What is TMAO? & what does it have to do with the Kidneys?

Today I wanted to discuss a lesser-known compound that has been linked to the development and progression of kidney disease, cardiovascular disease and diabetes, among other health conditions and that compound is called TMAO. 

What is TMAO?

https://www.mdpi.com/2072-6651/8/11/326

TMAO (or Trimethylamine-N-oxide) is a metabolite produced by gut bacteria from choline, phosphatidylcholine and L-carnitine-rich foods (mainly fish, meat, eggs and dairy). When consumed, these nutrients are processed by gut bacteria resulting in the release of various metabolites including TMA (Trimethylamine) into the blood. TMA is then transported to the liver where it becomes oxidised into TMAO, primarily by the enzyme FMO3. TMAO is then excreted in the urine. 

Elevated levels of TMAO in the body have been linked to a wide variety of diseases including:

• Cardiovascular disease- including blood clots, heart attack, stroke, heart failure
• Atherosclerosis (hardening of arteries)
• Diabetes
• Bowel cancer
• Chronic Kidney Disease
• Inflammation
• Liver Dysfunction- liver damage and non-alcoholic fatty liver disease
• Obesity 
• Neurodegenerative disease

What causes high levels of TMAO?

Diet plays a key role in the generation of TMAO. The foods best known for increasing TMAO levels are animal products, particularly red meat, dairy products, eggs and fish because these foods are highest in choline and carnitine which gets converted into TMAO by gut bacteria. Recent research has shown that between choline and carnitine, dietary carnitine is the principal driver of high TMAO levels.

Gut dysbiosis, which can be a reduced diversity of gut bacteria or an imbalance of bacteria in the gut is the second key causative factor of elevated TMAO levels. Because TMA is produced by specific bacteria in the gut, the health of our gut and the type of bacteria living there play a really important role in TMAO levels. 

Studies have found that people with a less diverse gut microbiome and more Firmicutes than Bacteroidetes gut bacteria were more likely to have elevated TMAO levels when eating a diet high in carnitine and choline. 

Other factors linked to elevated TMAO include:

• High-fat diet

• Carnitine supplements

• Gastric Bypass Surgery

• Sleep deprivation

• Pollutants 

Clinical effects of elevated TMAO levels

As I mentioned earlier, elevated TMAO levels have been linked to a variety of health conditions but there are two that I specifically want to highlight: cardiovascular disease and diabetes.

Cardiovascular disease

Over the last two decades, several large clinical studies have shown that elevated blood TMAO levels are associated with a greater risk of cardiovascular disease. In a meta-analysis of 19 studies with almost 20,000 people, high TMAO levels were associated with increased rates of cardiovascular diseases such as heart failure and stroke. Also, people consuming higher levels of TMAO precursors like carnitine and choline were 1.4 times more likely to suffer from heart failure, stroke or other heart diseases.

https://pubmed.ncbi.nlm.nih.gov/28663251/

Diabetes

Elevated TMAO levels have also been associated with type 2 diabetes. A meta-analysis of 12 studies involving 15,000 people found that high circulating concentrations of TMAO were associated with an increased prevalence of diabetes. People with higher TMAO levels were approximately 50% more likely to have diabetes than people with lower levels.

https://onlinelibrary.wiley.com/doi/10.1111/obr.12843

The link between TMAO and CKD

So now we know that TMAO is linked to an increased risk of cardiovascular disease and diabetes, what about kidney disease?

Let’s take a look at what the research shows us:

• Elevated levels of TMAO are associated with progressive loss of kidney function and the development of CKD
• People with CKD commonly have higher levels of TMAO
• Elevated TMAO levels in people with CKD are associated with higher rates of adverse cardiovascular disease events and mortality
• Inhibiting TMAO production can prevent both renal functional impairment and fibrosis (scarring)
• Animal studies have shown that elevated TMAO levels significantly increased renal inflammation and renal fibrosis (scarring)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203662/pdf/nihms-1576640.pdf

https://pubmed.ncbi.nlm.nih.gov/29061990/

Why is TMAO increased in people with CKD?

