With the last few weeks’ definitive guide and follow-up on fish, a reader asked me about trimethylamine N-oxide, or TMAO. What is it?
TMAO is the latest justification given for why eating meat just has to be bad for you. Saturated fat didn’t take. Animal protein didn’t work. Iron was a dud. IGF-1 hasn’t panned out. Methionine isn’t enough. So now they’re using TMAO to convince you not to eat that steak.
How’s it supposed to work?
When certain gut bacteria encounter choline (found in eggs and liver) or carnitine (found in meat, especially red meat), some of it is converted to trimethylamine, or TMA. TMA is the compound that gives fish its “fishy odor.” Fish is actually extremely high in TMA, which I’ll discuss later on. Then, the liver converts a portion of the TMA to TMAO. Studies have shown that elevated serum levels of TMAO are linked to heart disease, type 2 diabetes, kidney disease, and even all-cause mortality. There’s definitely some heterogeneity among the studies, but enough have found a strong connection between TMAO and all manner of poor health conditions that researchers have focused on this compound.
Okay, so anything that contains choline or carnitine will increase TMAO, which should in theory increase your risk of heart disease. Right? Let’s go down the list.
Eggs. The best source of TMAO-precursor choline in our diet—eggs—should absolutely skyrocket TMAO levels. Except it doesn’t happen.
Three eggs a day has no effect on TMAO levels, even as it increases choline levels and HDL cholesterol.
Okay, so maybe the choline slipped past the TMA-producing gut bacteria in that study, but what about if you quickly switch people from eating oatmeal for breakfast to eating eggs. Surely bad things will happen, right?
No. Eating eggs instead of oatmeal has no effect on TMAO levels. It increases carotenoid and choline levels, though.
Liver. Okay, liver has to do the trick. It has high levels of both carnitine and choline. But no: feeding liver (among other foods) to men fails to increase TMAO levels above control.
Carnitine. Forget meat. What if you go straight to the offensive precursor itself and give actual human women a big daily dose of carnitine for, I don’t know, 24 weeks? Surely it will do something bad.
Nope. TMAO skyrockets, an indication that these ladies’ gut bacteria are converting carnitine to TMA and TMAO, but serum C-reactive protein, interleukin-6, L-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and lipid profile markers are completely unaffected. If gut bacterial conversion of carnitine to TMAO is the preeminent risk factor for heart disease, you’d think some of these ladies’ cardiovascular risk factors would have responded. They had half a year to respond. They did not.
Okay, but maybe there’s lag time between TMAO increases and deleterious changes to health. Nope. They followed those same ladies after cessation of carnitine supplementation. Their TMAO levels dropped, but their health markers stayed the same. No change.
And here’s a study where they used carnitine to increase TMAO levels in patients on dialysis. Not only did nothing bad happen, but the carnitine even reduced markers of vascular injuries. Higher TMAO, better health.
Seafood. As I mentioned earlier, fish and shellfish come pre-contaminated with the TMAO precursor TMA. It’s what gives the characteristic fishy odor, and it definitely gets converted to TMAO. In fact, a human study from a few years ago found that feeding people fish spiked TMAO levels by 60 times. A more recent study even concluded that elevated TMAO levels are a reliable marker for cod intake. The more fish you eat, the more TMAO your body will process.
If you’re going to claim that TMAO is dangerous and causes heart disease, you’ll have to make the case that fish is dangerous and causes heart disease. All the evidence we have points in the opposite direction—that fish and shellfish are protective against heart disease.
How do we explain the connection between increased TMAO and poor heart health?
Here it is linked to atrial fibrillation.
Here it is linked to stroke.
Here it is predicting heart events.
The connection is there. And in animal models, TMAO even appears to mechanistically increase atherosclerosis. The mice they dosed with TMAO to increase atherosclerosis were genetically engineered to be ApoE knockouts, a strain of lab mouse that gets heart disease from almost everything, but still.
The connection isn’t causal. It’s an observation. There are no controlled studies giving people foods (or even supplements) that raise TMAO and increase disease or death. There aren’t even prospective observational studies where they track a group’s food intake, TMAO levels, and death/disease over time.
You know what I think (and have always thought)?
High TMAO can be a marker for metabolic disease. It could indicate inhibited kidney function, as the kidneys are response for disposing of excess TMAO. It could indicate poor health in general.
The latest evidence is confirming what I’ve long suspected: the reason high TMAO levels are linked to cardiovascular disease and overall mortality is that both type 2 diabetes and chronic kidney disease cause elevated TMAO levels. The causality is reversed.
What’s one of the kidney’s primary jobs? Excreting waste materials and toxins. What’s going to happen if the kidney begins to fail or lose its functioning? The stuff that used to be excreted starts backing up. TMAO is supposed to be excreted in the urine via the kidneys. If the kidneys aren’t working, TMAO levels skyrocket.
But even then, high TMAO isn’t even necessarily a bad thing. Check out that study I linked to earlier where women were given carnitine every day. Their TMAO levels skyrocketed but nothing bad happened. No health markers worsened. In one study, they even improved.
That’s the thing with biology. There are dozens of reasons TMAO could be elevated, some of them bad, some of them harmless, some of them good.
There simply exists no credible evidence that increased TMAO because you’re eating fish, or eggs, or liver, or meat, does anything untoward to your health. I’m not ruling it out. But the evidence just isn’t there. There’s far more evidence that eating fish, eggs, liver, and meat improve your health.
That’s it for today, folks. If you have any further questions about TMAO, leave them down below. Until then, enjoy your choline and carnitine!
Thanks for reading.
References:
Schiattarella GG, Sannino A, Toscano E, et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J. 2017;38(39):2948-2956.
Dimarco DM, Missimer A, Murillo AG, et al. Intake of up to 3 Eggs/Day Increases HDL Cholesterol and Plasma Choline While Plasma Trimethylamine-N-oxide is Unchanged in a Healthy Population. Lipids. 2017;52(3):255-263.
Missimer A, Fernandez ML, Dimarco DM, et al. Compared to an Oatmeal Breakfast, Two Eggs/Day Increased Plasma Carotenoids and Choline without Increasing Trimethyl Amine N-Oxide Concentrations. J Am Coll Nutr. 2018;37(2):140-148.
Zhang AQ, Mitchell SC, Smith RL. Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol. 1999;37(5):515-20.
Samulak JJ, Sawicka AK, Hartmane D, et al. L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women. Ann Nutr Metab. 2019;74(1):11-17.
Samulak JJ, Sawicka AK, Samborowska E, Olek RA. Plasma Trimethylamine-N-oxide following Cessation of L-carnitine Supplementation in Healthy Aged Women. Nutrients. 2019;11(6)
Fukami K, Yamagishi S, Sakai K, et al. Oral L-carnitine supplementation increases trimethylamine-N-oxide but reduces markers of vascular injury in hemodialysis patients. J Cardiovasc Pharmacol. 2015;65(3):289-95.
Svingen GFT, Zuo H, Ueland PM, et al. Increased plasma trimethylamine-N-oxide is associated with incident atrial fibrillation. Int J Cardiol. 2018;267:100-106.
Liang Z, Dong Z, Guo M, et al. Trimethylamine N-oxide as a risk marker for ischemic stroke in patients with atrial fibrillation. J Biochem Mol Toxicol. 2019;33(2):e22246.
Haghikia A, Li XS, Liman TG, et al. Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes. Arterioscler Thromb Vasc Biol. 2018;38(9):2225-2235.
Jia J, Dou P, Gao M, et al. Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis. Diabetes. 2019;68(9):1747-1755.
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