Search Results for: TMAO

Lessons From The Latest Red Meat Scare

Posted by on April 10, 2013 109 comments

I’ve had about ten requests for thoughts on the new paper in Nature Medicine [1] that finds red meat can promote atherosclerosis by a roundabout route: carnitine in the meat is metabolized by gut bacteria into a compound called TMA, which the liver converts to TMAO, which in high doses promotes growth of atherosclerotic plaques.

The same group has done similar studies with other molecules; two years ago the culprit was not carnitine but phosphatidylcholine. [2]

The Scare

Some of the news stories:

It sounds like red meat is dangerous! The best line came from the New York Times:

Lora Hooper, an associate professor of immunology and microbiology at the University of Texas Southwestern Medical Center, who follows the Paleo diet, heavy on meat, exclaimed, “Yikes!”

The Big Picture

The issue here is closely related to one discussed in page 77 of our book:

Protein is not food for us alone; gut bacteria can ferment protein.

Although fermentation of carbohydrates by gut bacteria is usually beneficial, fermentation of protein is not: it generates toxic compounds, including amines, phenols, indoles, thiols, and hydrogen sulfide, which make a foul-smelling stool.

It seems likely, therefore, that high protein intakes are suboptimal for gut health.

When protein is fermented, nitrogen is released, and many nitrogenous compounds are toxic.

The group behind the new research, led by Stanley Hazen, has been looking at another pathway by which bacterial fermentation of meat might be dangerous – the pathway that runs through Trimethylamine. Trimethylamine (TMA) has a simple structure; three methyl groups bonded to a nitrogen atom: N(CH3)3.

Compounds such as choline and carnitine that contain both methyl groups and nitrogen are potential precursors to TMA.

TMA is responsible for the fishy smell of decaying fish. It is highly abundant in fish.

The liver converts TMA into its oxide, TMAO. The Hazen group in a series of papers has argued that higher TMAO levels in blood are associated with atherosclerosis. In a recent paper they assert, “TMAO levels explain 11% of the variation in atherosclerosis.” [3]

So, the equation they are putting together is: fermentation of meat in the gut produces TMA leading to TMAO production which may increase your chance of atherosclerosis by 11%.

Risk is Highly Dependent on the Nature of Your Gut Flora

Here is the key data from the new paper [1]. The “d3” prefix means that the carnitine was labeled with deuterium, an isotope of hydrogen, to help trace its molecular destinations.

In the left panel of part (e), subjects have been fed a steak (eaten in 10 minutes) plus a 250 mg deuterated carnitine supplement – in total, the carnitine equivalent of 1.5 pounds of meat. Deuterated TMAO levels in blood rise to about 1.8 parts per million after 24 hours.

Then subjects are given antibiotics for a week to suppress their gut flora, and fed steak and deuterated carnitine again. On antibiotics, their blood has no deuterated TMAO at all 24 hours after the meal.

In the right panel, 3 weeks after coming off antibiotics to allow gut flora to regrow, subjects are challenged again with steak and deuterated carnitine. Their blood level of deuterated TMAO now exceeds 12 parts per million – 7 times higher than before the antibiotics.

They go on to test the mix of flora in subjects, and show that flora composition is closely correlated with blood levels of deuterated TMAO after consumption of deuterated carnitine. Some types of gut bacteria produce a lot of TMA from food carnitine, others produce little.

So the amount of TMAO entering the blood from bacterial metabolism of food carnitine is highly dependent on the nature of the gut flora. If you kill off normal flora with antibiotics, then eat meat and carnitine, you will get an overgrowth of bacteria specialized to feed on meat and carnitine. That might not be good for you.

The Vegan vs Omnivore Comparison

Food carnitine is far from the only source of blood TMAO. In fact, TMA is a natural breakdown product of choline, one of the most abundant molecules in the body, and the body has evolved an enzyme for converting TMA into TMAO — the gene is FMO3. So we should ask, how much does metabolism of carnitine by gut bacteria affect blood TMAO levels? For that we need measurements of normal TMAO, not just deuterated TMAO.

We can see what that data looks like in a plot comparing blood TMAO levels between vegans and omnivores (panel c of their Figure 2):

These are the TMAO levels normally circulating in the fasting blood of SAD omnivores and vegetarians. As you can see, there’s considerable overlap between the two distributions. 75% of the omnivores had TMAO levels within the same range as 90% of the vegetarians.

So about 75% of omnivores and 90% of vegetarians have normal TMAO levels. What about the 25% of omnivores and 10% of vegetarians whose TMAO levels are elevated?

