In recent years, research has suggested that trimethylamine oxide (TMAO) may be a therapeutic target for insulin resistance and gastrointestinal (GI) cancers. As stated in one 2017 scientific review:1
“By digesting animal protein and other components of animal products, the commensal bacteria in the gut (gut microbiota) form metabolites that can contribute to the development of insulin resistance and cancer.
Trimethylamine-N-oxide (TMAO) is a molecule that has recently attracted a lot of attention because it may be a risk factor for—and a link between—the gut microbiota and cardiovascular and kidney disease.
Furthermore, TMAO is expected to be important as a biomarker – or even an independent risk factor – for other undesirable conditions, including insulin resistance… TMAO arises from a precursor, trimethylamine (TMA) which is a metabolite of various precursors. ; Mainly choline and carnitine from ingested foods.”
in paper2 Led by James De Nicolantonio, Ph.D., who is also the co-author of my book “Superfuel: Ketogenic Keys to Unlock the Secrets of Good Fats and Bad Fats and Great Health,” we show how the real potential cause of high TMAO levels — which are linked to an increased risk of cardiovascular disease. Hematologic (CVD) – is hepatic insulin resistance.
Furthermore, the paper shows that krill oil, astaxanthin, fish oil, and berberine may be among some of the best supplementation strategies for those with high levels of TMAO after diet improvement, simply because it is a reflection of insulin resistance in the liver.
DiNicolantonio has a book called “longevity solutionJason Fung, who delves into the benefits of omega-3s, including fish oil and krill oil.
What causes high levels of TMAO?
As mentioned earlier, TMAO is created when gastrointestinal bacteria metabolize dietary choline and carnitine found in eggs, liver, meat, and fish, to name a few. Bacteria convert choline and carnitine into trimethylamine, which is subsequently absorbed and oxidized to TMAO with the help of flavin monooxygenases in the liver, primarily FMO3.
Flavin monooxygenases are a family of enzymes that oxidize xenosubstrate substrates, allowing the compounds to be secreted. Because choline and carnitine increase TMAO, which is thought to be a risk factor for cardiovascular disease and type 2 diabetes, some recommend limiting dietary and supplemental intake of these nutrients. However, Dinicolatonio and colleagues point out a significant flaw in this theory, stating:3
“[N]Epidemiology fails to criminalize dietary choline as a CV risk factor; Supplemental carnitine is known to have high protection in patients with vascular diseases; And fish, which is the richest food source of preformed TMAO, is also a preventative.
Hence, TMAO, at least in the moderate concentrations observed in those with severe renal impairment, is not an intermediate risk factor for vascular disease, but serves as an indicator of factors that promote vascular disease and diabetes.
Impaired kidney function is one of these factors, but it is not the only one. The possibility that some gastrointestinal bacteria skilled at producing trimethylamine may also be detrimental to vascular health and metabolism, remains undocumented. Factors that increase hepatic FMO3 are under suspicion.
Indeed, abnormal hepatic insulin activity associated with hepatic insulin resistance enhances hepatic FMO3 expression. Hepatic insulin resistance can result from 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 CV diseases and diabetes.
Therefore, diets, nutrients, and medications that combat hepatic insulin resistance may be beneficial to mitigate the health risks associated with elevated TMAO.”
Elevated TMAO – a risk factor for cardiovascular disease and metabolic disease?
As noted in the featured research paper, the evidence linking elevated TMAO to CVD risk is mixed. Numerous studies4And the5And the6And the7 They concluded that elevated levels of TMAO in the blood are predictive of major adverse cardiovascular events in people who have previously had heart disease, while others have failed to find support for this connection.8And the9
Still, a meta-analysis10 Of 11 studies published in 2018 found that higher TMAO levels were associated with a 23% increased risk of cardiovascular disease and a 55% increase in all-cause mortality. Animal studies cited in the DiNicolantonio paper also indicate that very high oral doses of TMAO or its precursors, phosphatidylcholine and carnitine, can have a pro-atherosclerotic effect.
Case-controlled epidemiological studies have also linked elevated TMAO to an increased risk of type 2 diabetes and metabolic syndrome. In fact, the associations between TMAO and diabetes risk appear to be stronger than those associated with cardiovascular risk.
However, there is little evidence to suggest that dietary intake of TMAO or its precursors actually promotes cardiovascular disease, provided your kidney function is normal. Conversely, choline is important not only for brain, nervous system, and cardiovascular function but also for healthy liver function and detoxification.
In fact, it appears to be essential for preventing fatty liver disease and is found in high amounts 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. Di Nicolantonio writes:11
Regarding carnitine and CV risks, a meta-analysis12 From prospective clinical trials in patients who have recently experienced myocardial infarction it was concluded that L-carnitine supplementation is significantly protective with respect to total mortality, ventricular arrhythmias and new angina pectoris…
Clinical trials13And the14 It also reported positive effects of supplemental carnitine or carnitine esters on angina pectoris, intermittent claudication, and heart failure.
