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.

 

Leg of Lamb with Cinnamon-Thyme-Fennel Rub

Posted by on April 7, 2013 17 comments

This was our Easter dinner. As you’ll see, the idea was stolen from Gordon Ramsay with few changes; it came out great.

Preparation

Begin with a 4-5 pound (2 kg) boneless leg of lamb. Drive a narrow but sharp knife into the lamb, twirling it to carve out cylindrical holes. Make 3 or 4 holes and into each place a cinnamon stick and a sprig of thyme. (This is illustrated in Ramsay’s video below.)

Here’s a picture of the cinnamon sticks and thyme sprigs that we used, plus some vegetables, seasoning, and honey that we’ll use later:

Next, mix some dry seasonings for a rub. We used:

  • 1 tsp fennel seed
  • 1 tsp smoked paprika
  • ½ tsp cayenne pepper
  • ½ tsp cinnamon
  • ½ tsp allspice
  • ½ tsp turmeric
  • ½ tsp cloves

Coat the lamb in the rub. Don’t worry if you don’t have all of these seasonings; use whatever assortment you like. We do recommend including the smoked paprika and allspice.

By the way, over the past few years we bought a number of disposable pepper grinders that contained whole peppercorns, and gathered a collection of empty grinders. Recently we began buying spices as whole seeds and storing them in the grinders, grinding the spices fresh as we need them. Freshly ground spices do taste better than pre-ground spices!

The next step is to prepare some vegetables – we used carrot, celery, and onion – and to sear the surface of the lamb on the stove so that the meat will retain moisture in the oven.

In previous recipe (“Roast Beef, Beets, and Potatoes,” April 8, 2012), we skipped the stovetop step. In that recipe, to seal the surface we pre-heated the oven to 400 F and after 10 minutes cooking reduced the heat to 300 F.

In Gordon Ramsay’s rendering (see video below), he sautées the vegetables with olive oil and honey before searing the lamb. The honey caramelizes, adding flavor.

We decided to take an intermediate approach that is more in line with our preference for gentle cooking. We briefly cooked the vegetables in olive oil at low heat on the stove, and added honey so as to coat the vegetables evenly.

Here were the vegetables on the stove, in the pyrex pan we used also in the oven:

After a few minutes we pushed the vegetables to the side of the pan and seared the lamb at medium heat, 1 minutes per side. After searing the seasoned lamb is ready for the oven, placed fatty side up:

We cooked at 300ºF (150ºC) for one hour. It came out like this:

Sliced, it looks like this:

We had space in the oven so we baked some potatoes and beets along with the lamb. They were placed in a cake pan that hasn’t been used for its original purpose in many years:

We’ve found it’s least messy to cook the beets first and peel them after cooking.

The final step was making a sauce to drizzle over the meat. This was composed of a simple mixture of:

  • Juice and zest from one lemon
  • 3 tbsp olive oil
  • 1 tsp mustard

Served on the plate, it looked like this:

Conclusion

Gordon Ramsay’s video offers a good view of the process:

It’s an easy dish to prepare, but quite delicious!

Weight Loss Guru Radio

Posted by on April 2, 2013 32 comments

A quick note: I’ll be appearing live tomorrow on Weight Loss Guru Radio with host Pete Cohen. The show will be at 3 pm Eastern time / noon Pacific / 8 pm London time, and can be heard on Blogtalkradio here.

Pete is a London-based talk show host and his previous guests include a broad range of interesting people, many outside the Paleo community but also such familiar names as Gary Taubes, Mark Sisson, Zoe Harcombe, and Sean Croxton. Check out his prior shows here.

UPDATE: Pete mentioned that he liked our recipes and Shou-Ching’s photo art, which can be found here.

A Few Discounted Products

Posted by on April 2, 2013 5 comments

Every once in a while vendors offer product discounts to PHD readers. I usually don’t pass them on, but here are a few that strike me as attractive.

First, Neely Quinn of PaleoPlan has put together an extensive package of Paleo products at a significant discount. I’m not usually interested in these packages but this one has some interesting items, such as:

All told the package has retail products with a list price of $485 for $39. Go here to learn more.

Second, Vintage Tradition wants to offer PHD readers a 20% discount on their body balm made of grass-fed tallow, olive oil, and essential oils. The balm was reviewed positively in the Wise Traditions newsletter of the Weston A Price Foundation. To get your 20% discount, follow this link.