Deeper Dive: Another possible strike against the relationship between TMAO and heart disease

Ten years after trimethylamine N-oxide (TMAO) was first correlated with heart disease^[1] in observational research, it has become a candidate risk factor for cardiovascular disease^[1][2], obesity^[3], colon cancer^[4], diabetes^[5], and kidney disease^[6][7]. Aside from its adaptive, physiological role of protecting kidney cells^[8] stressed by excess urea or fluid imbalances, TMAO is also a waste byproduct of choline metabolism^[9]. Research suggests that choline^[10] and L-carnitine^[11] — most highly concentrated in meat, seafood, eggs, dairy, and dietary supplements — and, to some extent betaine^[12], are metabolized by omnivore-specific^[13] gut bacteria into trimethylamine (TMA). TMA is in turn metabolized in the liver to TMAO by the enzyme flavin-containing monooxygenase 3 (FMO3). Animal studies and ex vivo studies in humans suggest that, once in the blood, this molecule may trigger clotting^[10], inflammation^[14], and endothelial dysfunction^[15], which may cause heart disease, stroke, and kidney disease^[6].

Figure 1: The choline-TMA-TMAO pathway

However, the theory that TMAO causes heart disease is not fully established. Although the hypothesis is supported by numerous observational studies^[15], TMAO does not, as might be expected from this data, always predict cardiovascular outcomes in high-risk populations^{[16][17][18][19][20]}. Moreover, the positive relationship between dietary choline intake and heart or renal disease is not consistently confirmed in epidemiological studies^[18][21][22]. Hence, scientists speculate that TMAO may just be a correlate of metabolic disease or dysbiosis (a byproduct of disease rather than a causative agent) and that the associations in observational studies may be due to a variable other than TMAO^[8].

Furthermore, some choline sources are generally recommended as heart healthy^[23]. Plants like dark leafy greens, cruciferous veggies like broccoli, cauliflower, and kale, as well as nuts, legumes, and whole grains make up a significant portion of average choline and betaine intake^[24]. In contrast to what the choline-TMAO hypothesis of heart disease would suggest, all these foods are shown to have positive effects on cardiometabolic health in study after study^[25][26]. The situation is even more paradoxical for fish. Not only is fish another concentrated source of choline, but many types also provide significant amounts of preformed TMAO^[27]. And yet fish, in contrast to other animal-based choline sources, is often associated with better heart health^[28][29].

One explanation for these inconsistencies is the protective effects of the food matrix^[30]. Using this reasoning, other anti-inflammatory components of food (e.g. fiber, omega-3 fatty acids, antioxidants, phytochemicals, etc.) may overcome the negative effects of TMAO. On the other hand, the damage thought to be caused by TMAO in certain foods could be due to other components of the food matrix, making the food matrix argument a particularly weak explanation. The oxidative byproducts of char-grilled foods may explain part of the association between red meat and heart disease^[31]. However, an explanation is lacking as to why dairy^[32] and eggs^[33], which make up a good portion of average choline intake and consistently raise TMAO, are only inconsistently^[31] or mildly^[33] associated with heart disease.

So, if TMAO is an important risk factor for heart disease, why are foods that contain it not consistently associated with cardiometabolic disease risk? The study under review was designed to uncover the effect of foods generally regarded as healthy on TMAO levels and cardiometabolic risk factors.

TMAO, which is mainly produced by gut bacteria from dietary phosphatidylcholine and L-carnitine, may be associated with heart and kidney disease. However, not only is the relationship inconsistent, it also does not explain why some choline sources have been shown to have a neutral or overall beneficial effect on heart health. How consistent is the relationship between TMAO and its dietary precursors choline, carnitine, and betaine? How do healthy sources of choline affect TMAO levels and cardiometabolic risk factors?