Is TMAO from Fish, Meat and Eggs Harmful?

According to new stories, fish, a staple of the Mediterranean diet, as well as meat and eggs may be doing more harm than good thanks to a compound called trimethylamine-N-oxide (TMAO). TMAO is found in fish and produced in the body after eating meat and eggs. TMAO is linked to greater risk for heart attack, stroke and death; yet the research isn’t crystal clear. Is it time to give up fish meat and eggs or ignore the recent media headlines?

This post will cover:

• • What is TMAO?
  • TMAO: More than a Gut Reaction—What gives us higher TMAO levels?
  • TMAO and health?
  • The bottom line

What is TMAO?

TMAO is a metabolite produced by the bacteria living in the gut and metabolized by the liver. It plays a role in systemic inflammation, atherosclerosis (clogging of the arteries) and vascular (blood vessel) dysfunction.

TMAO: More than a Gut Reaction

Blood levels of TMAO are ~ 50 times higher after eating fish compared to eggs or beef. The human body absorbs intact TMAO like the kind found in fish, easily. However, the human body’s production of TMAO, after eating foods containing the essential nutrient choline (found in eggs and meat) and the compound l-carnitine (found in meat and pork and in much smaller quantities in chicken breast and dairy products), depends on your diet, the makeup of bacteria in your gut (which is influenced by your diet), kidney functioning and genetics.

In one study, regular meat eaters produced more TMAO than a vegetarian did after eating steak (which contains ~ 180 mg of l-carnitine). After wiping out their gut bacteria with antibiotics, the carnivores didn’t produce any TMAO after consuming 250 mg l-carnitine. The makeup of gut bacteria in the habitual meat eaters was presumably responsible for greater TMAO production compared to the vegetarian, yet this was a small study and we don’t know anything else about the participants’ diet. Was it the meat that altered gut bacteria or something else in their diet? After all, a steady diet of red meat may mean double cheeseburgers on white bread with regular servings of French fries and soda on the side. This isn’t exactly the diet you want for promoting good bacteria in your gut.

Another study found blood levels of TMAO were greater in those with a less diverse makeup of microbes and greater amounts of a less healthy type of bacteria (firmicutes), compared to one that is healthy (bacteroidetes). A diet higher in saturated fat will promote this environment. Additionally, three separate studies found a high fat diet promotes greater production of TMAO, reduced TMAO clearance in the body after a meal, and greater TMAO in the bloodstream. A low fat diet is associated with lower production of TMAO.

While bacteria seem to influence TMAO production from l-carnitine, l-carnitine also influences the makeup of gut bacteria. A study in mice found those with their gut bacteria wiped out thanks to antibiotics produced a different makeup of bacteria in the gut after consuming l-carnitine while also doubling the risk of plaque buildup in their arteries.

Higher TMAO levels come from:

• Eating fish
• Less diverse array of gut bacteria and increased levels of bad versus good bacteria
• Consuming l-carnitine (mouse study)

TMAO and Health

A few human studies found higher blood levels of TMAO were associated with greater risk for heart disease. However, all research isn’t pointing in the same direction. One study in over 300 patients found blood TMAO levels were not associated with heart attack or heart disease over the course of eight years, following the initial test for TMAO. However, TMAO levels were higher in those with diabetes, patients with metabolic syndrome and those with declining kidney functioning. Another study examined over 800 people between the age of 33 and 55 and found blood TMAO levels were not associated with clogged arteries, insulin resistance (this comes before type 2 diabetes) and inflammatory markers or negative changes in blood lipids suggesting TMAO levels might not contribute significantly to the progression of clogged arteries. However, this study shows TMAO levels were significantly lower than in previous research, showing an association between TMAO and heart disease.

TMAO is considered a risk factor for cardiovascular disease. In those with type 2 diabetes, higher TMAO levels are associated with greater risk for death, heart attack, heart failure and unstable angina (chest pain). Also, higher levels of circulating TMAO are associated with higher risk of death in those with chronic kidney disease and greater risk of certain cancers. Yet, there are several confounding factors. Fish is the primary culprit for higher acute circulating TMAO levels, yet fish-based diets are associated with reduced risk for heart disease. Also, levels of TMAO are dependent upon disease state and the makeup of gut bacteria. Therefore, at this time it isn’t entirely clear which came first – does TMAO cause disease or does TMAO increase due to disease?

The Bottom Line

The story on TMAO isn’t crystal clear, so there’s no reason to avoid fish, meat and eggs in an effort to decrease TMAO levels. All three of these foods are good sources of several nutrients important for health. Though processed red meats are linked to higher risk of colorectal and stomach cancers, when cooked appropriately (lower, moist heat for example) red meat can fit into a healthy diet and deliver important nutrients including iron, zinc and vitamin B12. Eggs are an economical source of protein and contain many nutrients and compounds that contribute to health including two antioxidants important for eyesight.

Though there is no reason to completely avoid these foods, you can alter your diet to help diversify gut bacteria and also increase the amount of good versus bad bacteria. Probiotic rich foods such as yogurt and kefir with live and active cultures, miso soup, tempeh and other fermented foods contain good bacteria. Fiber-rich plant foods (fruits, vegetables, legumes) are important food sources for bacteria to thrive in your body.

References
Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013 Apr 7.

Boutagy NE, Neilson AP, Osterberg KL, Smithson AT, Englund TR, Davy BM, Hulver MW, Davy KP. Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity 2015;23:2357–2363

Boutagy NE, Neilson AP, Osterberg KL, Smithson AT, Englund TR, Davy BM, Hulver MW, Davy KP. Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity. 2015;23:2357–2363

Cho CE, Caudill MA. Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire? Trends Endocrinol Metab 2016 Nov 4. [Epub ahead of print]

Cho CE, Taesuwan S, Malsheva OV, Bender E, Tulchinsky NF, Yan J, Sutter JL, Caudill MA. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial. Mol Nutr Food Res 2016 Jul 5.

Carnitine. Health Professional Fact Sheet, NIH. https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/

Hui DY. Intestinal phospholipid and lysophospholipid metabolism in cardiometabolic disease. Curr. Opin. Lipidol 2016;27:507–512.

Mueller DM, Allenspach M, Othman A, Saely CH, Muendlein A, Vonbank A, Drexel H, von Eckardstein A. Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control.Atherosclerosis 2015;243(2):638-44.

Meyer KA, Benton TZ, Bennett BJ, Jacobs DR Jr., Lloyd-Jones DM, Gross MD, Carr JJ, Gordon-Larsen P, Zeisel SH. Microbiota-Dependent Metabolite Trimethylamine N-Oxide and Coronary Artery Calcium in the Coronary Artery Risk Development in Young Adults Study (CARDIA). J Am Heart Assoc. 2016 Oct 21;5(10). pii: e003970.