Paleo Diet Increases TMAO - Linked to Heart Disease

Paleo Diet Increases TMAO - Linked to Heart Disease

Despite reaching peak popularity in 2013, the Paleo diet still remains incredibly popular amongst dieters looking to adopt healthier eating habits and shed a few unwanted pounds.

Founded on the premise of eating as our caveman ancestors did during the Paleolithic era, the Paleo diet prioritizes the consumption of meat, fish, poultry, eggs, fruits, vegetables, and healthy fats (avocado, walnuts, etc.), while scorning all things not commonly eaten by our cave-dwelling forefathers -- grains, legumes, tubers, dairy, refined sugar, and refined vegetable oils. 

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The reason this cornucopia of foods is persona non grata in the Paleo community stems from the belief that these foods are a relatively recent “invention” of the agricultural revolution, and as such our bodies have not evolved to process them properly (even though evidence exists that prehistoric man consumed some of these “bad” foods from time to time).

It is for this reason why Paleo proponents believe these foods are associated with inflammation and, as a result, numerous chronic diseases including type 2 diabetes, heart disease, and cancer.

Basically, according to the Paleo mindset, food advancements outpaced human evolution, and, as a result of our inability to adapt in a reasonable amount of time, seemingly harmless foods like whole grains, beans, and potatoes are causing us to become fat and sick.

Beyond its claims to being a healthier way to eat, the paleo diet is also viewed by many as a superior eating plan to follow when seeking weight loss and promote a healthy gut. Now, the paleo diet does do a number of things right -- focusing on whole, minimally-processed, nutrient-dense foods. But where it drops the ball is the abject fear/avoidance of starchy carbohydrates.

And, according to the findings of a new study, the Paleo diet may not be as healthful as it is believed to be.

The Study

For the cross-sectional comparator study, researchers from Edith Cowan University put out an APB for healthy men and women (BMI < 30 kg/m2) aged 18-70 to determine the impact of a Paleolithic diet vs a typical Australian diet on markers of gut health and a metabolite closely associated with cardiovascular disease called trimethylamine-N-oxide (TMAO).

We’ll discuss TMAO in further detail in a bit, but first, let’s discuss what this new study found.

A total of 92 people took part in the study (44 paleo and 48 “normal” dieters) and were told to complete a 3-day weighed diet records, as well as provide blood, urine and stool samples. To be considered for inclusion in the paleo group, prospects had to be eating primarily paleo for over a year and consuming no more than one serving of grains or dairy products per day. [1]

Fig. 1. Flow diagram of the study. Of the 231 enquiries received, 92 participants were accepted into the study. Two participants in the control group withdrew due to illness, with partial data available for one subject. 44 Paleolithic and 46 controls completed the study data collection. [1]

Candidates were also excluded if they had taken antibiotics in the previous six months (as antibiotics can significantly alter gut bacteria composition). Other factors eliminating candidates from inclusion were:

  • Current or previous digestive disorder,
  • GI tract surgery
  • Usage of anti-hypertensive or lipid or glucose-lowering medication
  • Prior cardiovascular events or diagnosed cardiovascular disease

As mentioned above, to track the subjects daily food intake, researchers used a 3-day Weighed Food Records (two weekdays and one weekend day), which are considered the "gold standard" for assessing an individual’s daily food intake. [3]

The reason weighed food records are regarded as the “gold standard” is that this method weighs each food the subjects consume, which gives a more accurate assessment of nutrient and energy intake compared to dietary recalls, which are well-known to have high degrees of variability (and therefore, accuracy).

In addition to weighed food records, participants also completed a diet history interview. And based on the findings of the 3-day weighed food record, researchers further subdivided the paleo group into:

  • Strict Paleo: <1 serving per day of grains and/or dairy
  • Pseudo-Paleo: >1 serving per day of grains and/or dairy

Study Results

Of the 92 that began the study, 90 completed it.

Researchers found that dieters following the “strict” paleo diet had similar daily fiber intake compared to the control group, despite eating lower total carbohydrates. However, those following the “pseudo” paleo diet consumed less fiber than the control group and also fell below the recommended Australian adequate intake (AI) of 25 grams of fiber per day. [1]

Resistant starch intake was significantly lower in both paleo groups compared to the control group.

Why is this important?

Resistant starch is a type of fiber that serves as food for our gut bacteria from which short-chain fatty acids are generated. [4] One of the most important short-chain fatty acids produced from the fermentation of these resistant starches is butyrate.

