I’ve been writing a lot about choline lately. Most recently, my article entitled “Nonalcoholic Fatty Liver Disease: A Silent Epidemic of Nutritional Imbalance” contained a major section on the role of dietary choline in protecting against fatty liver disease, which itself is a powerful and independent risk factor for heart disease.
It may be of concern, then, that a recent paper published in Nature suggests that dietary choline may be contributing to heart disease:
Yikes! Are we to eat liver and egg yolks to support our liver health and mental health only to wind up with heart disease as a result?
Here’s a diagram representing the hypothesis that these authors have offered us (image from the associated commentary by Rak and Rader):
The authors argue that dietary choline, found mostly as phosphatidylcholine, enters the intestine where our gut bacteria convert it to free choline and then to trimethylamine, a gas that smells like rotting fish. Then our livers detoxify the trimethylamine to an odorless product called trimethylamine oxide (TMAO). While this prevents us from walking around smelling like we’ve been swimming in a barrel full of fermenting cod livers, the authors argue that TMAO fills our arteries with plaque.
In support of this hypothesis, the authors showed that blood levels of choline, its metabolic byproduct betaine, and TMAO all correlated with the incidence and severity of cardiovascular disease in humans, although this was not prospective data showing that the occurrence of these compounds in the blood early in life predicted the development of heart disease later in life.
They also showed that feeding mice phosphatidylcholine did in fact produce TMAO, but only in the presence of gut bacteria. Further, feeding mice five-fold or ten-fold higher concentrations of choline chloride than they would ordinarily receive, or simply feeding them TMAO itself, increased atherosclerotic lesion size, and atherosclerotic lesion size correlated with blood levels of TMAO.
There’s just one major problem with this hypothesis. Studies in humans have shown that neither phosphatidylcholine nor choline-rich foods produce detectable increases in trimethylamine.
Here’s a figure from a 1983 study by Ziesel and colleagues showing urinary excretion of trimethylamine after supplementation with different types of choline in humans:
The third bar in each panel represents the excretion of trimethylamine in the urine. Choline chloride and choline stearate led to the production of large amounts of trimethylamine, but lecithin (phosphatidylcholine), the main form of choline found in food, led to only a small increase.
It turned out, however, that their lecithin was contaminated with some trimethylamine. If they “cleaned” it to remove the contamination, shown in the fourth panel, the lecithin did not increase urinary excretion of trimethylamine at all.
A 1999 study by other authors came to similar conclusions. They looked at the urinary excretion of both trimethylamine and its detoxification product TMAO in humans. They found that 60 percent of free choline and 30 percent of carnitine, another potential precursor, was excreted in the urine as one of these two products, but that neither betaine nor phosphatidylcholine converted to either product at all.
In fact, these authors even fed 46 different foods to humans and looked at the subsequent excretion of trimethylamine and TMAO. Choline-rich foods like liver and eggs did not produce any increase in urinary trimethylamine or TMAO over control levels. In fact, even carnitine-rich meats failed to increase excretion of these compounds. The only foods that increased excretion of TMAO were seafoods, which naturally contain some trimethylamine, giving them their “fishy” smell.
Here is a representative selection of seafoods and other animal foods:
Here we see that only seafoods, naturally contaminated with trimethylamine, increase the urinary excretion of trimethylamine and TMAO in humans. Liver, eggs, and meat do not.
These authors explained their results by citing research showing that the enzyme phospholipase A cleaves phosphatidylcholine, or lecithin, into a compound called lysolecithin in the small intestine where it is efficiently absorbed. By contrast, other forms of choline travel to the colon where gut bacteria make enzymes that convert them to trimethylamine.
Should we presume, then, that it is not liver and egg yolks, but rather fish and shellfish that contribute to heart disease? Perhaps, although this seems doubtful given that populations such as the Kitavans eat plenty of fish, even in fermented form, yet appear to be free of heart disease.
In order to even begin supporting such a hypothesis, we would have to first see to what degree eating seafood leads to the accumulation of TMAO in the blood, and here we only have urinary data. If the kidneys efficiently dispose of TMAO into the urine after eating seafood, TMAO may be unlikely to accumulate in the blood for any length of time.
Indeed, the massive increases in urinary trimethylamine and TMAO following meals rich in seafood suggests that our kidneys excrete these compounds very efficiently.
So how, then, should we interpret the correlation between heart disease risk and plasma concentrations of choline, betaine and TMAO in humans?
Blood levels of choline are currently considered an emerging marker for destabilization of coronary plaques or ischemia in acute coronary syndrome, as reviewed here. During the process of blood clotting, inflammatory enzymes release choline from membrane phospholipids in order to also generate phosphatidic acid, which is used as an important signaling molecule. Elevated blood levels of choline, then, and perhaps its metabolite betaine, could simply reflect an inflammatory or pro-clotting environment.
Elevated TMAO could reflect dietary trimethylamine or TMAO from seafood, but it could also reflect impaired excretion into the urine, or enhanced conversion of trimethylamine to TMAO in the liver.
The enzyme Fmo3 carries out this conversion, mainly in the liver, as reviewed here. There are a number of genetic variants affecting the activity of this enzyme, some of which appear only in certain ethnicities, and the enzyme also processes a number of drugs used to treat psychoses, infections, arthritis, gastro-esophageal reflux disease (GERD), ulcers, and breast cancer. Iron or salt overload may also increase the activity of the enzyme. TMAO could, then, be a marker for ethnicity, drug exposure, genetically determined drug efficacy, or other conditions.
If we had strong epidemiological evidence showing that consumption of fish and shellfish early in life is associated with an increased risk of developing heart disease later in life, then the animal studies reported in the Nature article would present a strong justification for considering the hypothesis that trimethylamine contaminating these foods is somehow increasing the risk of heart disease.
Yet, we do not have that. Alas, we instead have evidence that islanders who eat traditional diets containing fish tend to be free of heart disease.
Perhaps future work will in fact elucidate a role for harmful gut bacteria in increasing TMAO levels and subsequent development of heart disease, in which case the clear implication would be that we should figure out how to normalize the gut bacteria. Right now, we have no evidence that eating choline-rich animal foods increases TMAO at all, so a hypothesis dependent on this apparently fictitious process is as yet an impotent one.
Pass the liver and egg yolks please. And maybe some folks fasting for Lent may say pass the fish, shrimp or octopus. Consuming these choline-rich foods will produce much better mental health than worrying in the face of contrary evidence that they are clogging your arteries.
Read more about the author, Chris Masterjohn, PhD, here.