Detractors of the Paleo diet often mention how it may increase a molecule called trimethylamine N-oxide, or TMAO, which has been correlated with disease states. Proponents of a vegan diet use TMAO as rationale for avoiding animal protein, like Dr. Joel Kahn did recently during a highly publicized debate with Paleo advocate Chris Kresser.

In recent weeks, unpublished data from a group of researchers in Australia has received media attention for correlating increased TMAO with the Paleo diet. The researchers suggest that, because TMAO is correlated with cardiovascular disease, the Paleo diet therefore increases risk of cardiovascular disease. The author cites low fiber intake due to the avoidance of whole grains as the reason behind elevated TMAO in the study’s “Paleo” subjects.

There’s a lot to unpack here to get to the truth of the matter, but let’s first start with what TMAO is. TMAO is a molecule produced by gut bacteria using choline, betaine, and carnitine, all of which come primarily from animal sources. It makes sense then that foods known to increase TMAO levels include red meat, eggs, and fish.

In addition to diet and microbiome composition, TMAO levels are also determined by kidney and liver function—and by genetics. Over the last several years, beginning with a 2013 article in the New England Journal of Medicine, TMAO has been linked with increased risk of cardiovascular disease.

If higher TMAO increases risk of heart disease, then animal protein causes heart attacks, right?

Not so fast.

There are two primary reasons TMAO and animal proteins are not a concern. Additionally, examining this TMAO research helps inform the best way to implement a Paleo diet.

Studies Show that TMAO Causes . . . Nothing

The first reason not to fear TMAO is that it has not definitively been shown to cause cardiovascular disease or any other medical problem. It has simply been correlated with cardiovascular disease and a variety of other medical conditions such as insulin resistance/diabetes, cancer, neurological conditions, and renal disease. Put another way, people who have these medical problems are more likely to also have high TMAO. But that doesn’t mean that TMAO caused the medical problem.

In fact, the opposite could be true: Poor diet and health disrupts the microbiome, elevating TMAO, while at the same time, separately, the same poor lifestyle also leads to medical problems.

Correlation, we must always remember, does not equal causation. In fact, an October 2018 review article in Nutrients concluded, “It is questioned whether TMAO is the mediator of or a bystander in the disease process.” Two other recent review articles concluded, “The implication that TMAO itself is a causative factor for cardiovascular and other diseases is controversial,” and, “The mechanism by which TMAO promotes atherosclerosis also remains speculative.”

So the case isn’t as open and shut as vegan advocates would suggest. One major argument against the blaming TMAO is the fact that the richest dietary source of TMAO is fish. Consuming fish is firmly associated with a reduction in the incidence of cardiovascular disease. If fish is both cardio-protective and the highest dietary source of TMAO, how can TMAO increase the risk of cardiovascular disease?

Another flaw in the argument that TMAO causes heart disease is the fact that diets high in resistant starch increase TMAO levels. Resistant starch sources, such as fruits, vegetables, and whole grains, are known to be protective against heart disease. If healthy dietary fiber increases TMAO, it doesn’t follow that TMAO increases risk of heart disease.

TMAO also has a U-shaped association with mortality: higher TMAO is associated with greater risk of death, but low TMAO is also associated with greater risk of death.

Some studies haven’t even shown a correlation between TMAO and heart disease. One study of 339 patients found that TMAO was higher in patients with insulin resistance, but that the elevated TMAO was not associated with a history of heart attack, coronary heart disease, or any cardiovascular event during the following eight years. Another study found no correlation between elevated TMAO and known heart disease risk markers CRP and LDL cholesterol. In another example, a study of patients with existing cardiovascular disease showed that those with atherosclerosis (hardened/narrowed arteries) did not have elevated TMAO levels. In fact, this group with heart disease had overall decreased levels of TMAO.

Not only is the correlation between TMAO and heart disease poor, but interventional studies have failed to show a mechanism. In one, scientists used L-carnitine supplementation to increase TMAO in patients. This increased TMAO did not induce any markers of atherosclerosis in healthy aged women. No lipid profile changes or other markers of adverse cardiovascular events were detected in these women over 24 weeks.

In another example, carnitine supplementation increased TMAO levels but decreased markers of vascular injury in patients undergoing hemodialysis. Thus, carnitine supplementation (which elevates TMAO) is recommended as cardioprotective for these patients. In fact, carnitine (a TMAO producer) has been shown by other studies to be helpful for treatment of cardiovascular disease.

