SUMMARY: Microbiome Awareness TMAO was summarized in the May 26th seminar, and I suggested condiment size portions for red meat regardless of meat quality (pastured or confined feed lot operations). Carnitine in red meat acts as an antioxidant and plays a crucial role in the mitochondria—the energy-producing structures in cells—notably in muscles, including heart muscle. But carnitine has a dark side — TMAO. This post shares TMAO follow-up so that all can benefit, even those unable to attend! A subsequent post will share more conversation from that evening, but TMAO is a lot of good information, and it deserves a post of its own.
TMAO is made in our liver from a gut flora metabolic (TMA) which is made from red meat, eggs, energy drinks, and some supplements. TMAO is associated with heart disease, chronic kidney disease and IBD UC. TMAO is a “greater risk for inflammation and all things that go along with inflammation like stroke, memory loss, impotence, decaying orgasm quality, wrinkling, cancer, and brain rot,” says Dr. Michael Rozin, MD, chief wellness officer and chairman of the Wellness Institute at the Cleveland Clinic. This post expands the Microbiome Awareness TMAO conversation! Follow along, learn great tips, and amaze yourself with how much you actually learned and know! Comment if I don’t touch on your thoughts; lets continue the Microbiome Awareness TMAO conversation!
First, my take on TMAO. Until the dust settles and studies confirm human dietary modulation of the microbiome that mitigates TMA and TMAO production,
Consider consuming condiment size red meat (and up to 2 eggs a day if desired) as described in the Pegan diet (detailed below) crafted by Dr. Mark Hyman, Director of Cleveland Clinic Center for Functional Medicine.
Further, consider integrating meat prep using these TMAO mitigation strategies (shown in recent mice studies, April 2016 and Dec 2015):
- Marinate meat in EVOO and/or balsamic vinegar,
- Consume along with salad dressing containing EVOO and/or balsamic vinegar, and
- Have that glass of red wine along with the red meat.
- Though not yet tested, add other antioxidant spices, phytonutrients, and flavonoids (see Drs. Mimi Guarneri and Jeff Blands thoughts below).
- Make certain the EVOO is unadulterated, organic, and cold pressed — for sourcing tips scroll to below the light-bulb on the post, Meet The Fats & Best Salad Dressing Oil, Part 1.
- For Balsamic vinegar insights… they are pricey and yet most are not “Real Balsamic Vinegar” due to insufficient barrel aging and crazy additives. The “real balsamic vinegar“ I recommend is Olivier Napa Valley which is SCD/GAPS legal as it is fermented properly (25 years) and free of additives. Olivier’s was actually pulled from Williams-Sonoma stores a few years back as they introduced their own brand. Due to customer demand, Olivier’s is now back in their stores or online, or get it direct from Olivier’s online.
A picture is worth a thousand words, so here are some pics of condiment meat meals we frequently have. Test question from the Microbiome Awareness Seminar, “Do you spot the components actually nourishing your microbiome and know what they are called?”
What is TMAO (trimethylamine-N-oxide) and TMA (trimethylamine)?
TMAO is a metabolic end by-product of certain gut microbes (a.k.a. metabolites). TMAO forms following ingestion of red meat and eggs no matter the quality (pastured or confined feed lot operations) unless you are vegan, in which case, little TMAO forms since the vegan microbiome either neutralizes it or keeps those microbes in check that produce the metabolite. The exact mechanism is still unknown! TMAO is a gut flora-dependent metabolite resulting from the oxidation of TMA. The quality of the red meat or eggs, grass-fed or pastured, means that the Omega-3 fatty acid profile improves but the same compounds that are used to produce TMAO, L-carnitine and choline, are still present regardless of quality.
Berkeley Wellness, University of California, Carnitine in Meat: Heart Hazard explains carnitine and choline:
- The word carnitine comes from the Latin word for meat because red meat—even if it’s lean—is by far the richest dietary source. Pork and lamb also have fair amounts; chicken, fish and dairy products contain small amounts. The biologically active form is called L-carnitine. The body makes carnitine from amino acids (lysine and methionine), which are building blocks of protein.