Furthermore, studies of atherosclerosis in rodents, in which L-carnitine was administered in doses reasonably proportional to clinically used supplement doses, found L-carnitine to be anti-atherosclerotic, despite its tendency to increase TMAO…
It is therefore reasonable to suspect that moderately elevated TMAO, rather than a mediator of CV-related risk, is a marker of factors that promote CV events and increase TMAO in plasma. “
Impaired liver function increases TMAO significantly
According to DiNicolantonio, a major factor appears to be insulin resistance in the liver, which has been shown to significantly raise TMAO. he is writing:15th
“TMAO arises when dietary choline and carnitine are metabolized by gastrointestinal bacteria to produce trimethylamine, which is then absorbed and oxidized to TMAO by hepatic flavin monooxygenase (FMO), primarily FMO3… Abnormal hepatic insulin activity, as is It is present in people with liver disease. [liver] Insulin resistance, and enhances hepatic FMO3 expression and thus TMAO levels. “
DiNicolantonio goes on to suggest that elevated FMO3 activity in the liver could be a reflection of insulin resistance in the organ, which in turn affects cardiovascular health risks. He believes this “could justify the epidemiology of TMAO”. He explains:16
“Hepatic insulin resistance, and accompanying hepatic steatosis, are associated with an increased risk of cardiovascular disease, as well as a higher risk of type 2 diabetes—risks also associated with elevated TMAO.
It is therefore easy to assume that TMAO could act as a marker of hepatic insulin resistance, and this explains at least part of the cardiovascular disease and diabetes risks associated with TMAO.”
How to reverse insulin resistance in the liver
If elevated TMAO is indeed a reflection of hepatic insulin resistance that increases cardiovascular risk, what can you do to correct it and reduce risk? For starters, you may want to normalize your weight.
Two more beneficial strategies in this regard are a cyclic ketogenic diet and intermittent fasting. For best results, they should be performed together. You can learn more about these strategies in the hyperlinked articles provided. Certain nutritional supplements can also be very helpful in treating hepatic insulin resistance, including:17
• BerberineIt works like metformin, a drug commonly used to treat diabetes. Both work, at least in part, by activating AMPK-activated protein kinase (AMPK). Known as the “Master Metabolic Key,” AMPK is an enzyme that controls how energy is produced in the body and how it is used by cells.
By activating this enzyme, berberine and metformin help to regulate biological activities that normalize lipid, glucose and energy imbalances. Berberine, used in Chinese medicine to treat diabetes, has also been shown to combat hepatic insulin resistance in diabetic rodents.18And the19
• astaxanthinIt is a powerful carotenoid antioxidant, and is a PPARalpha 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 ameliorate hepatic insulin resistance in animals fed high-fat or fructose diets, and to reduce the risk of cardiovascular events in patients with metabolic syndrome.
• krill oil Another alternative, as it contains the form of astaxanthin, which increases its bioavailability, along with long-chain omega-3 fats that are essential for good health, including heart health. As mentioned in the DiNicolantonio paper:
“Krill oil, even when compared to fish oil, prevents hepatic steatosis in rodents. This may be due to its astaxanthin content, which is not found in fish oil.”
Moreover, krill oil, and not fish oil, reduces the content of diacylglycerol and ceramides in the liver. It has also been observed that the phospholipid fraction of krill oil reduces hepatic glucose production, unlike fish oil.
Thus, krill oil, as a source of a highly bioavailable form of astaxanthin, appears to have additional benefits for reducing hepatic steatosis and hepatic insulin resistance compared to fish oil.”
Brief overview of the results
In summary, while there is some evidence to suggest that elevated levels of TMAO may be a risk factor for type 2 diabetes, atherosclerosis and an increased risk of cardiovascular disease, nutritional epidemiology studies have not been able to demonstrate an adverse effect. For the dietary choline and carnitine, from which TMAO is made.
Studies do not support the idea that dietary sources of TMAO, such as fish, have a detrimental effect on cardiovascular health. Quite the contrary. The DiNicolantonio paper suggests that the only time when TMAO is elevated may actually be a CVD risk factor is when it is accompanied by impaired liver function, and elevated TMAO may in itself be a sign of impaired liver function.
The good news is that you can improve your liver function and lower your TMAO level with the help of nutritional supplements; Berberine, astaxanthin and krill oil are three of the essential oils. Di Nicolantonio writes:
In conclusion, there is reason to suspect that the elevated risk of vascular events and type 2 diabetes associated with elevated TMAO, after correcting for recognized risk factors, is largely mediated by hepatic insulin resistance and the metabolic factors that induce it…
[I]If this analysis is accurate, various measurements attenuate hepatic insulin resistance – correction of visceral obesity, AMPK activation with metformin or berberine, PPARalpha activation with fenofibrate or astaxanthin, amplification of adiponectin production with pioglitazone or plant-based diets, and clinical strategies that enhance the production or bioactivity of GLP-1 – elevated TMAO would be expected while also reducing the risk of vascular events and diabetes associated with this risk factor. Figure 1 summarizes these relationships…
Importantly, this analysis does not exclude the possibility that TMAO is directly pathogenic at the very high levels typically seen in acute renal dysfunction. Indeed, cell culture studies indicate that TMAO can be a pro-inflammatory at the plasma concentrations achieved during renal failure. It is generally wise to reduce the consumption of nitrogenous compounds in this context.”