The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It's Not All Bad

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.

Keywords: diabetes; gut microbiome; insulin production; insulin resistance; metabolic diseases; metabolic tissue function; obesity; oxidative stress; trimethylamine n-oxide (TMAO); western diet.

Figure 1

Trimethylamine N-Oxide (TMAO) Accumulation in Serum. (A) The microbiome-liver-kidney axis regulates TMAO production and accumulation. Choline and related compounds from dietary animal proteins and fats are metabolized by gut bacteria expressing choline utilization cluster (Cut) genes including E. coli. The resultant trimethylamine (TMA) is absorbed by enterocytes and metabolized by hepatic flavin-containing monooxygenase (FMO) enzymes. Serum TMAO is excreted via renal glomerular filtration and uptake by proximal tubular cells through organic cation transport proteins. (B) Choline, TMA, and TMAO structures. This figure was created with biorender.com.

Figure 2

TMAO Effects on Metabolic Tissues. Elevated serum TMAO is generally associated with metabolic diseases and molecular effects are mainly observed in pathogenic and not healthy conditions. Molecular TMAO effects are best defined in hepatocytes where it worsens reverse cholesterol transport and drives non-alcoholic liver disease and gallstone formation. However, TMAO also improves oxidative and endoplasmic reticulum (ER) stress associated with hepatic insulin resistance. While poor renal function drives TMAO accumulation, it in turn aggravates chronic kidney disease. Although direct mechanisms are unclear, TMAO is associated with cognitive diseases including autism spectrum disorder and Alzheimer’s disease. Interestingly, TMAO is liked with increased adiposity associated with obesity and type 2 diabetes (T2D), but it also reduces adipocyte ER stress. In cardiovascular disease research, TMAO may increase or decrease cardiac muscle hypertrophy associated with heart failure. In skeletal muscle, TMAO benefits enzyme kinetics but is debated to drive insulin resistance. Therefore, TMAO effects may be positive or negative depending on the context of metabolic disease and molecular mechanisms are not well understood. This figure was created with biorender.com.

Figure 3

TMAO Effects on Blood Glucose Management. Elevated serum TMAO levels are associated with elevated blood glucose levels, a hallmark of metabolic diseases. Insulin resistance at target tissues or β-cell glucose intolerance can drive this phenotype. While associative studies generally link TMAO to worsened insulin resistance, the molecular evidence in hepatocytes, adipocytes, and skeletal muscles is divided. One study investigates TMAO effects on β-cell containing pancreatic islets and report improved glucose tolerance which beneficially lowers blood glucose in the T2D condition. This figure was created with biorender.com.