- Carnitine plays a crucial role in the mitochondria—the energy-producing structures in cells—notably in muscles, including heart muscle. It also acts as an antioxidant. As we age, carnitine levels drop and mitochondrial function becomes impaired, which may contribute to some adverse effects of aging as well as to some diseases. Thus, it’s hoped, carnitine supplements may help prevent these problems.
- L-carnitine is sold as a supplement. It’s in many “healthy-aging” products and formulas claiming to improve athletic performance and build muscle. It’s also promoted as a treatment for many disorders, including heart disease, diabetes and dementia, and is supposed to boost energy, improve memory and promote weight loss. Most of this is just marketing hype or wishful thinking.
- Choline is a vitamin-like compound that plays key roles in the body. It is found in many other healthful foods—salmon, sardines, broccoli, milk and beans—along with meat and poultry.
Reducing dietary choline or carnitine would lower TMAO levels, but may have undesirable effects.
TMAO is implicated in vascular inflammation and formation of unstable plaques in arterial walls, and more. “TMAO levels predict risk for atherosclerosis [15, 112, 115], and are elevated in patients with chronic kidney disease (CKD)  and obesity [17, 98], and decreased in ulcerative colitis ... [While] supplementation with lower levels of l-carnitine than needed for TMAO formation may improve cardiovascular function  A meta-analysis of 13 controlled trials (n = 3629) showed that l-carnitine supplementation reduces all-cause mortality by 27 % . While potentially beneficial for cardiovascular health, choline deficiency markedly increases risk for non-alcoholic liver disease [NAFLD prevalence is 19.0% in US].” — Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions, April 2016.
Dr. Rob Knight was asked in a class I took, “What are your thoughts on red meat?” [–]DrRobKnight replied, “A Western diet, which often includes more meat has been linked repeatedly to differences in the gut microbiota (when compared with diets based more heavily on plant material). See, for example, Human gut microbiome viewed across age and geography and Diet rapidly and reproducibly alters the human gut microbiome. Also, a study by Stan Hazen’s group, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis… [which] showed that when gut microbes metabolize a certain compound (L-carnitine) found in red meat, they produce another compound (TMAO) that can lead to a hardening of the arteries. So red meat affects both your gut microbiota and your health, and gut microbes appear to be playing a role in determining HOW red meat affects your health.
Berkeley Wellness, University of California, Carnitine in Meat: Heart Hazard explains:
- A week after the Cleveland Clinic study on carnitine appeared, an analysis in Mayo Clinic Proceedings looked at 13 clinical trials testing supplemental L-carnitine in people who had a prior heart attack. It concluded that the supplements reduce the risk of angina, serious arrhythmias and premature death. And it noted carnitine’s “excellent safety profile.”
- How could carnitine be both good and bad for heart health?
- The proposed mechanisms (the negative one involving atherosclerosis, the positive one the heart muscle itself) are very different.
- The studies involved different populations.
- Finally, the supplements may be digested and absorbed somewhat differently than carnitine in meat.
- It’s known that heart muscle contains high levels of carnitine, that carnitine levels are depleted during a heart attack, and that carnitine deficiency can cause heart enlargement and rhythm abnormalities. In our 2009 article on carnitine supplements, we concluded that the evidence of cardiovascular benefits is promising, though not conclusive. We saw no research indicating cardiovascular risk even from high doses.
How Gut bacteria is Linked to Heart Disease
For generations, eggs and red meat have topped the list of foods implicated in cardiovascular disease because of their high levels of dietary cholesterol. While dietary intake of cholesterol fat has been exonerated as the cause of elevated serum cholesterol — red meat and eggs are NOT off the hook. Why? A whole new line of investigation focusing on intestinal bacteria (our microbiome) is keeping red meat and eggs in the spotlight. Note: The studies related to intake of dietary fat cholesterol NOT altering serum cholesterol for most of us are in the section below titled Summary of Dr. Mark Hyman’s Pegan diet concept.
