Drug Discovery and Development of Novel Therapeutics for Inhibiting TMAO in Models of Atherosclerosis and Diabetes
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Published on: February 20, 2019
Ian Steinke1, Nila Ghanei1, Manoj Govindarajulu1
1Drug Discovery and Development, Auburn University, Auburn, AL, United States.
Abstract:
Diabetes mellitus exists as a comorbidity with congestive heart failure (CHF). However, the exact molecular signaling mechanism linking CHF as the major form of mortality from diabetes remains unknown. Type 2 diabetic patients display abnormally high levels of metabolic products associated with gut dysbiosis. One such metabolite, trimethylamine N-oxide (TMAO), has been observed to be directly related with increased incidence of cardiovascular diseases (CVD) in human patients. TMAO a gut-liver metabolite, comes from the metabolic degenerative product trimethylamine (TMA) that is produced from gut microbial metabolism. Elevated levels of TMAO in diabetics and obese patients are observed to have a direct correlation with increased risk for major adverse cardiovascular events. The pro-atherogenic effect of TMAO is attributed to enhancing inflammatory pathways with cholesterol and bile acid dysregulation, promoting foam cell formation. Recent studies have revealed several potential therapeutic strategies for reducing TMAO levels and will be the central focus for the current review. However, few have focused on developing rational drug therapeutics and may be due to the gaps in knowledge for understanding the mechanism by which microbial TMA producing enzymes and hepatic flavin-containing monoxygenase (FMO) can work together in preventing elevation of TMAO levels. Therefore, it is critical to understand the advantages of developing a novel rational drug design strategy that manipulates FMO production of TMAO and TMA production by microbial enzymes. This review will focus on the inspection of FMO manipulation, as well as gut microbiota dysbiosis and its influence on metabolic disorders including cardiovascular disease and describe novel potential pharmacological therapeutic development.
Insights
Diabetes and heart failure share links through gut bacteria metabolites like trimethylamine N-oxide (TMAO). Reducing TMAO may prevent cardiovascular events in diabetic patients.
Area of Science:
- Cardiovascular Medicine
- Metabolic Disorders
- Microbiome Research
Background:
- Diabetes mellitus frequently co-occurs with congestive heart failure (CHF), a leading cause of mortality in diabetic patients.
- Gut dysbiosis in Type 2 diabetes is linked to elevated metabolic products, including trimethylamine N-oxide (TMAO).
- TMAO, a gut-liver metabolite derived from microbial trimethylamine (TMA), correlates with increased cardiovascular disease (CVD) incidence and adverse events.
Purpose of the Study:
- To review potential therapeutic strategies for reducing TMAO levels.
- To address the knowledge gap in understanding the interplay between microbial TMA production and hepatic flavin-containing monooxygenase (FMO) in TMAO elevation.
- To explore rational drug design targeting FMO and microbial enzymes for TMAO management.
Main Methods:
- Review of recent studies on TMAO metabolism and its role in cardiovascular disease.
- Inspection of flavin-containing monooxygenase (FMO) manipulation strategies.
- Analysis of gut microbiota dysbiosis and its impact on metabolic and cardiovascular health.
Main Results:
- TMAO promotes atherosclerosis by enhancing inflammation and disrupting cholesterol/bile acid metabolism, leading to foam cell formation.
- Elevated TMAO levels are directly correlated with increased risk of major adverse cardiovascular events in diabetic and obese individuals.
- Several therapeutic strategies for reducing TMAO are emerging, but rational drug development is limited by mechanistic understanding.
Conclusions:
- Understanding the microbial and hepatic pathways of TMAO production is critical for developing effective therapeutics.
- Targeting FMO and microbial TMA-producing enzymes offers a promising avenue for novel pharmacological interventions.
- Manipulating gut microbiota and TMAO metabolism holds potential for managing metabolic disorders and cardiovascular disease in diabetic patients.
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