Trimethylamine: A link between the gut microbiome and metabolic disease

Author: Anita Tait

February 2021

 

In the world of microbiology and nutrition science, there has been an explosion of new research linking the gut microbiome to health and disease. This growing interest in the gut microbiome stems from compelling new discoveries made possible due to advancements in technology. These advancements allow us to measure the billions of microbes living within our gut as well as their function which most importantly allows us to understand how these microbes influence our health.

 

The gut microbiome and TMA

One of these discoveries is the microbial metabolite, Trimethylamine (TMA). TMA is a microbial metabolite that is produced by our gut bacteria and has been shown to be associated with chronic health conditions such as cardiovascular disease and diabetes.

 

 

What is the clinical relevance of TMA?

Once TMA is produced by the gut microbiome, it is transported from the gut to the liver where it is converted to trimethylamine oxide (TMAO). TMAO has been shown to be involved in blood sugar control, atherosclerosis, platelet aggregation and inflammation¹ (see Fig.1).

 

In addition, we now have a strong body of evidence that suggests blood TMAO levels can predict health outcomes across a range of metabolic health conditions. When comparing those with the highest to the lowest blood TMAO levels, a series of meta-analyses reported a 47% increase in all-cause mortality², a 62% increase in major cardiovascular events³, an 89% increase in Diabetes Mellitus risk⁴ and a 0.27mg/L increase in the inflammatory marker CRP⁵.

 

How does diet have a role in TMA production?

We know that what we eat plays an important role in the production of TMA within the gut microbiome. While we have understood for some time that microbes are able to produce TMA from both choline and carnitine, recent research has shown that dietary carnitine is the principal driver of plasma TMAO levels^6-7. The amino acid, carnitine is found in many dietary sources, with the richest source being red meats, such as kangaroo and beef⁸.

In a study by Wang and colleagues,⁶ a red meat diet intervention (2x serves per day) resulted in a 3-fold increase in mean fasting TMAO plasma levels when compared to white meat or non-meat diet. This increase in TMAO levels translates to a very clinically significant 4.6% increase in relative risk of all-cause mortality. Of note, the response was highly individual with some participants showing up to a 10-fold increase in TMAO blood levels in response to the red meat diet. The role of the microbiome in determining this individualised response was confirmed by a 2020 study⁷ which highlighted the role of the microbiome in determining the impact of dietary carnitine on plasma TMAO levels.

 

 

What dietary interventions can reduce TMAO production?

For those that have a high potential to produce TMA in their gut microbiome, reviewing dietary carnitine intake may be warranted  However, reducing red meat is not a one size fits all approach and should be considered in the context of the individual.  Red meat can be an important dietary source of key vitamins and minerals, such as vitamin B12, iron and zinc, whose intake can be especially critical in young children, pregnant women and the elderly.

The Heart Foundation provides useful guidelines of aiming for less than 350g of red meat per week (cooked weight). Replacing red meat with pulses, legumes, nuts and seeds can also reduce carnitine intake while still providing good sources of iron and zinc.

Another dietary intervention to consider is increasing the intake of vegetables from the Brassica family, such as broccoli, kale, cabbage, cauliflower and Brussel’s sprouts. These vegetables contain the bioactive metabolites indole-3-carbinol (I3C) and its dimer diindolylmethane (DIM) which have been noted to inhibit the FMO3 enzyme which converts  TMA to TMAO in the liver^9-10. ​Increasing these types of vegetables will also provide the body with many important vitamins and minerals as well as a good source of prebiotic fibre.

 

Applying Clinical Interventions

Although it has long been understood that excessive red meat intake is associated with cardiovascular disease, recent scientific advancements have made the role of the microbiome clear in this process. Therefore, assessing a patient’s capacity to produce TMA in their microbiome allows for further targeted dietary interventions to more effectively manage an individual’s personal cardiovascular risk factors.