How it works: Berkeley Wellness, University of California, Carnitine in Meat: Heart Hazard, explains Dr. Stanley Hazen MD, PhD “L-carnitine challenge test” study, Intestinal Microbiota Metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med. 2013;19:576-585. The “L-carnitine challenge test” was 250 mg d3-carnitine vegetarian capsule and where appropriate, a natural source of L-carnitine was added in (an 8 ounce sirloin steak cooked medium on a George Forman Grill) in a 10 minute period concurrent with taking the capsule containing the 250 mg d3-carnitine capsule:
- Red meat and eggs (plus some dietary supplements and energy drinks) contain choline and L-carnitine. Bacteria in your digestive system can turn choline and l-carnitine into TMA. TMA then travels to the liver. TMA is a precursor that the liver converts to TMAO. TMAO is then released into the bloodstream. There, TMAO becomes a factor that promotes vascular inflammation and formation of unstable plaques in arterial walls.
- 51 habitual meat eaters with 26 vegetarians or vegans were compared.
- When the mice and human subjects were given antibiotics (Metronidazole 500 mg bid, Ciprofloxacin 500 mg bid) for a week—which killed off many of the intestinal microbes—and then consumed carnitine, there was almost no TMAO in blood or urine, confirming the role of the microflora.
- When vegetarians were told to consume carnitine from meat or supplements, they produced far less TMAO than omnivores did, apparently because their microflora was different as a result of their customary diet. It’s theorized that a diet high in carnitine may alter the composition of the microflora in favor of organisms that like carnitine.
- The researchers also looked at 2,600 people undergoing cardiac evaluation and found that those who had high blood levels of L-carnitine and TMAO were at increased risk for cardiovascular disease, independent of traditional cardiac risk factors such as blood pressure and cholesterol levels.
Who is Dr. Stanley Hazen MD, PhD? Section Head of Preventive Cardiology and Rehabilitation at Cleveland Clinic. He has published many studies linking the metabolic product of bacterial digestion of substances found in red meat and egg yolks with development of pathologies ranging from atherosclerotic plaque to heart failure to chronic kidney disease. According to Dr. Hazen’s findings, increased blood levels of a compound formed by gut microbes following consumption of foods such as red meat and egg yolks are associated with increased risk of adverse cardiovascular outcomes, including death, even when controlling for other cardiovascular risk factors and traditional blood test results.
The influence of TMAO on cardiovascular disease is significant enough that Dr. Hazen developed an assay to assess cardiac risk by measuring plasma TMAO; you can ask your doctor for this test.
How much can you eat of red meat and eggs to not have TMAO concerns?
Not much! Dr. Mark Hyman interviewed Dr. Michael Rozin, MD, the chief wellness officer and chairman of the Wellness Institute at the Cleveland Clinic. Email me if you want a copy of the transcript of the interview, Separating Fat From Friction. But the key point is:
“…more than 100 grams [4 ounces in one week] of carnitine, lecithin, or choline, or any combination of them, changed the way your gut bacteria metabolized those themselves to produce two things, butyl butane, which in the long term causes kidney disease and kidney failure, and TMA which you absorb and then the liver converts to TMAO which is a greater risk for inflammation and all things that go along with inflammation, heart disease, stroke, memory loss, impotence, decaying orgasm quality, wrinkling, cancer, and brain rot.” — Dr. Michael Rozin, MD. Did “decaying orgasm quality” and “impotence” get your attention?
Should you change the amount of red meat or eggs you consume? Here’s three credible takes:
- The Pegan diet concept crafted by Dr. Mark Hyman, the Director of the Cleveland Clinic Center for Functional Medicine, recommends consuming condiment size red meat and up to 2 eggs a day. This is what I subscribe to until the dust settles, but each needs to make up their own minds based on the evidence, family history, and unique health concerns.
