In recent years, studies have suggested that trimethylamine-N-oxide (TMAO) may be a therapeutic target for insulin resistance and gastrointestinal (GI) cancers. As a 2017 scientific review stated:1
“By digesting animal protein and other components of animal products, commensal bacteria in the gut (gut microbiota) form metabolites that contribute to the development of insulin resistance and cancer.
Trimethylamine-N-oxide (TMAO) is one such molecule that has recently attracted a lot of attention as a possible risk factor between the gut microbiome and cardiovascular and kidney disease—and the link between them.
In addition, TMAO is expected to have significance as a biomarker (or even an independent risk factor) for other adverse conditions, including insulin resistance…mainly from choline and carnitine in ingested food. “
in a paper2 Led by James DiNicolantonio, MD, co-author of my book “Super Fuel: The Ketogenic Key to Unraveling the Secrets of Good Fats, Bad Fats, and Health,” we show the possible real causes of elevated TMAO and the heart A level associated with an increased risk of vascular disease (CVD) is hepatic insulin resistance.
Furthermore, the paper suggests that krill oil, astaxanthin, fish oil, and berberine may be one of the best supplementation strategies for people with high TMAO levels after an optimized diet, as it is only a reflection of hepatic insulin resistance.
DiNicolantonio has a book called “Longevity Solutions” An in-depth look at the benefits of omega-3s, including fish and krill oil, with Dr. Jason Fung.
What causes TMAO levels to rise?
As previously mentioned, TMAO is produced when gastrointestinal bacteria metabolize dietary choline and carnitine found in eggs, liver, meat, and fish, to name a few. Bacteria convert choline and carnitine to trimethylamine, which is subsequently absorbed and oxidized to TMAO with the help of flavin monooxygenase (mainly FMO3) in the liver.
Flavin monooxygenases are a family of enzymes that oxidize heterologous substrates, allowing the compound to be excreted. Because choline and carnitine increase TMAO, which is considered a risk factor for CVD and type 2 diabetes, some recommend limiting dietary and supplemental intake of these nutrients. However, DiNicolantonio and his co-authors point to a major flaw in this theory, stating:3
“[N]utritional epidemiology fails to list dietary choline as a risk factor for CV; carnitine supplementation is known to be highly protective in patients with vascular disease; fish, the richest dietary source of prepared TMAO, is also protective.
Thus, at least the moderate concentrations of TMAO seen in people without severe renal insufficiency are not a mediating risk factor for vascular disease, but rather serve as a marker for factors that promote vascular disease and diabetes.
Impaired kidney function is one of these factors, but not the only one. The possibility that certain gastrointestinal bacteria that are good at producing trimethylamine are also detrimental to vascular and metabolic health remains unproven. Therefore, factors that increase hepatic FMO3 are suspected.
In fact, subnormal hepatic insulin activity associated with hepatic insulin resistance promotes hepatic FMO3 expression. Hepatic insulin resistance may be caused by metabolic syndrome and visceral obesity, and may reflect suboptimal activity of adiponectin or glucagon-like peptide-1—all of which can play a mediating role in cardiovascular disease and diabetes.
Therefore, diets, nutraceuticals, and medications that combat hepatic insulin resistance may help reduce the health risks associated with elevated TMAO. “
Elevated TMAO—a risk factor for cardiovascular and metabolic disease?
As noted in the monograph, the evidence linking elevated TMAO to CVD risk is mixed.multiple studies4,5,6,7 It was concluded that elevated blood TMAO levels predicted major adverse cardiovascular events in people with heart disease, while others failed to find support for this link.8,9
However, meta-analyses10 Eleven studies published in 2018 found that higher TMAO levels were associated with a 23% increased risk of cardiovascular events and a 55% increased all-cause mortality. Animal studies cited in DiNicolantonio’s paper also suggest that oral administration of very high doses of TMAO or its precursors, phosphatidylcholine and carnitine, can produce pro-atherosclerotic effects.
Case-control epidemiological studies have also linked high TMAO with a significantly increased risk of type 2 diabetes and metabolic syndrome. “In fact, the association between TMAO and diabetes risk appears to be stronger than cardiovascular risk,” DiNicolantonio wrote.
That said, as long as your kidneys are functioning properly, there is little evidence that dietary intake of TMAO or its precursors actually promotes CVD. Instead, choline is not only essential for your brain, nervous system, and cardiovascular function, but also for healthy liver function and detoxification.
In fact, it appears to be critical for preventing fatty liver disease and is found in high levels in foods like fish, which are known for their beneficial effects on cardiovascular disease—in part due to the benefits of long-chain omega-3 fats. DiNicorantonio wrote:11
“On carnitine and cardiovascular risk, a meta-analysis12 A prospective clinical trial in patients who had recently experienced myocardial infarction concluded that carnitine supplementation had a significant protective effect on total mortality, ventricular arrhythmias, and new-onset angina…
Clinical Trials13,14 The beneficial effects of carnitine or carnitine ester supplementation on angina, intermittent claudication and heart failure have also been reported.
