Understanding TMAO

Understanding TMAO

This One is For the Vegans      
In my writing, I have often stated my belief that the vegan diet is not natural for humans (no historical precedent), and can be unhealthy if not carefully planned out, with the use of supplements to provide essential nutrients missing from a diet containing no animal products. However, while the research covered in this newsletter is tricky to fully understand, it certainly could be used to support the vegan dietary principles.

Microbiome and Stroke   
Scientists from Cleveland Clinic’s Lerner Research Institute have spent over a decade examining the role of the gut microbiome in cardiovascular health and disease. Their most recent research breaks new ground by showing that the state of one’s gut microbiome has a demonstrable effect on the severity of a stroke, and the level of functional impairment following a stroke.  This particular study looked at a chemical called TMAO (trimethylamine N-oxide), which is produced in the gut as a by-product of the digestion of specific nutrients found in red meat, and some other animal products.

“In this study, we found that dietary choline and TMAO produced greater stroke size and severity, and poorer outcomes in animal models,” said Dr. Hazen, chair of the Department of Cardiovascular & Metabolic Sciences and director of Cleveland Clinic’s Center for Microbiome & Human Health.

Dr. Hazen, and his fellow researchers, had already found that high TMAO levels can lead to cardiovascular disease, and they demonstrated a link between elevated TMAO and increased risk of blood clotting. Furthermore, in their clinical studies (analyzing thousands of people) they have found blood levels of TMAO to predict future risk of heart attack, stroke and death. And, these findings have been confirmed by many other studies, from around the world. So, the bottom line is, those who have high levels of TMAO show more brain damage and a greater degree of post-stroke motor and cognitive malfunction, than subjects with lower levels of TMAO.

Now, as we shall see, it is tricky to blanket condemn the foods that elevate TMAO, so we should also mention another culprit in this scenario. This study also discovered that a gut microbe enzyme, called CutC, which is required to produce TMAO, increased stroke severity and worsened post-stroke functionality.  One of the researchers, Dr. Zhu, stated that, “When we genetically silenced the gut microbe gene that encodes CutC, stroke severity significantly diminished. Ongoing research is exploring this treatment approach.”

Dr. Zhu went on to discuss the potential for dietary changes to help reduce levels of TMAO, and thus stroke risk, “since both a Western diet and a diet rich in red meat are known to elevate TMAO levels. Switching to plant-based protein sources helps to lower TMAO.”    Study

Now we are going to look at TMAO in more depth, and you will see why I deem the subject “tricky”. From an omnivore perspective, many of the foods that raise levels of TMAO are otherwise considered to be of great benefit to general health.  So for example, it could be that the aforementioned CutC enzyme is more of a danger factor than that of TMAO. Or, that it is the quality of these animal proteins that makes a difference: organic and grass fed versus industrial animals given a diet high in inflammatory omega-6 foods (corn and soy).

Nonetheless, let’s get some details about TMAO, that may help influence our dietary choices to be of a healthier nature.  TMAO is produced from TMA (trimethylamine), a common by-product of plant and animal decomposition. When gut bacteria metabolize choline, lecithin, and L-carnitine, TMA is generated. The TMA then moves to the liver, by way of the bloodstream, where becomes oxidized and turns into TMAO.

Obviously, those foods highest in choline, lecithin, and L-carnitine, are going to be the foods we are most concerned about, given they provide the building blocks for TMAO. And, the foods richest in these compounds are dairy, eggs, red meat, and saltwater fish.

So, score one for the vegans, but the problem is these compounds are generally considered to be of importance to the body, for a variety of biochemical functions. Choline and lecithin for the production of the neurotransmitter acetylcholine, required for learning and memory, and L-carnitine for the heart muscle, and to shuttle fat into the mitochondria for the purposes of burning it for fuel.

Diseases Associated with High TMAO

Cardiovascular Disease: We have already looked at the link between heart disease and high TMAO levels. This has been confirmed by a meta-analysis of studies covering almost 20,000 people. These studies also indicated that people consuming high levels of TMAO precursors, such as choline and L-carnitine, were 1.4 times more likely to experience heart disease or stroke.

Diabetes: Two studies, done on around 3,000 subjects, found that high TMAO levels were associated with increased rates of type 2 diabetes. In these studies, it was discovered that dietary TMAO increased insulin levels and insulin resistance, and also increased inflammation in mice fed a high-fat diet. Now, this might be one clue to the paradox of otherwise healthy nutrients being responsible for increasing this potentially dangerous compound. In fact, the high fat diet might be the reason these good nutrients allow the production of a dangerous by-product.

Kidney Disease: Another study found that patients with chronic kidney disease had higher levels of TMAO than the controls.

Cancer: A link between high TMAO and colon cancer was established in a study on 1,670 women, which also found high levels of choline to be associated with a 2.4 times greater incidence of this form of cancer. To further the confusion, another study (including 1,300 men) found “only elevated choline but not TMAO was associated with an increased risk of colon cancer.”

TMAO was also found to be associated with elevated rates of aggressive prostate cancer in 200 prostate cancer patients. Mind you, high egg intake has already been linked to prostate cancer, and eggs are a primary source of choline. But, most eggs are high in inflammatory omega 6 fatty acids, due to the diet fed commercial chickens. So, this may be a factor, leading one to conclude that organic eggs, or eggs high in omega-3s, may be a healthier choice.

Liver Disease  
A study done on 1,600 people found “high TMAO levels were associated with more severe liver damage and non-alcoholic fatty liver disease”. This study was confirmed by rat studies showing high TMAO to cause liver damage and fatty liver disease.

