis.
Aim 2) Testing the hypothesis that gut flora plays a modulatory role in atherosclerosis.

Public Health Relevance

Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and cardiovascular disease pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for the treatment and prevention of atherosclerotic heart disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL103866-05
Application #
8656400
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Seldin, Marcus M; Meng, Yonghong; Qi, Hongxiu et al. (2016) Trimethylamine N-Oxide Promotes Vascular Inflammation Through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-κB. J Am Heart Assoc 5:
Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Serban, Maria-Corina; Sahebkar, Amirhossein; Mikhailidis, Dimitri P et al. (2016) Impact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials. Sci Rep 6:19188
Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558
Senthong, Vichai; Wu, Yuping; Hazen, Stanley L et al. (2016) Predicting long-term prognosis in stable peripheral artery disease with baseline functional capacity estimated by the Duke Activity Status Index. Am Heart J 184:17-25
Hammadah, Muhammad; Brennan, Marie-Luise; Wu, Yuping et al. (2016) Usefulness of Relative Hypochromia in Risk Stratification for Nonanemic Patients With Chronic Heart Failure. Am J Cardiol 117:1299-304
Senthong, Vichai; Li, Xinmin S; Hudec, Timothy et al. (2016) Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. J Am Coll Cardiol 67:2620-8
Hammadah, Muhammad; Georgiopoulou, Vasiliki V; Kalogeropoulos, Andreas P et al. (2016) Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure. Circ Heart Fail 9:e002115
Organ, Chelsea L; Otsuka, Hiroyuki; Bhushan, Shashi et al. (2016) Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure. Circ Heart Fail 9:e002314

Showing the most recent 10 out of 62 publications