In panel e, you can see that the enterotype of the gut flora is a much better predictor of blood TMAO levels than whether someone eats meat. Those with high Prevotella, low Bacteroides averaged about triple the TMAO levels of those with low Prevotella, high Bacteroides flora.

So it really is the gut flora that determine blood TMAO levels.

What Drives the Gut Flora?

What determines whether you have the bad gut flora?

The general picture is this. The immune system regulates the number of microbes living in the gut. When levels become high, antimicrobial peptides are released into the gut to kill some off. When levels are low, antimicrobial peptide production is reduced to let microbes multiply.

This means that if the proportion of bacteria who feed on protein, carnitine, and choline is too high, it’s probably because there is insufficient food for the competing bacteria who feed on carbohydrate forms of fiber. If you have a lot of gut bacteria feeding on fiber, there’s no room in the gut for large amounts of bacteria who feed on meat.

So the 25% of omnivores and 10% of vegan/vegetarians with high TMAO levels are probably the people on low-fiber diets – the ones who get their carbs from flour and sugar. On such a diet, the good bacteria are starved and the bad bacteria that produce TMA multiply.

How Does TMAO Produce Atherosclerosis?

The explanation offered by the Hazen group is that TMAO suppresses “reverse cholesterol transport” conceived broadly as the process of migrating excess cholesterol out of macrophages for transport to the liver and excretion in feces via the bile.

Basically, the idea here is:

  1. Atherosclerosis begins with metabolic syndrome, a state characterized by high LDL levels and caused by endotoxemia (high levels of endotoxins entering the body from the gut).
  2. As we’ve discussed (“Blood Lipids and Infectious Disease, Part II,” July 12, 2011), LDL particles have an immune function. They are oxidized by microbial cell wall components. The resulting oxLDL particles are taken up by macrophages, which then present the microbial cell wall components to other immune cells for antibody formation.
  3. Endotoxemia initiates the process of atherosclerosis by (a) poisoning the liver to cause metabolic syndrome which raises LDL levels, and (b) oxidizing LDL – since endotoxins are bacterial cell wall components that can oxidize LDL – and driving the oxLDL into macrophages.
  4. After macrophages have separated the microbial cell wall components from their accompanying LDL particle, the cholesterol and fat have to be exported to keep them from building up in the cell.
  5. If cholesterol and fat cannot be exported quickly enough, the macrophage is injured and becomes a “foam cell.” Disabled foam cells accumulate in specific locations and form atherosclerotic plaques.
  6. TMAO suppresses bile acid creation, reducing the excretion of cholesterol from the body and leading to higher LDL levels and a greater likelihood that macrophages will become foam cells.

If this is true, then TMAO is not intrinsically atherosclerotic. TMAO in blood only becomes atherosclerotic in the context of metabolic syndrome brought on by endotoxemia.

What causes endotoxemia? A dysbiotic flora generated by a diet high in sugar, flour, and omega-6 fats (see our book, pp 220-222).

Conclusion: Lessons Learned

The lessons of this study are:

  1. Don’t eat a high-sugar, high-flour, low-fiber diet.
  2. Do eat natural whole foods that have the kind of fiber we and our probiotic gut flora co-evolved eating; mainly, resistant starch from in-ground starches like potatoes and soluble fiber from fruits and vegetables.
  3. Don’t eat excessive amounts of meat. As we noted in the book, excess protein is available to gut bacteria for fermentation and that produces a number of toxic byproducts.
  4. Do eat PHD levels of meat – one-half to one pound per day. This level of meat consumption will provide healthful and nourishing amounts of protein, choline, and carnitine, and will not cause any harm if accompanied by PHD levels of healthy plant foods.

None of these lessons is new. This study doesn’t overturn any established dietary wisdom. It is just one more piece of data reminding us to eat a balanced diet consisting of the foods we evolved eating – plant as well as animal.

References

[1] Koeth RA et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 Apr 7. http://pmid.us/23563705.

[2] Wang Z et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011 Apr 7;472(7341):57-63. http://pmid.us/21475195.

[3] Bennett BJ et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013 Jan 8;17(1):49-60. http://pmid.us/23312283.

 

Around the Web; and Why Is Aspirin Toxic to Cats?

Posted by on April 9, 2011 31 comments

[1] Interesting posts this week: Melissa McEwen assures us: Robb Wolf is not Satan. Kurt Harris’s reader Tara makes the most persuasive case I’ve seen for grass-fed meat through pictures. Emily Deans compares eating disorders to addictions.

