During my appearance on the nearly 4-hour discussion of diet and health on the Joe Rogan Experience #1175 on September 27, 2018 (viewed and listened to millions of times), I brought up TMAO, a metabolite formed in the liver after ingesting red meat, eggs, and certain supplements.
I have written about TMAO recently to dispel rumors that blood levels rise after eating vegetables. TMAO can be measured in the blood and has been identified as a potential cause of coronary heart disease (CHD) and kidney scarring. I raised TMAO as a discussion point as an example of a list of reasons to avoid meat, along with perennial favorites like the excess of saturated fat, neu5GC, advanced glycation end products, and amino acids triggering aging pathways like mTOR.
My capable opponent, Chris Kresser, was ready to pounce and had slides at hand to counter my punch. The argument he offered went something like “some fish have TMAO preformed in their flesh, fish are generally regarded as heart healthy, so any science on TMAO is invalid and not a reason to reduce meat consumption”. This interchange was summarized in podcast notes under the heading Round 3. That few minutes of the long slugfest has spawned (pun intended) many comments on social media and analyses of the debate. Was Kresser right? Is the rapidly expanding science on TMAO worthless?
Briefly, a few comments about TMAO. Turn back the clock 50–60 years and the role of cholesterol as a necessary factor in the development of coronary heart disease (CHD) was just starting to be appreciated (although cholesterol science goes back a century or more at a minimum) and was rarely measured. In a similar manner, the metabolite TMAO has emerged as a putative factor in the development of CHD with over 1,000 scientific publications this decade reporting associations in a variety of serious health conditions of the cardiovascular system and beyond. The relationship may extend beyond a role for TMAO as simply a marker for CHD, and an understanding of how TMAO directly promotes atherosclerosis such as the CD36/MAPK/JNK pathway are known.
What is the issue with fish, TMAO and heart disease? I have done research on this topic before and after the Rogan show and there are points worth reviewing. However, the importance of pre-formed TMAO in certain fish and any direct role in CHD awaits further research from the team at the Cleveland Clinic. For now, these points are worth noting:
1) Some fish have pre-formed TMAO (but not all)
While not all fish have significant tissue levels of TMAO, some do. In a study of teleosts (a family of deep water fish such as garfish and sturgeons) it was found that “the deep-caught species had significantly greater TMAO content than shallow- or moderate-caught species. In all teleosts, muscle had substantially more TMAO than a ll other tissues”. In astudyof 89 species of fish in Hong Kong, TMAO was not detected in most freshwater fish. Human studies do indicate that eating some species of fish may acutely raise blood TMAO levels. Whether the acute rise and fall of a single meal of fish promotes atherosclerosis or endothelial (artery wall lining) dysfunction in humans is not known but it has been reportedin an animal model.
In an article in Forbes on the issue of TMAO and dietary fish, Stanley Hazen, MD, chair of the Department of Cellular and Molecular medicine at the Cleveland Clinic and an American Heart Association Distinguished Scientist 2017, was quoted as indicating that “some forms of fish that have very high levels of TMAO, such as deep sea fish in Arctic waters, which use TMAO as anti-freeze and have extraordinarily high TMAO levels. Surface fish, like trout, tend to have very low TMAO.”
In an email exchange I had with Wilson Tang, MD, the Director of Cleveland Clinic’s Center for Clinical Genomics, Research Director, and staff cardiologist, he indicated that:
“As far as I’ve been able to find, there is no comprehensive analysis of TMAO content in common fish/seafood used in the North American diet. However, its generally accepted that TMAO levels tend to increase as the habitat depth of the fish deepens and the water temperature becomes colder.
Wild-caught freshwater lake and river fish are the least likely to have high concentrations of TMAO. This includes trout and perch. Saltwater fishes however are more likely to have higher levels, including, shark, rays, mollusks, and crustaceans. Various types of cod including Chilean seabass, a cold-water cod fish, have high levels. One exception is the generally freshwater tilapia. Tilapia species may have higher TMAO due to the food it is eating. Farm raised fish tend to have higher TMAO than their wild-caught counterparts. TMAO and TMAO precursors are common nutrients in farm-raised fish diets.”
In an email exchange I had with Dr. Hazen he indicated that:
“Not all fish are equal. Most are TMAO free. That — and — in fact, there really are no prospective intervention diet studies to show eating fish (and which specific kinds especially) are healthier for you compared to vegetarian diet, Mediterranean diet or any other diet for that matter. If faced with choice between fish versus red meat. Fish, I believe, easily wins. But if choosing between a fatty fish like cod or tilapia versus salmon/tuna or trout, the latter are far better.”
Bottom line, the majority of fish do not have TMAO in their flesh and the fact that a few species can cause a transient rise in blood TMAO levels in humans without known consequences does not deny the huge amount of data linking TMAO to CHD.
2) The TMAO/Fish Debate Exists in the Medical Literature
An interesting exchange of opinions on fish and TMAO occurred in response to an article in 2016 linking elevated TMAO levels to CHD in humans. Researchers in Oslo, Norway wrote in a letter to the journal that “the hypothesis that TMAO is directly involved in development of atherosclerosis therefore seems like a paradox, as intake of seafood is generally accepted as cardioprotective”. They suggested that ingesting TMAO directly from seafood should not be regarded as “fishy business”.
Drs. Tang and Hazen of the Cleveland Clinic got the final word in on this issue in their response in the same journal. They wrote that they rejected the idea that “anything and everything derived from the sea and ingested in any quantity must be heart healthy” and even equated the oil extracted from blubber to bacon fat! They pointed out that the “benefits of large quantities of TMAO-rich fish in patients who have been associated with elevated TMAO levels (e.g. chronic kidney disease) have not been demonstrated”.
Finally, in a review article last year the group of Cleveland Clinic researchers commented on the issue of fish and TMAO. They wrote that “ a paradox concerning TMAO is the high levels of this metabolite in fish and the associations of diets high in fish to be beneficial for cardiovascular health. Clearly, fish intake (especially deep sea fish) is associated with detectable increase in urinary TMAO excretion…transient (usually in a few hours’ time) before returning to its steady state”. The referenced the study in mice relating fish intake and atherosclerosis to indicate that the matter of fish and health is not resolved. They concluded that there was “no study that directly demonstrates the beneficial effects of fish intake in patients with advanced chronic kidney disease, a population in which TMAO clearance is likely impaired.”
While more study needs to be done on the topic of the health consequences of eating species of fish high in preformed TMAO, with more data anticipated in 2019, there are some take home points.
1) The majority of fish do not have TMAO in their flesh
2) The similarities, if any, of a transient rise in preformed TMAO from those species of fish versus the regular exposure to TMAO metabolized by daily meat and egg consumption need to be considered.
3) A blood test is widely available for TMAO. In my clinic, I have measured this metabolite in several thousands of patients. When the TMAO level is elevated I advise my patients to limit or eliminate red meat, egg yolks, deep water fish, and supplements with L-carnitine and choline. I recheck the level in a month and it usually drops to normal. If someone regularly eats fish I would advise having the TMAO level checked, along with a blood mercury level which is often markedly elevated in patients in my clinic eating fish several times a week. I use the level to determine if it would be advisable to adjust their diet.
4) It is easy to appreciate why the conversation about TMAO and fish on the Joe Rogan Experience a few months back could not be concluded with a simple sound bite.