Defining the dietary context of TMAO as a cardiovascular risk factor

Trimethylamine oxide (TMAO) is a small molecule found in the body as well as in blood and urine. It is made from the breakdown of our food both by cells in our body and the gut microbiome, the collection of microbes that live inside our gut which under normal conditions help us metabolise food and recover nutrients. There has been much interest in TMAO as a potential biomarker of heart and circulation diseases, following the discovery that it is increased in people that go on to develop heart disease, and feeding the molecule to mice that are genetically engineered to develop heart disease increases disease severity.

From large-scale human studies across different countries high levels of TMAO have been linked to the consumption of unhealthy diets that are high in red and processed meat, while TMAO levels are low in people who eat diets high in vegetables and fruit. The interest in TMAO being used to predict future heart and circulation diseases has led to some heart clinics in the US offering this as a test to diagnose patients of future risk.

However, TMAO (and molecules that are converted into TMAO) is also known to be high in certain fish including cod, haddock, halibut and salmon. Indeed, we have shown that regular consumption of fish can increase blood TMAO to higher levels than detected in meat-based diets. We also know from previous studies and literature that diets high in fish, particularly oily fish, are protective for heart disease.

The association of TMAO with diets high in fish appears to be at odds with TMAO being a biomarker for heart disease.

This investigation will recruit volunteers at risk of developing heart disease, as determined by the fats found in their blood (termed dyslipidaemia), into one of two studies. The first will consist of feeding volunteers diets where the main source of protein is meat-based (standardised to what the average person in the UK typically eats) and then fish-based.

We will randomise the order they receive the diet to help us to better determine the impact of the two diets. The second study will consist of meat-based and plant-based diets. These diets will be designed to be nutritionally identical apart from this main source of protein.

Each diet will be fed for 6 weeks in a random order so we can compare the change in TMAO that is linked to each diet, as well as measuring the metabolic consequences of the diet. We will take particular interest in the pathways that are thought to contribute to heart disease, including how the microbiome may be altered. By comparing these outcomes, we will be able to determine whether TMAO is a cause for concern with those that eat a high fish diet, or whether fish should be considered a healthy alternative to eating meat-based diets in terms of heart disease.

We will communicate these results to the general public through social media and outreach events and also reach out to government using our established networks given the importance of a good diet for maintaining health throughout the life course.