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A Recent Study Finds the Paleo Diet Raises TMAO Levels – But Does it Actually Study the Paleo Diet?

By Trevor Connor, M.S., CEO
August 11, 2019
A Recent Study Finds the Paleo Diet Raises TMAO Levels – But Does it Actually Study the Paleo Diet? image

At the heart of the scientific process is debate. Debate is critical because everything in science is a theory and theories can only be improved by constantly challenging and refining them.

In nutritional science the debate often gets heated and even that can be a good thing. Scientists debating the merits of various diets often cite vastly different and contradictory studies. Sometimes they can even doggedly argue polar opposite interpretations of the same study.

But as long as you can back it up with research, almost anything is fair game.

Almost anything.

One thing you cannot do is create your own definition of a theory and then debate the merits of that definition.

For example, if we were going to debate the merits of the Paleo Diet vs the Mediterranean Diet, we couldn’t argue that the Mediterranean is unhealthy because people on the diet eat a pound of Oreos every day. They don’t. That’s not part of the definition.

In fact, we recently wrote an article comparing the nutrient density of the Paleo Diet to the Mediterranean Diet. To make this comparison we used the gold-standard Mediterranean sample menu as defined in the literature.[1] It took me hours to find the most acknowledged version, but it was time well spent because we wanted to debate the Mediterranean Diet and that meant debating the accepted definition.

Unfortunately, not everyone shares our standards and right now there’s a study making the rounds in the media that broke this important rule.

The study by Genoni et al has made claims about serious health concerns with the Paleo Diet. The authors found that people on a Paleo Diet have significantly higher levels of serum trimethylamine-N-oxide (TMAO) which has been associated with heart disease.[2]

Not only was the definition of a “Strict Paleo Diet” in their study not Paleo, but it matched up almost perfectly with fad low-carbohydrate diets which advocates of the Paleo Diet have stated clearly are neither Paleo, nor healthy.[2, 3]

Comparing the Diets: Why It Wasn’t Paleo

The study focused on a group that the authors referred to as the “Strict Paleolithic group” Their primary finding was that “consumption of a long-term Paleolithic diet was associated with markedly higher serum TMAO concentrations, but only in those who adhered to the diet strictly.”

So just how Paleo was this strict Paleo group?

In the Revised Edition of The Paleo Diet – the original Paleo Diet book and still recognized as the book that defines the diet – Dr Loren Cordain dedicated the first chapter not to defining the diet, but to warning readers against confusing fad low-carbohydrate diets with the Paleo Diet. In fact, this first chapter is titled “Not Just Another Low Carb Diet.”[3]

On page 24, the book breaks down a standard Paleo Diet next to a fad low-carb diet and shows what makes them different.

In Table 1 below, we have reproduced that comparison and placed next to them the breakdown of the three diets in the TMAO study by Genoni et. al.. We also included the breakdown of two sample Paleo Diet menus created by Dr. Cordain. One is from page 29 of his book and the other is from a 2002 study Dr Cordain published in the Journal of the American Neutraceutical Association (JANA) showing the nutrient composition of a sample Paleo Diet.[4]

Table 1. Comparison of the compositions of the three diets in the Genoni et. al. to two sample Paleo Diet menus and compositions of a proper Paleo Diet and Fad Low-Carbohydrate Diet as defined in the Revised Edition of The Paleo Diet.[2, 3]

A Recent Study Finds the Paleo Diet Raises TMAO Levels – But Does it Actually Study the Paleo Diet? image

* taken from the 2011 Revised Edition of The Paleo Diet, the first and still considered the definite definition of the Paleo Diet
** taken from a 2002 study by Dr Cordain published in JAMA containing one of the first analyses of a sample Paleo Diet menu
***6.7g of the polyunsatured fats (32%) were in the form of Omega-3s compared to 1.0g in a typical Western diet

What is most striking is that the “Strict Paleo Diet” group in the study by Genoni et. al. lines up almost perfectly with the definition of a fad low-carbohydrate diet and does not line up at all with the Standard Paleo Diet (highlighted in pink.)

In fact, strictly by the breakdown in the table, the Control group, which was defined as “consuming a diet typical of national recommendations,” lined up better with the Standard Paleo Diet than the Strict Paleo Diet group in the study.

