Unraveling the Effects of Trimethylamine N-Oxide on Stroke: “The lower, the better?”

Abstract

Trimethylamine N-oxide (TMAO) is a small organic compound generated from choline, carnitine, and betaine via gut microbial and host metabolism (Fig.1). Increased TMAO levels are associated with a higher risk of major adverse cardiovascular events (death, myocardial infarction, or stroke) as TMAO involves increased foam cell formation, decreased reverse cholesterol transport, and enhanced platelet aggregation . Since solid evidences are reported, considerable research interest has arisen on clinical use of TMAO as a biomarker or therapeutic target as well as TMAO productivity of gut microbiota in many prevalent disorders such as heart failure, coronary artery disease, and other atherosclerotic diseases including stroke. Potential therapeutic strategy of diet and drugs in reducing TMAO levels have emerged . Until now, several studies from China have addressed the relationship between TMAO and stroke. Two case-control studies of Chinese population confirm that higher serum TMAO levels were associated with increased risk of first stroke . Hypertensive patients in the upper tertile (TMAO≧3.19 μmol/L) had 37% higher risk of first stroke than those in the lowest tertile (TMAO <1.79 μmol/L). Higher TMAO levels were associated with an increased risk of first attack and the severity of stroke in patients . Conversely, another case-control study of Chinese patients with stroke and transient ischemic attack showed that plasma TMAO levels of patients with stroke and transient ischemic attack were lower compared with control patients with asymptomatic atherosclerosis, which was the opposite of our expectations. The authors postulated that either stroke event or the treatment may reduce TMAO levels; however, this postulation must be verified in the future. In this issue of the journal, Sun et al. conducted a large-scale case-control study enrolled 953 ischemic stroke cases and same control subjects and presented a positive association between plasma TMAO and the risk of ischemic stroke in Chinese population. The authors performed multivariable conditional logistic regression analysis to diminish effects of confounding factors and demonstrated that subjects with highest plasma TMAO (TMAO >3.83 μmol/L) had 80% higher risk of first ischemic stroke compared to those with lowest plasma TMAO (TMAO ≦1.53 μmol/L). The results of increased odds were consistent with prior observations of cardiovascular events and supported the idea that plasma TMAO involved stroke incidence and was an independent risk factor for stroke. More interestingly, the authors demonstrated that ischemic stroke risk increased steeper at less than 2.46 μmol/L of plasma TMAO and increased slowly when the TMAO levels rose more than 2.46 μmol/L. This data is extremely suggestive when we consider molecular mechanisms of TMAO underlying stroke incidence. For instance, biological action of TMAO may not be in a dose-dependent manner when TMAO levels become higher; or TMAO-mediated functional changes of target cells may occur in different TMAO concentrations and cell dependent. We hope to understand the implication of the truth behind clinical research results. There are some points to be considered when we interpret their results. First, the exact mechanism underlying the correlation between TMAO and stroke is still unknown. It is assumed that TMAO activates inflammation and thrombus formation and results in increased cardiovascular events, so far. Second, we did not possess detailed information regarding medications of study participants. Taken medication have a