- Dr. Hazen explains, “While multiple studies with thousands of subjects show high levels of TMAO predict increased future risks for heart attack, stroke or death, studies haven’t yet directly tested whether lowering TMAO lowers cardiac risk.” For now, Dr. Hazen recommends moderation. “If you eat a lot of red meat, this study argues to consider cutting back,’’ he says, noting that the same goes for eggs. Eat meat, eggs, butter, nuts, dairy and some oils in moderation. — Cleveland Clinic Health Essentials, Your Diet and Heart Disease: Rethinking Butter, Beef and Bacon, Roundup of the latest developments.
- Bottom line from Berkeley Wellness, University of California, Carnitine in Meat: Heart Hazard: Coronary artery disease is multifactorial, involving many competing and/or overlapping biochemical mechanisms, plus genetic and environmental factors. The new research highlights the complex roles intestinal microbes play, but it doesn’t change the basics of a healthy diet. It shouldn’t scare you off eggs, for instance, though if it makes you eat less red meat, that’s a good thing. As for carnitine supplements, we can’t recommend them unless large, long studies establish their benefits and safety.
Consider eating red meat and eggs along with foods common to Mediterranean Diet (resveratrol/red wine, EVOO, balsamic vinegar, and grapeseed oil) which may mitigate TMAO and TMA production.
Mimi Guarneri, MD, FACC, ABIHM, AIHM President wrote about TMAO mitigation in AIHM President’s Choice No. 71: DIETARY DIVERSITY = MICROBIOME DIVERSITY = BETTER HEALTH explaining:
- “TMAO is an atherogenic microbial metabolic product that can be formed after ingesting carnitine or red meat. That story is still unfolding, but the authors explain here [A healthy gastrointestinal microbiome is dependent on dietary diversity] that phosphatidylcholine, rich in foods such as shellfish, eggs, milk, red meat and poultry, are converted by intestinal microbes to TMA, which is efficiently absorbed by the host and oxidized to the atherosclerotic associated TMAO . However, including dietary foods common to Mediterranean diets such as balsamic vinegar, red wine, cold-pressed extra virgin olive oil or grapeseed oil contains an inhibitor of TMA production .” For more on this study, read the article, Reduction in Dietary Diversity Impacts Richness of Human Gut Microbiota.
- Dr Guarneri furthers shares that phytonutrients and antioxidants can mitigate our chronic disease risk: “Jeff Bland, PhD, FACN, CNS, recently spoke at the Natural Supplements conference. He gave a great lecture about phytonutrients, reminding us that for all of the oxidative stress we experience as part of life, nature has really provided everything we need to keep ourselves healthy and in balance, including a natural abundance of antioxidants in the plants we are meant to be consuming. There are over 10,000 phytonutrients in our food supply, and by consuming a diversity of plant based foods within a balanced diet, we really can mitigate our risk of chronic disease.”
The Resveratrol study, Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota, April 2016, showed for the first time that in mice, resveratrol reduced levels of TMAO and inhibited TMA production in the gut bacteria; TMA is necessary for the production of TMAO. The study showed that the protective effects of resveratrol against atherosclerosis was related to changes in the gut microbiome.
“In our current study, we found that resveratrol can remodel the gut microbiota including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Prevotella, and increasing the relative abundance of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in mice,” said Dr. Mi. “Resveratrol reduces TMAO levels by inhibiting the gut microbial TMA formation via remodeling gut microbiota.” — Targeting gut microbiome to fight heart disease
The balsamic vinegar and olive oil study. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis, Dec. 2015, identified a molecule, that is commonly found in balsamic vinegar and olive oil that reduced TMAO levels produced by gut bacteria in mice fed a high L-carnitine or high-choline diet. The molecule is called 3,3-dimethyl-1-butanol (DMB). DMB was able to shift the microbiome towards bacteria that did not produce TMAO. Another related article is Drugging the microbiome to decrease atherslcerosis.
