Abstract
Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic β-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.
Highlights
Trimethylamine N-oxide (TMAO) chemistry has been investigated since the 1890s and TMAO was first reported in human urine samples in 1934 [1,2,3,4,5]
Other radiolabeled TMAO feeding studies show that TMAO retroconversion to TMA by the microbiome is possible [21]. This retroconversion is the hallmark of trimethylaminuria, called fish odor syndrome because this reaction is present in rotting fish [121,122,123,124,125]. These findings demonstrate that while dietary TMAO can be directly absorbed at the small intestine, microbiome metabolism of choline at the large intestine generates the bulk of TMA levels which are absorbed and delivered to the liver via the portal vein
Using healthy and endoplasmic reticulum (ER) stress animal and hepatocyte models, this study showed that TMAO upregulated unfolded protein response (UPR) and apoptosis genes which were reversed by FMO3 knockdown [136]
Summary
Trimethylamine N-oxide (TMAO) chemistry has been investigated since the 1890s and TMAO was first reported in human urine samples in 1934 [1,2,3,4,5]. Urine TMAO levels have since been associated with dietary choline consumption and chronic diseases [6,7,8]. Emerging molecular level studies are beginning to elucidate TMAO’s effects on various relevant metabolic tissues; direct TMAO mechanisms are still unclear. While it is debated whether TMAO plays predominantly positive or negative roles in the metabolic disease contexts, TMAO is generally considered deleterious and strategies to reduce its accumulation are proposed for better CVD treatment [50,69,70,71,72,73,74,75,76].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
