Gut Microbe and Obesity, TMAO (trimethylamine-N-oxide) and Cardiometabolic Disease

TMAO has been associated with atherosclerosis, heart failure and chronic kidney disease. Two new studies show, that TMAO from dietary choline (abundant in animal protein) is prothrombotic causing heart attacks and stroke and is also positively associated with obesity and type 2 diabetes.

Hazen and colleagues from Cleveland Clinic (Circulation 2017), studied 18 healthy subjects (vegans and omnivores) and found that dietary choline supplementation led to increased gut microbial generated metabolite TMAO. The rise of TMAO correlated with a significant prothrombotic effect. This effect was mediated through a corresponding rise in platelet aggregation (clumping and stickiness) and hyper-responsiveness which increase the risk of clotting events such as heart attack and stroke. Figure below. The rise of TMAO levels and platelet response was attenuated in the presence of low dose aspirin.

Another study published by Brown and colleagues (Cell Reports 2017) demonstrates that TMAO is mechanistically linked to the pathogenesis of obesity and obesity-related diseases like diabetes.
• Circulating TMAO is a strong predictor of type 2 diabetes risk in humans.
• Circulating TMAO is linked to obesity and energy metabolism in humans.
• TMAO is positively associated with body weight, fat mass, visceral fat and subcutaneous fat in mice and humans.
• Knocking down expression of the gene (FMO3) that encodes the TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) can protect against obesity in mice fed a high-fat, high-calorie diet.
• Knocking down the FMO3 gene stimulates transformation of white adipose tissue into heat-generating beige adipose tissue in mice.

To establish clinical relevance, the researchers investigated the relationship between circulating levels of TMAO and type 2 diabetes in a cohort of human subjects. Their data showed subjects with type 2 diabetes have higher levels of TMAO. Moving on to the mouse model, they demonstrated that circulating TMAO levels in various strains of mice were positively associated with body weight, fat mass, visceral fat and subcutaneous fat.
(Figure 1)

Bringing the study back to humans, they looked at FMO3, the gene that encodes the enzyme that makes TMAO. They found that FMO3 was expressed more abundantly in the fat tissue of overweight or obese subjects than in lean subjects. FMO3 turned out to be positively related to body mass index, waist-to-hip ratio and adiposity. The researchers went on to validate this finding across a diverse group of men and women of European American and African American ethnicity.

Next they explored what would happen if they blocked the effects of TMAO by inhibiting the action of FMO3. Returning to the mouse model, they found that inhibition of the FMO3 enzyme in mice fed a high-fat diet significantly decreased body weight gain relative to mice fed a normal diet.. Moreover, among a broader group of mice fed the high-fat diet, those with FMO3 knockdown had significant reductions in body weight gain and fat mass and a significant increase in lean mass compared with mice without FMO3 knockdown — even though both groups of mice ate the same amount of high-fat food. Thus, FMO3 knockdown effectively protected mice from the obesogenic effects of a high-fat diet.

Finally, the researchers found that inhibiting FMO3 (and, by implication, its product TMAO) promoted transformation of white fat into beige fat — a change associated with greater energy expenditure and weight loss
(Figure 2).