Butyrate is a preferred energy source of the cells lining our colon. Beyond that, butyrate has also been shown to:

  • Boost metabolism
  • Decrease inflammation
  • Improve resistance to stress

The most common source of resistant starches in the diet are found in cooked and cooled starchy foods (boiled rice that is refrigerated and then reheated, for instance), raw potatoes and bananas, oats, and beans.

In addition to serving as food for the good bacteria in our gut, resistant starch also helps increase the concentration and diversity of the microbiome. [5,6]

Other notable findings from the study were that all groups consumed more than the recommended daily intake of saturated fat and overall fat intake was significantly higher in both Paleo compared to the control.

During their analysis of the participants gut microbiome, researchers noted that concentrations of good gut bacteria species were lower in the Paleo groups, and they also had greater concentrations of bacteria that produce TMAO -- which is most likely due to the avoidance of grains, legumes, and tubers as these foods are rich in resistant starch and are omitted from paleo diets.

And, despite the differences in resistant starch intake between the paleo and control groups, researchers did not observe any significant differences between groups in short-chain fatty acid excretion. Remember, short-chain fatty acids are the byproduct of resistants starch metabolism by our gut bacteria.

Interestingly, researchers noted that only those who were long-term followers of the “strict” paleo diet were associated with higher serum TMAO concentrations. Individuals following the “pseudo” paleo diet did not have statistically different TMAO levels from the control.

What is TMAO?

TMAO is formed from trimethylamine (TMA), which is created when our gut bacteria metabolize certain nutrients, such as choline, betaine or carnitine -- all of which are prevalent in animal-based proteins.

The liver then converts trimethylamine into TMAO, and from there, TMAO is typically cleared by the kidneys. Note that it can also be delivered to various tissues to function as an osmolyte.

As we just mentioned, a number of studies have found an association between increased levels of TMAO and an increased risk for clot-related events, including heart attack and stroke. [7,8,9]

Recently an analysis including over 2000 patients with coronary artery disease found that high concentrations of TMAO were associated with higher rates of premature death. [10]

In fact, individuals with the highest levels of TMAO had a four-fold increase in the risk of dying from any cause over the following five years.

However, not all studies have found a link between elevated TMAO levels and adverse cardiovascular events. [13]

Furthermore, various types of seafood also contain high levels of TMAO, and sea-faring protein is widely regarded as some of the healthiest food around.

So, what could be the possible link between TMAO and heart disease?

TMAO and Heart Disease

While the exact mechanism by which TMAO promotes atherogenic effects has yet to be fully elucidated, researchers believe it lies in the ability to TMAO to: [2]

  • Alter cholesterol, sterol, and bile metabolism,
  • Encourage the formation of foam cells,
  • Activation of inflammatory pathways, and
  • Change sterol transporters in the liver and intestine

Basically, researchers think that TMAO adversely impacts bile acid pathways in the body, and blocking this pathway may lead to atherogenesis.

Furthermore, in vivo rat studies and in vitro studies using human cells have found that TMAO can induce expression of inflammatory cytokines (via the NF-κB signaling pathway) even at normal physiological levels. [2]

But, the data isn’t so cut and dry on TMAO and cardiovascular events as some research shows elevated levels of the chemical were inversely correlated with atherosclerotic lesion size. Based on these findings, researchers suggested that TMAO may confer a protective effect as opposed to a causative one regarding atherosclerosis development. [11]

Suffice it to say that the jury is still out on TMAO and heart disease. Researchers have found some evidence that elevated TMAO levels are associated with increased heart disease and mortality, but other research gives evidence otherwise.

For all we know, TMAO could find itself alongside saturated fat and dietary cholesterol, blamed for something that isn’t really its fault.

We will have to wait and see...


In concluding the study, the authors noted an association between Paleo diets and less “good” gut bacteria as well as increased concentrations of TMA-generated bacteria, which is the reason for the elevated TMAO levels as TMA is converted to TMAO in the liver.

They conclude the study by saying:

“The rationale to exclude whole grains is not supported by data presented here; being inversely associated with body weight and TMAO concentrations. Despite the maintenance of SCFA excretion, and stool frequency and form, the differences noted in microbiota composition associated with the high fat and low carbohydrate intake may not be beneficial for long-term health.”