The problem with jumping on the PALEO band wagon and eating red meat with abandon
thinking just drink red wine, marinate red meat using olive oil and balsamic vinegar, and eat red meat along with olive oil and balsamic vinegar, to mitigate TMAO is that much still needs learned about this approach for humans. The mitigation studies are less than 6 months old and are in mice. These authors note:
- Future clinical trials are needed to determine the safety and efficacy of [these] CutC/D [DMD] inhibitors in reducing TMAO levels and disease in humans, as well as whether resistance to their effects will occur with long-term treatment strategies. Nevertheless, this revolutionary strategy of selective, non-lethal inhibition of microbial function likely represents an important new front in the pharmacological treatment of human diseases. — Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions, April 2016.
- “To fully exploit the potential of the gut microbiota for disease prevention, we need a much greater understanding of how dietary components and host genetics affect the production of various metabolites. Finally, translation of these findings to clinical practice will require the development of widely available clinical chemistry methods to detect changes in an individual’s key metabolites.” — Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions, April 2016.
- The resveratrol study authors note that these results open a new avenue of research regarding the potential cardiovascular protective effects of resveratrol and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular disease. — Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota, April 2016
Summary of Dr. Mark Hyman’s Pegan diet concept
The premise of Pegan diet is to eat a low glycemic load diet AND avoid inflammatory foods from added sugars, processed foods, dairy, gluten, too much meat, and refined oils, as both drives inflammation in the body. Stress causes weight gain; this stress includes that due to inflammatory foods. Eating Pegan calms down and reduces inflammation in the body due to high glycemic and inflammatory foods. Read more at:
- Why I am a Pegan – or Paleo-Vegan – and Why You Should Be Too! and listen to his explanation at
Dr. Hyman Explains the Pegan Diet, along with Pegan Diet Rules.
In summary, a Pegan or Paleo Vegan eater looks like:
- Focus on the glycemic load of your diet. Pegan is a low glycemic diet. This can be done on a vegan or paleo diet, but it is harder on a vegan diet. Focus on more protein and fats. Nuts (not peanuts), seeds (flax, chia, hemp, sesame, pumpkin), coconut, avocados, sardines, olive oil.
- Eat the right fats – stay away from most vegetable oils such as canola, sunflower, corn, and especially soybean oil which now comprises about 10 percent of our calories. Focus instead on omega 3 fats, nuts, coconut, avocados and yes, even saturated fat from grass fed or sustainably raised animals.
- Eggs and Cholesterol. Eat two WHOLE eggs (that means eat the yolks too) a day. New dietary guidelines have eliminated cholesterol as something we should restrict from our diet. Eggs are not linked to heart disease. They are full of protein, and they are a great source of choline (brain food), vitamins and minerals.
Cholesterol 101 from the Cleveland Clinic article, Your Diet and Heart Disease: Rethinking Butter, Beef and Bacon, Roundup of the latest developments: “High cholesterol is a metabolic condition that can only be moderately influenced by diet. Most circulating cholesterol is produced by the liver. Dietary cholesterol accounts for only about 15 to 20 percent of blood cholesterol. Changing the diet typically has only a modest effect on serum cholesterol levels,” says Steven Nissen, MD, chair of Cardiovascular Medicine at Cleveland Clinic.
The Scientific Report of the 2015 Dietary Guidelines Advisory Committee, notes: “Available evidence shows no appreciable relationship between consumption of dietary cholesterol and serum (blood) cholesterol.”
That said, high-levels of cholesterol in the blood are strongly associated with coronary artery disease in patients of all types and ages. But they aren’t high because of the cholesterol you ingest from your foods for most people. If you have a high level of cholesterol in your blood, you need to work with your doctor to make it lower, or face a higher risk of heart attack, stroke or other cardiovascular event. — Cleveland Clinic Health Essentials, Your Diet and Heart Disease: Rethinking Butter, Beef and Bacon, Roundup of the latest developments.