What’s equally striking is how easy it is to see these contradictions. Anyone can recreate this table simply by looking at page 24 of The Paleo Diet and the diet chart in the TMAO study. You don’t need a degree in statistics nor do you need a Ph.D.

However, a Ph.D. leading a major research study should know better.

The fact is, the authors did not work with the accepted definition of the Paleo Diet. Instead, they worked with their own definition. Literally. In their Introduction they claim, “The Paleolithic diet can be classed as a low carbohydrate diet [5}.” That sole references is to a study by the same lead author – Genoni.[5] In other words, they referenced themselves for their definition of the diet.

And unfortunately, the criteria in their definition were woefully inadequate. Subjects only needed to eat minimal grains and dairy. That is not a sufficient definition of the Paleo Diet and as the study unfortunately proved, does not differentiate between a fad low-carb diet and a true Paleo Diet.

The two Paleo groups in this study were actually following a fad low-carb diet and the inability of Genoni et al to make this differentiation brings into question the primary conclusions of their study:

The Paleo Diet is Not Another Low Carbohydrate Diet

In a recent Newsweek article, lead author Genoni pointed to the low carbohydrate nature of the Paleo Diet as one of the major concerns. “We also found that populations of beneficial bacterial species were lower in the Paleolithic groups, associated with the reduced carbohydrate intake.”

It’s worth pointing out that their healthy control group fits within the carbohydrate range for a standard Paleo Diet. And while the sample Paleo Diets in table 1 are lower in carbohydrates than this control group, the two Paleo groups in the study clearly do not fit within the Paleo Diet carbohydrate definition.

We actually share the author’s concerns with very low-carbohydrate diets and have written about it.

Can She Blame Low Fiber Consumption?

In another interview with Paleo Magazine, Genoni said that elevated TMAO from consuming fish is not a concern because it is transient. Her concern was chronic TMAO elevation on a Paleo Diet due to the low-fiber in the diet. However, not only is the Paleo Diet not low in fiber, the breakdown of the two sample Paleo Diet menus in Table 1 have a higher fiber content than any of the diets in the study at 42.5g and 47g respectively. The control diet in the study only averaged 29.7g.

Or Fats?

“Conversely the direction of the shift in microbiota composition associated with fat consumption was in the opposite direction and suggests a more deleterious profile.” That’s a heavy quote. But it was a lead in to a substantial portion of the conclusions where the authors explained that the high-fat and particularly high-saturated fat content of the Paleo Diet may cause unwanted changes in our gut bacteria.

While the fad low-carbohydrate diets in the study are very high in fats, the two sample Paleo Diets published by Dr Cordain are comparable to the study’s control diet in total fat. In fact, the sample Paleo diets are actually lower than all of the study’s diets in saturated fat at 18g and 21g respectively. Even the study’s control diet averaged 27.3g of saturated fat.

In a Good Scientific Debate, You Come Armed with Scientific References

As we already pointed out, the sole reference the researchers had for claiming a Paleo Diet is low carbohydrate was one of their own studies. But that wasn’t the only place Genoni et al made strong claims with little backing.

The very first line of the study states that “The Paleolithic diet is promoted worldwide for improved gut health. However, there is little evidence available to support this claim.” Their sole reference for this prominent line in the study is a 2016 Australian cookbook.[6]

If you’re going to reference books instead of studies, what about all the books that actually popularized the Paleo Diet internationally. Better yet, what about referencing actual research about gut health. To start with, what about all the respected scientists who spent years living with and studying still existent hunter-gatherer societies. Their large body of research has consistently reported a robust microbiome, remarkable gut health, and nearly non-existent heart disease in these societies despite the fact that they’ve never eaten a single whole grain. [7-14]

We recommend starting with The Diverse Microbiome of the Hunter-Gatherer published in Nature – one of the most respected journals in the world. Scientifically, it certainly has more to say than an Australian cookbook.

We’re Ready to Debate… When You Are

To the authors of this study, we welcome a debate with you. We will give you full credit that the statistical analysis in your study was high quality, and you found concerning trends in plasma TMAO related to diet.

However, we have real concerns with the design of your study. Not the least of which is the fact that you did not study the Paleo Diet. The diet in your study was a fad low-carbohydrate diet that we have already stated is not Paleo and agree is not healthy.