The same lack of causation exists in other areas of TMAO research. For example, TMAO is correlated with insulin resistance as well as type 2 and gestational diabetes. Although more TMAO is produced by the microbiome in people who are obese and insulin resistant, there is no proof that the TMAO itself is dangerous. The lifestyle that leads to metabolic syndrome is obviously dangerous, though, and increased TMAO production could be a marker of this condition.

In a 2016 review article, scientists concluded that “It is possible that accumulation of TMAO in humans in disease state may be an adaptation of cells to stress and, hence, a marker rather than a mediator of disease.”

The Concern Is Not Quality Animal Protein but Gut Health

The second primary reason not to fear animal protein is that long-term TMAO elevation is known to be caused by dysbiosis (an imbalance of the microbiome), not by a serving of animal protein. When gut bacteria is imbalanced, it will produce more TMAO on an ongoing basis. Dr. Angela Genoni, who lead the recent Australian study correlating the Paleo diet with increased TMAO, told Paleo Magazine that the TMAO in fish is not a concern. She’s worried about the chronic TMAO elevation resulting from the dysbiosis caused by a low-fiber diet.

So a transient TMAO increase caused by a nutrient-rich food is not the issue. This is supported by many longevity studies that correlate fish consumption with long lifespan. As an analogy, think of candy. An occasional piece of candy is not a big deal. If you eat candy for every meal and snack, however, you’re in big trouble, one reason being that consistent sugar intake will cause microbiome dysbiosis. So even if TMAO were dangerous, the critical focus should be on improving gut health, not the transient TMAO increases caused by meals.

Avoiding dysbiosis is critical. The primary controllable cause of dysbiosis is poor diet and lifestyle. This could explain why studies sometimes find a correlation between TMAO and a myriad of medical problems (heart disease, diabetes, neurological disease, cancer, and renal disease). Poor diet and lifestyle cause these diseases; poor diet and lifestyle also cause dysbiosis. Then dysbiosis, in turn, elevates TMAO. TMAO is the bystander or marker, not the cause.

In other words, it’s not the beef in the burger that’s the problem. The problem is the white bun, the fries cooked in hydrogenated oils, and the sugar-sweetened soda likely to come with the beef. A sedentary lifestyle, poor sleep, and high stress levels also contribute to dysbiosis.

The Fiber Factor

Overall, the TMAO research clarifies the picture of the best way to implement a Paleo diet. The link between dysbiosis and lifestyle-related disease demonstrates that feeding the microbiome is critical to health. The primary dietary way that we support our microbiome is by consuming sufficient quantities of dietary fiber (and by avoiding foods that harm gut bacteria).

In reporting on the new, yet-unpublished data criticizing the Paleo diet, the argument has been made that people who follow a Paleo diet long-term (for more than one year) have elevations of TMAO and thus consume too little fiber. The suggestion is that the Paleo diet is, therefore, unhealthy because it excludes whole grains. This reasoning is clearly false.

Paleo is not an inherently low-carbohydrate (low-fiber) diet. In fact, most ancestral populations have a seasonal variation between high- and low-carbohydrate/fiber intake. Many ancestral populations actually eat high amounts of fiber, some over 100 grams per day. On the other hand, western populations (where “whole grains” are emphasized) average about half of the minimum fiber recommendations (25 grams for women and 38 grams for men), consuming about 15 grams per day. When properly implemented, the Paleo diet is much more protective against dysbiosis and disease than modern diets when it comes to fiber intake.

Some people who follow the Paleo diet, however, do stay on long-term low-carbohydrate or even ketogenic versions of the diet. This way of eating could pose a risk of dysbiosis and possible resulting disease.

This recent TMAO research may be a cautionary tale: long-term low-carbohydrate intake may not be safe unless extreme caution is taken. The ancestral model is to introduce seasonal variation of carbohydrate intake (sometimes low and sometimes high). The important thing is to ensure consumption of pre- and probiotic foods—from vegetables, fruits, nuts, seeds, and fermented foods. When carbohydrate intake is low, sufficient consumption of these foods is more challenging to achieve. Getting enough fiber on a low-carbohydrate diet is possible, but it takes deliberate effort. When dietary carbohydrate and fiber is not well tolerated, it’s important to reach out to a trained healthcare professional to improve tolerance to the degree that the microbiome can be supported with sufficient fiber.

You don’t have to fear your fish fillet, eggs, or even your steak. Eating quality meat is always key, but TMAO from animal protein is not a serious risk. The real lessons here are to take extreme caution to ensure sufficient dietary fiber intake from Paleo-friendly sources, and to reach out for help if you need it.