Animal Products
As we have established, dairy products, eggs, fish, and red meat are rich in carnitine, choline, and lecithin, which are converted into TMAO by gut bacteria. So, a variety of studies looked first at the diet, rather than at the level of TMAO in subjects.

One study, including 300 people, found fish and meat consumption increased TMAO levels. In another study, done on 40 healthy young men, fish consumption increased TMAO levels even more than beef or eggs. And, in a rodent study, fish protein increased TMAO more than soy protein or casein (milk protein). This is also confusing, given the mounds of clinical research showing that fish consumption is protective against heart disease and stroke, in part because of providing omega-3 fatty acids.

Now, eggs are generally considered to be a healthy food, if consumed in moderation, in part because they are a rich source of choline, required for acetylcholine production. Yet, in six subjects, eating more than two eggs per day increased TMAO levels. (Though, frankly I consider eating two eggs per day already to be higher than ideal.)

Back to the confusion: In another egg study (38 healthy people), eating up to three eggs per day did not increase TMAO levels, but had beneficial effects such as increasing HDL (“good”) cholesterol.

As far as dairy products go, in a study involving 270 subjects, dairy consumption was associated with higher TMAO levels. But, in a study with 38 overweight or obese women, “increased consumption of dairy resulted in lower TMAO levels”.

Confused Yet?
Even the experts in this field are not suggesting a radical shift to a vegan diet. They point out that the benefits gained from consuming eggs and fish, and moderate amounts of other animal proteins, may outweigh the effects of higher TMAO levels.  And, they acknowledge that “diets rich in choline or carnitine also have beneficial effects on human health. These (animal) foods are important sources of nutrients, such as iron and vitamin B12”.  Thus, even the scientists suggest that such studies be taken with a grain of salt, as they do not yet have the whole picture.

As I mentioned, there are aspects of the studies that are unavailable to us. Perhaps some of the conflicting studies were done in different parts of the world, leading us to have to consider the quality of dairy, eggs, fish and meat consumed.

For example, there are two types of milk products consumed in the world, the safer type being derived from European cows.  North American dairy cows are a species that produces milk containing both A1 and A2 beta-casein, but European cows produce milk that contains only A2 beta-casein. Studies (and anecdotal feedback) have indicated that A1 beta-casein may be harmful, and more allergenic, and that A2 beta-casein is a safer choice.  (A few farmers in North America are now introducing cows that produce A2 milk, but they are few and far between.)

Also, industrial meat animals are often fed better, and receive less in the  way of hormones and antibiotics in Europe, compared to North America. And, when we compare grain-fed animals to grass-fed ones, we see another big difference in the healthfulness of different meats.  Finally, let’s look at fish. In mice, dioxin-like environmental pollutants, which are highly toxic, raised TMAO levels. Well, the highest source of dioxins in the diet is from farmed-fish, so here is another potential explanation for the mixed results we are seeing in these studies.

Decreasing TMAO Levels

As we wait for the dust to settle on the TMAO research, we can at least have a look at those things we can do to keep our levels in check.

  • Reduce intake of animal foods: In a study on over 150 people, vegetarians, vegans, and those who followed a Mediterranean diet (high in fruit, legumes, and vegetables) had lower TMAO levels.
  • Take vitamins B and D: While the study was small (52 people), it showed that supplementing the subjects with vitamin D and the B vitamins decreased TMAO levels. Here again we see something that might explain conflicting results, given that so many people are vitamin D deficient.
  • Eat these foods: Both Brussels sprouts and pistachios reduced TMAO levels in those who consumed either food daily. As well, a substance (3,3-dimethyl-1-butanol) found in balsamic vinegar, extra virgin olive oil, grapeseed oil, and red wine, has been shown to decrease TMAO levels. (All part of a Mediterranean diet.)
  • Use resveratrol: In mice prone to atherosclerosis (hardening of the arteries), resveratrol decreased levels of TMAO in the blood.

Support Your Microbiome 
A study was done on a mix of vegans and meat-eaters, giving them all supplemental L-carnitine. Those who ate meat had a greater increase in TMAO levels compared to the vegans. “This means that vegans and vegetarians have gut bacteria that produce less TMAO.”

This may be our biggest clue yet. Having an ideal mix of good bacteria in our microbiome may be the single most important thing to determine what our body does with those precursors to TMAO. Whether or not it converts choline, lecithin, and carnitine into something good or something bad.  Not so far fetched when we consider that mice fed red meat reduced their TMAO by over 60% when also given soluble fiber, which served as a prebiotic. Researchers concluded that having a high diversity of gut bacteria was a key aspect for controlling TMAO levels.  This thesis is confirmed by human studies, which found that “conventional probiotics were unsuccessful in decreasing TMAO”. (Source for above material)

If maintaining a healthy microbiome is, perhaps, the primary thing we can do to ensure that TMAO does not run amok in our bodies, and conventional probiotic mixes are not helpful here, once again I am left with suggesting the use of NutriStart’s Lactospore products. Serving as a superior form of prebiotic, bacillus coagulans will easily help one to maintain that diverse mix of friendly flora, which we all require.

And, of course, one can also shift to a diet based more on plant foods, and less on animal foods, such as the Macrobiotic or Mediterranean diets (or, if you insist, a vegan diet).  You can check your TMAO levels with a blood test however, as the test is relatively new, the reference values have not yet been fully established.

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