Furthermore, in rodent atherosclerosis studies where carnitine was administered at doses reasonably proportional to clinically used supplemental doses, carnitine was found to be anti-atherosclerotic, despite its tendency to elevate TMAO…
Thus, it is reasonable to suspect that moderately elevated TMAO, rather than a mediator of associated CV risk, is a marker of factors that promote CV events and increase plasma TMAO. “
Poor liver function significantly increases TMAO
According to DiNicolantonio, a key factor appears to be insulin resistance in the liver, which has been shown to significantly increase TMAO. He writes:15
“TMAO occurs when dietary choline and carnitine are metabolized by gastrointestinal bacteria to produce trimethylamine, which is then absorbed by heparin monooxygenase (FMO) and oxidized to TMAO, primarily FMO3… …Liver insulin activity is lower than normal, as found in patients with liver disease. [liver] Insulin resistance increases hepatic FMO3 expression, thereby increasing TMAO levels. “
DiNicolantonio went on to suggest that elevated FMO3 activity in the liver may reflect insulin resistance in the organ, which in turn affects cardiovascular health risk. This, he argues, “could rationalize the epidemiology of TMAO.” He explained:16
“Insulin resistance in the liver and its common concomitant hepatic steatosis is associated with increased cardiovascular risk and increased risk of type 2 diabetes — a risk also associated with increased TMAO.
Therefore, it is straightforward to hypothesize that TMAO may act as a marker of hepatic insulin resistance, which explains at least part of the risk of cardiovascular events and diabetes associated with TMAO. “
How to reverse insulin resistance in the liver
If elevated TMAO does reflect that hepatic insulin resistance increases your CVD risk, what can you do to correct it and reduce your risk? First, you need to normalize your weight.
The two strategies that are most helpful in this regard are the cyclic ketogenic diet and intermittent fasting. For best results, they should be done together. You can learn more about these strategies in the hyperlinked article provided. Certain supplements are also very beneficial for treating hepatic insulin resistance, including:17
• Berberine, which works much like metformin, a common drug used to treat diabetes. Both act, at least in part, by activating adenosine monophosphate-activated protein kinase (AMPK). Known as the “metabolic master switch,” AMPK is an enzyme that controls how energy is produced in your body and how your cells use it.
By activating this enzyme, berberine and metformin help regulate biological activities that normalize lipid, glucose, and energy imbalances. Berberine, used in traditional Chinese medicine to treat diabetes, has also been shown to counteract hepatic insulin resistance in diabetic rodents.18,19
• Astaxanthinis a powerful carotenoid antioxidant and a PPARα agonist with activity similar to that of the cholesterol-lowering drug fenofibrate. PPARalpha agonists indirectly stimulate AMPK in the liver and have been shown to reduce hepatic insulin resistance in animals fed a high-fat or fructose diet and reduce the risk of cardiovascular events in patients with metabolic syndrome.
• Krill Oil is another option because it contains an esterified form of astaxanthin, which increases its bioavailability, as well as long-chain omega-3 fats that are essential for good health, including heart health. As DiNicolantonio’s paper states:
“Krill oil inhibited hepatic steatosis in rodents, even compared to fish oil. This may be due to its astaxanthin content that is not present in fish oil.
In addition, krill oil (but not fish oil) reduces the levels of diglycerides and ceramides in the liver. Unlike fish oil, the phospholipid portion of krill oil has also been noted to reduce hepatic glucose production.
Therefore, krill oil, as a source of highly bioavailable astaxanthin, appears to have additional advantages in reducing hepatic steatosis and hepatic insulin resistance compared to fish oil. “
Summary of findings
In conclusion, although there is some evidence that elevated TMAO levels may be a risk factor for type 2 diabetes, atherosclerosis, and increased risk of cardiovascular events, nutritional epidemiological studies have failed to demonstrate the deleterious effects of dietary choline and carnitine, From which TMAO was synthesized.
Research also does not support the idea that dietary sources of TMAO, such as fish, have adverse effects on cardiovascular health. Quite the opposite. DiNicolantonio’s paper suggests that the only time elevated TMAO may actually be a risk factor for CVD is when it is accompanied by poor liver function, which itself may be a marker of poor liver function.
The good news is that you can improve liver function and lower your TMAO levels with the help of nutritional supplements; berberine, astaxanthin and krill oil are the main three. DiNicorantonio wrote:
“In conclusion, there is reason to suspect that the increased risk of vascular events and type 2 diabetes associated with elevated TMAO is primarily mediated by hepatic insulin resistance and the metabolic factors that induce it, after adjustment for recognized risk factors…
[I]If this analysis is accurate, multiple actions could be taken to reduce hepatic insulin resistance—correcting visceral adiposity, activating AMPK with metformin or berberine, activating PPARα with fenofibrate or astaxanthin, increasing adipose tissue with pioglitazone or a plant-based diet Gene production, and clinical strategies to promote GLP-1 production or biological activity—can be expected to reduce elevated TMAO, as well as reduce the risk of vascular events and diabetes associated with this risk factor. Figure 1 summarizes these relationships…
Importantly, this analysis did not rule out the possibility that TMAO may be directly pathogenic at the very elevated levels that are common in severe renal insufficiency. In fact, cell culture studies have shown that TMAO can be pro-inflammatory at the plasma concentrations achieved during renal failure. In such cases, it is often advisable to minimize the consumption of nitrogenous compounds. “