In other words, according to the researchers’ findings, consuming grains was not associated with higher body weights (in fact, it was just the opposite), indicating that carbohydrates aren’t the evil-doers that some paleo proponents make them out to be.

Individuals following strict paleo diets have greater amounts of TMA-generating gut bacteria, leading to higher TMAO concentrations.

However, there is no consensus yet on whether TMAO levels need to be reduced or to what level they should be reduced (as there is only an association between elevated TMAO concentrations and heart disease, but no causal relationship yet).


1) Angela Genoni, Claus T. Christophersen, Johnny Lo, Megan Coghlan, Mary C. Boyce, Anthony R. Bird, Philippa Lyons-Wall, Amanda Devine. Long-term Paleolithic diet is associated with lower resistant starch intake, different gut microbiota composition and increased serum TMAO concentrations. European Journal of Nutrition, 2019; DOI: 10.1007/s00394-019-02036-y

2) Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016;8(11):326. Published 2016 Nov 8. doi:10.3390/toxins8110326

3) Carlsen MH, Lillegaard IT, Karlsen A, Blomhoff R, Drevon CA, Andersen LF. Evaluation of energy and dietary intake estimates from a food frequency questionnaire using independent energy expenditure measurement and weighed food records. Nutr J. 2010;9:37. Published 2010 Sep 15. doi:10.1186/1475-2891-9-37

4) Birt DF, Boylston T, Hendrich S, et al. Resistant Starch: Promise for Improving Human Health. Advances in Nutrition. 2013;4(6):587-601. doi:10.3945/an.113.004325.

5) Wang, X. , Brown, I. L., Evans, A. J. and Conway, P. L. (1999), The protective effects of high amylose maize (amylomaize) starch granules on the survival of Bifidobacterium spp. in the mouse intestinal tract. Journal of Applied Microbiology, 87: 631-639. doi:10.1046/j.1365-2672.1999.00836.x

6) Topping, D. L., Fukushima, M., & Bird, A. R. (2003). Resistant starch as a prebiotic and synbiotic: state of the art. The Proceedings of the Nutrition Society, 62(1), 171–176.

7) Wang Z., Tang W.H., Buffa J.A., Fu X., Britt E.B., Koeth R.A., Levison B.S., Fan Y., Wu Y., Hazen S.L. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 2014;35:904–910. doi: 10.1093/eurheartj/ehu002.

8) Tang W.H., Wang Z., Fan Y., Levison B., Hazen J.E., Donahue L.M., Wu Y., Hazen S.L. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: Refining the gut hypothesis. J. Am. Coll. Cardiol. 2014;64:1908–1914. doi: 10.1016/j.jacc.2014.02.617.

9) Zhu W, Gregory JC, Org E, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016;165(1):111–124. doi:10.1016/j.cell.2016.02.011

10) Senthong V, Wang Z, Li XS, et al. Intestinal Microbiota-Generated Metabolite Trimethylamine-N-Oxide and 5-Year Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of Intestinal Microbiota in a COURAGE-Like Patient Cohort. J Am Heart Assoc. 2016;5(6):e002816. Published 2016 Jun 10. doi:10.1161/JAHA.115.002816

11) Collins H.L., Drazul-Schrader D., Sulpizio A.C., Koster P.D., Williamson Y., Adelman S.J., Owen K., Sanli T., Bellamine A. l-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in apoE(−/−) transgenic mice expressing CETP. Atherosclerosis. 2016;244:29–37. doi: 10.1016/j.atherosclerosis.2015.10.108.

12) Abbasi, J. (2019). TMAO and Heart Disease: The New Red Meat Risk?, 321(22). doi:10.1001/jama.2019.3910

13) Mueller D.M., Allenspach M., Othman A., Saely C.H., Muendlein A., Vonbank A., Drexel H., Von E.A. Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control. Atherosclerosis. 2015;243:638–644. doi: 10.1016/j.atherosclerosis.2015.10.091.

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Harold Wood - August 22, 2019

It’s good to find this kind of research here. It would be interesting to see an investigation with a Pseudo-paleo group that does not consume dairy, since around 65% of mankind lacks the ability to process this. The ‘healthy’ status of ‘sea-faring protein’ (fish?) could be also reconsidered, given the unfortunate ability of toxins (mercury, etc) to accumulate in increasing amounts towards the top of the oceanic food chain, especially in shark flesh, the favoured species of Australian fast-food outlets, sold as ‘flake’.

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