[2] Kurt Harris re-re-brands: Paleonu became PaNu became Paleo 2.0 becomes Archevore.com, archevore being a neologism for “one who eats of the essentials.”

Well, it’s more euphonious than “EM2vore,” for “one who eats of the evolutionary metabolic milieu.” A more descriptive name might have been “nontoxivore,” since Kurt’s primary theme is avoidance of “neolithic agents of disease – wheat, excess fructose and excess linoleic acid.”

It will be interesting to see where he’s taking this. Are Archevorean essentials the same as PaNu?

[3] Posts of the week: Chris Masterjohn posts always deserve special notice. On Tuesday he continued his important series investigating whether wheat causes leaky gut, which will trigger a few edits in the next edition of our book. I was asked about this last Saturday and said:

There’s no question that gluten causes problems in non-celiacs – that’s the main result of the Fasano paper Chris cites, and also of papers cited by Andrew Badenoch in a post I linked today. It’s just that leaky gut does not appear to be one of those problems.

It certainly doesn’t mean that wheat is safe to eat.

I may add that pathogens and other food toxins – even perhaps other wheat toxins besides gluten – can cause a leaky gut, providing a way for wheat toxins to enter the body. Moreover, some wheat toxins don’t even need a leaky gut to enter the body. As we discuss in the book (p 134), wheat germ agglutinin can cross barriers via transcytosis, enabling them to enter the body even if the intestinal barrier is intact. Finally, wheat toxins can damage the gut without entering the body at all. So there are many pathways through which wheat toxicity can matter.

Chris had another outstanding post on Friday, about fatty liver disease.

[4] Rosacea is an infection of the skin and vessels: That’s why it can be transmitted through facial skin grafts.

Source: Kanitakis J. Transmission of Rosacea from the Graft in Facial Allotransplantation. Am J Transplant. 2011 Mar 28. [Epub ahead of print] http://pmid.us/21443678.

[5] Special offer: The folks at Emerald Forest Xylitol noticed that we recommend their product and would like to give a special offer to PerfectHealthDiet.com readers. Use the coupon code FIRST to get 10% off all products at www.emeraldforestxylitol.com.

Also, Matt Willer of Emerald Forest Xylitol is looking for recipes that include Xylitol for use in his newsletter. If you have a recipe, send it to matt@xylitolusa.com.

[6] Animal photos: If you saw a grizzly charging straight toward you, would you stop to take this photo?

Photographer Alex Wypyszinski did in Yellowstone. The grizzly was chasing an injured bison, and the pair went right past him:

For the full story, see Grizzly versus Bison: the rest of the story (Drew Trafton, 10/29/10, KRTV, Great Falls, Montana). Hat tip Orrin Judd.

[7] Don’t hate the sun: From Britain comes the sad story of a 21-year-old who “hated the sun” and died of skin cancer at 21.

Dr. John Briffa has a summary of the relevant science.

[8] I couldn’t disagree more: Mike the Mad Biologist and Newt Gingrich are dead wrong in their prescription for research funding. We don’t need more concentrated funding, we need more distributed, decentralized funding that is patient-driven, not top-scientist driven.

Discovering cures can be cheap – if you’re looking in the right place. If you’re looking in the wrong direction, the cost of a cure may be infinite.

[9] I hate when that happens:

(Via Stephen Wangen)

[10] Are choline supplements toxic?: At the very beginning of the book (p 3) we state that “the perfect diet should … deliver … no excess nutrients for pathogens.”

Later in the book we give examples of nutrients that, in excess, primarily benefit pathogens: niacin (the primary vitamin for bacteria), iron (critical for metabolism of most pathogens, and a component of bacterial biofilms), and calcium (a component of bacterial biofilms). These are on our list of micronutrients we recommend not supplementing (beyond a multivitamin).

Two readers, Leonardo and Patricia (thank you both!), emailed us about a ScienceDaily article suggesting that choline, one of the micronutrients we most frequently recommend, should be added to this list:

When fed to mice, lecithin and choline were converted to a heart disease-forming product by the intestinal microbes, which promoted fatty plaque deposits to form within arteries (atherosclerosis); in humans, higher blood levels of choline and the heart disease forming microorganism products are strongly associated with increased cardiovascular disease risk.

The story didn’t have enough information, so I downloaded the paper. The paper notes that choline is metabolized by gut bacteria to a gas with a fishy odor called TMA, which is then oxidized in the liver to a compound called TMAO:

Briefly, initial catabolism of choline and other trimethylamine-containing species (for example, betaine) by intestinal microbes forms the gas trimethylamine (TMA), which is efficiently absorbed and rapidly metabolized by at least one member of the hepatic flavin monooxygenase (FMO) family of enzymes, FMO3, to form trimethylamine N-oxide (TMAO).

