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.
Highlights
Heart disease is the leading cause of death in the United States today
Therapies that seek to lower low-density lipoprotein (LDL) via clearance upon upregulation of LDL receptors have shown statistical significance in cardiovascular risk reduction (Silverman et al, 2016). These findings show promise in the ability to reorganize the levels of high-density lipoprotein (HDL) and LDL in circulation, yet many therapies are unable to improve energy regulation through glucose metabolism and insulin resistance in unison with cholesterol
DMB has only been shown to be effective as a nonlethal inhibitor of bacteria and inhibiting trimethylamine N-oxide (TMAO) levels, it has yet to be demonstrated that any improvements in glucose homeostasis or insulin sensitivity would be observed
Summary
Heart disease is the leading cause of death in the United States today. Diabetic patients are twice as likely to develop cardiovascular disease (CVD). Most recent reports on diabetes mellitus from the Center for Disease Control and Prevention estimate that 9.1% of the population in the United States of adults 18 years and older have been diagnosed, where type 2 diabetes (T2D) mellitus is being attributed to approximately 95% of these cases (Centers for Disease Control and Prevention, 2018)
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