 It’s not completely understood why TMAO levels are increased in people with CKD. It is thought that it may be due to a decrease in renal excretion of TMAO, but studies show that it’s more likely due to increased TMA gut production which may be related to higher TMA-containing nutrient intake (choline and carnitine) or to CKD-associated gut dysbiosis. 

It is well known that people with CKD are more likely to have gut dysbiosis for a number of reasons including slow intestinal transit time, delivery of undigested protein to the colon, decreased fibre intake, iron therapy, frequent use of proton pump inhibitors and antibiotics.

In people with CKD, there also appears to be increased metabolism of TMA to TMAO in the liver which will also contribute to elevated TMAO levels.

How does TMAO affect the kidneys?

The link between TMAO and kidney disease likely occurs directly and indirectly. Firstly, the two primary causes of CKD worldwide are diabetes and high blood pressure, so by increasing the risk of diabetes and high blood pressure, elevated TMAO levels may indirectly contribute to the development of CKD.

There does however seem to be more of a direct effect. TMAO promotes the release of inflammatory factors throughout the body, this inflammation can directly cause damage to the kidney. TMAO also contributes to renal fibrosis. Renal fibrosis or scarring is a process that drives the progression of CKD to end-stage kidney disease

How do you know if you have high TMAO levels? 

TMAO levels can be checked on a blood test however the test is relatively new so isn’t very commonly performed and the reference values are still being established. Hopefully, over time, we will start to see TMAO being measured routinely as part of a standard workup in people with kidney disease and cardiovascular disease. 

Ok, so now we know that people with CKD are at a higher risk of having elevated TMAO levels and that elevated TMAO can contribute to the progression of kidney disease, as well as increase the risk of cardiovascular disease which is the most common cause of death in people with CKD. The next question is- what can you do to lower TMAO?

Factors that may decrease TMAO levels

• Avoid red meat and dairy- red meat and dairy in particular increase TMAO levels because of higher amounts of carnitine in particular. They also proliferate certain species of gut bacteria associated with higher TMAO levels.

• Increase intake of plant-based foods and fibre- multiple studies have shown that people following a vegetarian or vegan diet actually produce very little TMAO.

• Avoid energy drinks (often contain carnitine).

• Avoid supplements that contain choline or carnitine unless recommended by your healthcare provider

• Increase your intake of dietary polyphenols eg. apples, onions, red cabbage, berries, herbs and spices.

• Increase intake of cruciferous vegetables- studies have shown that cruciferous vegetables may reduce the activity of the FMO3 enzyme in the liver so reduce the conversion of TMA to TMAO.

• Add garlic to your diet- animal studies have shown that dietary allicin (found in garlic) helps to prevent TMAO formation.

• Work on gut health and treat dysbiosis- if you want to know more about the link between dysbiosis and kidney disease and what you can do to improve your gut health, have a look at our blog post on this.

Supplements that may reduce TMAO:

• Vitamin D, vitamin B6, vitamin B12 and folate- a study showed that when people were supplemented with vitamin D and these specific B vitamins there was a 67% reduction of fasting blood TMAO levels.

https://pubmed.ncbi.nlm.nih.gov/27569255/

• Resveratrol- may reduce TMAO levels by inhibiting TMA production by the gut microbes by remodelling the gut microbiota.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817264/

• Probiotics- the following probiotics have been shown to lower TMAO levels: L.rhamnosus LRH11, L.plantarum SGL07, B.lactis LKM512

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767061/

Make sure you discuss any new supplements with your healthcare practitioner before starting on them to make sure they are appropriate for your use.

Final thoughts

There’s still a lot we don’t know about TMAO, but I think what we do know is pretty clear. Elevated TMAO levels are linked to a number of different health conditions and may be involved in the development and progression of CKD. Thankfully, there are a number of things we can do to lower TMAO levels in the body, primarily through altering our diet and looking after our gut health. We’ve said it before and we’ll say it again- all health begins in the gut and this is just another example of that.

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