They showed that (a) feeding phosphatidylcholine from egg yolk to mice led to increased blood levels of TMAO and that (b) in a separate study, people with atherosclerosis have elevated blood levels of TMAO, choline, and trimethylglycine.

Supplementing choline at 10 times normal levels to Apoe-knockout mice led to increased TMAO but not choline in blood:

Atherosclerosis-prone mice (C57BL/6J Apoe-/-) at time of weaning were placed on either normal chow diet (contains 0.08–0.09% total choline, wt/wt) or normal chow diet supplemented with intermediate (0.5%) or high amounts of additional choline (1.0%) or TMAO (0.12%)….

Analysis of plasma levels of choline and TMAO in each of the dietary arms showed nominal changes in plasma levels of choline, but significant increases of TMAO in mice receiving either choline or TMAO supplementation (Supplementary Fig. 10).

Serum TMAO levels were correlated with atherosclerotic plaque size and with macrophages turning into foam cells:

[A]ll dietary groups of mice revealed a significant positive correlation between plasma levels of TMAO and atherosclerotic plaque size (Fig. 3e and Supplementary Fig. 9b).

TMA (a gas with a fish odor) has to be converted in the liver to the toxic TMAO in order to produce these bigger atherosclerotic lesions. This conversion happened mainly in mice with low HDL:

Interestingly, a highly significant negative correlation with plasma high-density lipoprotein (HDL) cholesterol levels was noted in both male and female mice (Fig. 4b and Supplementary Fig. 12, middle row).

So if you’re an Apoe(-/-) mouse and eat ten times normal choline, if you have high HDL your arteries are safe but you smell fishy; if you have low HDL you smell fine but your arteries get injured.

What does this tell us about choline supplementation?

For humans with working ApoE alleles, I doubt we can infer anything yet.

For Apoe(-/-) mice fed ten times normal choline, I would suggest shooting for low HDL while dating, then high HDL after marriage.

Reference: Wang Z et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 2011; 472 (7341): 57 DOI: 10.1038/nature09922

[11] One-upping the standing desk: Jamie Scott has a walking desk:

[12] Why is aspirin toxic to cats?: In the book we mention that plant foods always contain toxins, but animal foods don’t – because in poisoning us, animals would poison themselves. As we point out in the book, Bruce Ames and Lois Gold estimate that over 99% of the toxins humans ingest come from plant foods – not industrial or environmental toxins.

One of the main functions of the liver is detoxification. A healthy liver enables us to consume plant foods.

But what happens to the livers of animals that never eat plant foods? If they and their descendants avoid plant foods for millions of years, how would their livers evolve?

The answer is in a fascinating piece by Ed Yong at Discover blogs: “Why Is Aspirin Toxic to Cats?”. The puzzle:

[C]ats are extremely sensitive to aspirin, and even a single extra-strength pill can trigger a fatal overdose.

Some scientists have been investigating this puzzle since the early 1990s. It turns out that all 18 of 18 species of cat studied, including housecats, cheetahs, servals, and tigers, have crippling mutations in a gene involved in liver detoxification. The same gene is also lost in other hypercarnivores, including the brown hyena and the northern elephant seal.

Mr. Yong explains:

Like many other “detoxifying” proteins, UGT1A6 evolved to help animals cope with the thousands of dangerous chemicals in the plants they eat….

But if an animal’s menu consists largely of meat, it has little use for these anti-plant defences. The genes are dispensable…. [T]he ancestral cats gradually built up mutations that disabled their UGT1A6 gene. Evolution is merciless that way – it works on a “use it or lose it” basis.

So – millions of years of hypercarnivory will disable the liver’s ability to metabolize toxins.

Pet owners, be kind to your cats: Don’t feed them plants!

And a new zero-carb danger: After ten thousand generations, your descendants may be unable to take aspirin.

Reference: Shrestha B et al. Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory. PLoS One. 2011 Mar 28;6(3):e18046. http://pmid.us/21464924.

[13] Not the weekly video: Best mobile phone commercial I’ve seen:

[14] Weekly video: I grew up near the University of Connecticut campus and have been a fan of their men’s basketball team since the late 1970’s. What Jim Calhoun has done there, building a minor program to national prominence and three championships, is one of the great accomplishment in coaching history. And this year’s team was a minor miracle: with unheralded and under-recruited freshmen playing half the minutes, they won a national championship.

Every year CBS makes a video montage of the tournament. Here it is, One Shining Moment: