 One way a diet rich in animal-sourced foods, meat, eggs, and cheese, may contribute to heart disease, stroke, and death is through the production of an atherosclerosis-inducing substance called TMAO. With the help of certain gut bacteria, the choline and carnitine found concentrated in animal products can get converted into TMAO. But wait a second. I thought atherosclerosis, hardening of the arteries, was about the buildup of cholesterol. Cholesterol is still king. TMAO just appears to accelerate the process. TMAO appears to increase the ability of inflammatory cells within the atherosclerotic plaque in the artery wall to bind to LDL cholesterol, which makes it more prone to gobble up that cholesterol. So it's just another piece of the puzzle of how cholesterol causes heart disease. And TMAO doesn't just appear to worsen atherosclerosis, contributing to strokes and heart attacks, but also heart failure and kidney failure. If you look at a really high-risk group like diabetics after a heart attack, nearly all those who started out with the most TMAO in their bloodstream went on to develop heart failure within 2,000 days, about five years. Whereas only about 20% of those starting out with medium levels in the blood went into heart failure and none in the low TMAO group. Not only do those with heart failure have higher levels of TMAO than controls, and those with worse heart failure have higher levels than those with lesser stage disease. If you follow people with heart failure over time, within six years half of those who started out with the highest levels were dead. This finding has since been replicated in two other independent populations of heart failure patients. The question is why? It's probably unlikely to just be additional atherosclerosis since that takes years. For most of those that die of heart failure, the heart muscle just conks out or there's a fatal heart rhythm. So maybe TMAO has toxic effects beyond just the accelerated build-up of cholesterol. What about kidney failure? People with chronic kidney disease are at particularly increased risk for the development of cardiovascular disease, thought to be because of a diverse array of uremic toxins. These are toxins that would normally be filtered out by the kidneys into the urine, but may build up in the bloodstream as our kidney function declines. When we think of uremic toxins, we usually think of the toxic byproducts of protein putrefying in our gut, which is why specially formulated plant-based diets have been used for decades to treat chronic kidney failure. Those who eat vegetarian form less than half of these uremic toxins in the first place. But those aren't the only uremic toxins. TMAO, from the breakdown of choline and carnitine in mostly meat and eggs, may be increasing heart disease risk in kidney patients as well, by apparently down-regulating reverse cholesterol transport, meaning subverting our own body's attempt at pulling cholesterol out of our arteries. And indeed, the worse our kidney function gets, the higher our TMAO levels rise, and those elevated levels correlate with the amount of plaque they have clogging up the arteries in their heart. But get a kidney transplant, get a working kidney going, and you can drop your TMAO levels right back down. So TMAO was thought to be kind of a biomarker for declining kidney function. But then this study was published from the Framingham Heart Study, which found that elevated choline and TMAO levels among individuals with normal kidney function predicted increased risk for developing chronic kidney disease, suggesting TMAO is both a biomarker and itself a kidney toxin. Indeed, when you follow kidney patients over time and assess their freedom from death, those with higher TMAO, even controlling for kidney function, live significantly shorter lives, indicating this diet-induced mechanism for progressive kidney scarring and dysfunction strongly implying the need to focus preventative efforts on dietary modification. What might that look like? Well, maybe we should reduce dietary sources of TMAO generation, such as some species of deep-sea fish, eggs, and meat. But it also depends on what kind of gut bacteria you have. Remember, you can feed a vegan a steak, and they still don't really make any TMAO because they haven't been fostering the carnitine-eating bacteria in their gut. Researchers are hoping, however, that one day they'll find a way to replicate the effects of a vegetarian diet by selective prebiotic, probiotic, or antibiotic therapies.