Cardiovascular disease (CVD) is the leading cause of death in the world. Many risk factors have been identified as well as foods thought to be associated with increased CVD risks such as meats, high-fat dairy products, saturated fats and egg yolks. We described a previously unrecognized A meta-organismal pathway involving gut microbial (gut flora) dependent metabolism of trimethylamine-containing nutrients abundant in these foods (choline and l- carnitine) to trimethylamine (TMA) that is converted by the host liver enzymes to trimethylamine-N-oxide (TMAO) which is an atherogenic compound. We have shown using basic, animal model and human clinical studies that gut flora take part in development of CVD and its associated unfavorable events. Microbial enzymes responsible for generating TMA from various dietary TMA-containing nutrients are TMA lyases. Two microbial TMA lyases have been identified and cloned, CutC/D and CntA/B, which show strict substrate specificity for cleaving choline and carnitine, respectively. We recently cloned and characterized a related TMA lyase, YeaW/X, which demonstrates broad substrate specificity. In unpublished studies we see additional TMA lyase substrate activities in gut microbiota based on substrate preferences that are not catalyzed by either CutC/D or CntA/B. We propose to examine the relationship between specific microbial TMA lyases and the increased blood TMAO levels and development of atherosclerosis. We will further define the microbial TMA lyases responsible for TMA and TMAO generation in vivo, and the involvement of specific microbial TMA complexes (YeaW/X, CutC/D, and CntA/B) in diet-induced atherosclerosis using animal models. We will also test the potential of microbial choline TMA lyase complex pharmacologic manipulation in impacting host diet-induced impairment in reverse cholesterol transport and atherosclerosis. The proposed studies will help define the contribution that individual TMA lyase enzymes in vascular disease, and provide important nutritional and pharmacological insights into the prevention and treatment of atherosclerosis.

Public Health Relevance

Cardiovascular disease is the leading cause of death world-wide. We have identified gut microbiota's involvement in metabolizing suspected atherogenic foods to trimethylamine (TMA) and then through conversion by host liver enzymes to trimethylamine-N-oxide (TMAO). We will examine the contribution of specific cloned microbial enzymes, TMA lyases that produce TMA from TMA-containing dietary nutrients to atherosclerosis and explore therapeutic strategies to block the action of these enzymes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130819-04
Application #
9619363
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2016-01-22
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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