We need cholesterol, it is an antioxidant. But too much indicates inflammation in the body and that inflammation needs reduced to reduce the excessively high cholesterol. While it is multi-factorial, one factor is “When you ingest fructose in high amounts without the associated fiber found in whole fruit, it turns on the cholesterol-producing factory in your liver called lipogenesis which makes super dangerous small LDL particles, jacks up your triglycerides, and lowers the HDL (or good) cholesterol. So does sugar in any form, including flour and refined carbs.” — 7 Ways to Optimize Cholesterol. Dr. Mark Hyman
- Eat mostly plants – lots of low glycemic vegetables and fruits. This should be 75 percent of your diet and your plate. I usually make 2 to 3 vegetable dishes per meal.
- Focus on nuts and seeds – they are full of protein, minerals, and good fats and they lower the risk of heart disease and diabetes.
- Avoid dairy – it is for growing calves into cows, not for humans. Try goat or sheep products and only as a treat. And always organic.
- Avoid gluten – Most is from Franken Wheat – so look for heirloom wheat (Einkorn); if you are not gluten sensitive, then consider it an occasional treat.
- Eat gluten-free whole grains sparingly– eat 1/2 cup a day of low glycemic grains since they still raise blood sugar and can cause inflammation which can trigger autoimmunity. A 1/2 cup of cooked grains is about the size of your palm or about the size of a lightbulb. Powerful gluten free grains are black rice — the blueberries of rice full of antioxidants, low glycemic load with lots of mineral (but I am interjecting that it will have arsenic load) and quinoa (lots of protein with great nutritional profile — see how & why to properly prepare soak quinoa here).
- Eat beans sparingly – eat about 1/2 cup a day of the smaller less starchy beans – lentils are best, and see how you feel. Stay away from big starchy types like kidney beans or Adzuki legumes. Those with digestive issues can have difficulty digesting beans and legumes and for diabetics, they can cause high blood sugar. Legumes are the seeds of the plants in the Fabaceae family – a family that includes beans, lentils, soybeans, peas, peanuts, and even alfalfa and clover.
- Eat meat or animal products as a condiment, not a main course. Get good protein, pastured low antibiotics/chemicals. Vegetables should take center stage and meat should be a side dish.
- Think of sugar as an occasional treat – in all its various forms (i.e., use occasionally and sparingly). Eating a lot of sugar raises adrenaline and cortisol in your body even if you are not mentally stressed. Choosing what you eat actually affects your stress response.
TMAO is commonly present in seafood, but fish oil in the seafood mitigates it! Surf and turf may make sense!
Some types of seafood (cods and other teleosts, sharks, rays, molluscs and crustaceans) are important direct sources of TMAO, so when you eat them your blood level rises. Yet fish is clearly associated with reduced coronary risk. TMAO has been found to have a harmful impact on glucose tolerance in high-fat diet (HFD)-fed mice, however, seafood also contains fish oil (FO), which has been shown to have beneficial effects on metabolism. The study, Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice, found that in mice, dietary FO ameliorated TMAO-induced impaired glucose tolerance, insulin signal transduction in peripheral tissue, and adipose tissue inflammation in HFD-fed mice. Three diets were tested:
- HF group was fed a diet containing 25% fat,
- The TMAO group was fed the HFD plus 0.2% TMAO, and
- The FO group was fed the HFD plus 0.2% TMAO and 2% FO.
Conclusion: Fatty acids were summarily discussed in the Microbiome Awareness Seminar, and for saturated fat, red meat, I suggested condiment size portions due to TMAO concerns regardless of meat quality. This post expands that TMAO conversation. Worth repeating, here are some pics of condiment meat meals we frequently have. Test question from the Microbiome Awareness Seminar, “Do you spot the components actually nourishing your microbiome and know what they are called?” A: Prebiotics, probiotics, and more!
Updated for SEO optimization. Last updated: September 28, 2016 at 10:43 am
In health through awareness,