So, before we engage in a debate with you, we ask two favors:

First, please make sure you stick to the rules of debate and learn the definition of the Paleo Diet before you show up. The one thing you do not get to do is create your own flawed definition of the diet and then attack those flaws.

Frankly, we’re sure your study was very expensive. It seems like it would have been prudent, before investing that sort of time and money, to have done your background research and learned what the Paleo Diet is. You know… read the first 30 pages of the New York Times bestseller that defined the Paleo Diet.

The truth is that we know you have done that. And what baffles us is that you seem to have completely forgotten the definition. You did conduct an earlier group of studies in 2016 where you had subjects read The Paleo Diet by Dr Loren Cordain and follow it’s guidelines. Those subjects did not see a rise in TMAO levels and actually saw health improvements including significant weight loss.[5, 15] How exactly did you forget the definition of the diet over those three years?

Second, until you understand the definition - or perhaps stop conveniently forgetting it - please stop using the term “Paleo Diet” or making claims about it. The fact is, your current research doesn’t study it.

Click Here to read a response to this study by fellow member of the Paleo Diet Editorial Board, Dr Mark J. Smith. Mark dived into the politics of this research and the Dieticians of Australia Association’s long standing debate with the Paleo Diet. Mark dives deeper into the fact that this was not actually the first study Genoni et al conducted of the Paleo Diet. In their first study, they gave subjects copies of “The Paleo Diet” by Dr Loren Cordain and instructed them to follow the books guidelines. That study found benefits to the Paleo Diet.


1. Ryan, M.C., et al., The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol, 2013. 59(1): p. 138-43.

2. Genoni, A., et al., Long-term Paleolithic diet is associated with lower resistant starch intake, different gut microbiota composition and increased serum TMAO concentrations. Eur J Nutr, 2019.

3. Cordain, L., The Paleo diet : lose weight and get healthy by eating the foods you were designed to eat. Rev. ed. 2011, Hoboken, N.J.: Wiley. xv, 266 p.

4. Cordain, L., The nutritional characteristics of a contemporary diet based upon Paleolithic food groups. Journal of the American Nutraceutical Association, 2002. 5(5): p. 15-24.

5. Genoni, A., et al., Cardiovascular, Metabolic Effects and Dietary Composition of Ad-Libitum Paleolithic vs. Australian Guide to Healthy Eating Diets: A 4-Week Randomised Trial. Nutrients, 2016. 8(5).

6. Evans, P., The complete gut health cookbook. 2016, Sydney: Pan Macmillan Australia Pty Ltd.

7. Schnorr, S.L., The diverse microbiome of the hunter-gatherer. Nature, 2015. 518(7540): p. S14-5.

8. Fragiadakis, G.K., et al., Links between environment, diet, and the hunter-gatherer microbiome. Gut Microbes, 2019. 10(2): p. 216-227.

9. Mancabelli, L., et al., Meta-analysis of the human gut microbiome from urbanized and pre-agricultural populations. Environ Microbiol, 2017. 19(4): p. 1379-1390.

10. Rampelli, S., et al., Metagenome Sequencing of the Hadza Hunter-Gatherer Gut Microbiota. Curr Biol, 2015. 25(13): p. 1682-93.

11. Crittenden, A.N. and S.L. Schnorr, Current views on hunter-gatherer nutrition and the evolution of the human diet. Am J Phys Anthropol, 2017. 162 Suppl 63: p. 84-109.

12. London, D. and D. Hruschka, Helminths and human ancestral immune ecology: What is the evidence for high helminth loads among foragers? Am J Hum Biol, 2014. 26(2): p. 124-9.

13. Cockburn, T.A., Infectious diseases in ancient populations. Curr Anthropol, 1971. 12: p. 45-62.

14. Davis, E.W. and J.A. Yost, The ethnomedicine of the Waorani of Amazonian Ecuador. J Ethnopharmacol, 1983. 9(2-3): p. 273-97.

15. Genoni, A., et al., Compliance, Palatability and Feasibility of PALEOLITHIC and Australian Guide to Healthy Eating Diets in Healthy Women: A 4-Week Dietary Intervention. Nutrients, 2016. 8(8).

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