Diet and Inflammation Part 2

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Pac manMy last post—part 1 of Diet and Inflammation—left off with my conclusion that the answer to the widespread prevalence of chronic inflammation was a nutritional imbalance incurred by the typical Western diet, specifically deficiencies or imbalances in 3 key nutrients: omega-3 (v. omega 6) fatty acids, salicylic acid and glycine (v. methionine).

What exactly happens in inflammation? Inflammation is the basic action of the innate immune system to destroy potentially pathogenic microbes that get into the internal body tissues. It is a non-specific aggressive action by amoeba-like cells called macrophages (derived from the Greek and meaning “big eaters”), the immune system’s first responders, which can literally gobble up bacteria and other microbes. Several types of these cells—called granulocytes—have long been recognized as circulating in the blood as a type of white blood cell. More recently, macrophages have been recognized as populating all sorts of organs and tissues.

But all these diverse types of macrophages are immune system cells, and all of them originate in the bone marrow. If there is tissue injury, injured cells and cell debris will be gobbled up by these macrophages. But if there is infection—the recognition of the generic signature of bacteria, for example—these macrophages get activated, producing toxins such as hydrogen peroxide in order to kill the bacteria. In order to amplify the reaction, these macrophages release chemical signals called prostaglandins to recruit and activate other macrophages, the purpose being to destroy the infecting microbes before they can destroy the host. Of course, like other first responders, the macrophages will put down the infection just like the firemen will put out the fire, but they will also do lots of damage to normal tissues.

Unfortunately, there is still lots of confusion out there about the role of inflammation and innate immunity; most medical authorities believing that inflammation is part of the healing response and a normal response to tissue injury. Why? Because it always seems to happen with tissue injury. You sprain your ankle, and it gets swollen and painful and immobilized; i.e., inflamed. But why should this happen if there is no route of infection? There are no microbes to kill. And we all know that, contrary to healing, the inflammation inhibits healing, which is why we have to put ice on the injury, to suppress inflammation. So why does your body do it?

Here’s where nutrition comes in. The activation of macrophages is affected by an electrochemical switch mechanism on the cell surface membrane. When these cells are at rest, they are, so to speak, switched off, there is a resting voltage between the outside and the inside of the cell (positive outside; negative inside). Just like a light switch on your wall, when it is off, there is a resting voltage (120 volts in the US) between the hot wire attached to the switch and the light fixture. When the light is switched on, the voltage drops as the energetic electrons flow through the switch and activate the fixture. The electrochemical switches in cells are channels in the membrane which allow positively charged ions (calcium or sodium ions) to flow across the membrane. The voltage drops when these channels open up momentarily, activating the cell. That’s how nerve impulses (called action potentials) activate muscles, for example. But it’s also how macrophages get activated.

However, the cell surface membrane is a very dynamic envelope, like a constantly moving, constantly changing, highly sophisticated soap bubble. In the course of ordinary activity, lots of leakage of ions occurs, and there are specialized channels in the membrane that let negatively charged chloride ions in to maintain the resting voltage of 0.07 volts. A substantial proportion of these chloride channels are operated—i.e., maintained in an open position—by the amino acid glycine. Glycine is ordinarily present in body fluids at high concentrations. But if they are not high enough, the glycine-gated chloride channels (aka glycine receptors) are not open enough to allow adequate chloride entry. Thus, the voltage between the outside and inside of the cell deteriorates and the cell is too easily activated, like when there is tissue injury but no infection. Once a macrophage is activated, the extent to which it recruits and activates other macrophages to the site of inflammation is related to the levels of the two other key nutrients: salicylic acid and omega-3 v. omega-6 fatty acids.

How the balance—or imbalance—in the intake of these types of polyunsaturated fatty acids (PUFAs) will be the subject of Part 3 in this series.

About the Author

Joel BrindJoel Brind, Ph.D. has been a Professor of Biology and Endocrinology at Baruch College of the City University of New York for 28 years and a medical research biochemist since 1981. Long specializing in steroid biosynthesis and metabolism and endocrine-related cancers, he has specialized in amino acid metabolism in recent years, particularly in relation to glycine and one-carbon metabolism. In 2010 he founded Natural Food Science, LLC to make and market glycine supplement products via http://sweetamine.com , which includes his own blog HERE.

33 Comments

  1. There’s a lot of buzz about gelatin these days either from bone broth or gelatin/collagen supplements. Do you believe an individual should supplement with a bone broth/gelatin/collagen that provides plenty of glycine especially in ratio to Methionine, or is it more advantageous to supplement with pure Glycine? I was curious if glycine works synergistically with other amino acids and if it’s important to have them properly balanced or if supplementing solely with pure Glycine will provide the anti-inflammatory benefits. Thanks.

    Reply
    • The inflammation regulation function is specific to glycine. I am not aware of specific key metabolic functions of the other amino acids abundant in collagen (proline, hydroxyproline, lysine), and glycine alone does provide all the anti-inflammatory benefits.

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      • Ray Peat states this about this very topic Brad…

        A generous supply of glycine/gelatin, against a balanced background of amino acids, has a great variety of antistress actions. Glycine is recognized as an “inhibitory” neurotransmitter, and promotes natural sleep. Used as a supplement, it has helped to promote recovery from strokes and seizures, and to improve learning and memory. But in every type of cell, it apparently has the same kind of quieting, protective antistress action. The range of injuries produced by an excess of tryptophan and serotonin seems to be prevented or corrected by a generous supply of glycine. Fibrosis, free radical damage, inflammation, cell death from ATP depletion or calcium overload, mitochondrial damage, diabetes, etc., can be prevented or alleviated by glycine.

        Some types of cell damage are prevented almost as well by alanine and proline as by glycine, so the use of gelatin, rather than glycine, is preferable, especially when the gelatin is associated with its normal biochemicals. For example, skin is a rich source of steroid hormones, and cartilage contains “Mead acid,” which is itself antiinflammatory.

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        • I used a highly recommended hydrolyzed collagen. I was taking the recommended dose 1 TBSP a day and it made me so sick. I went down to 1/4 tsp a day but even that made me sick…the though of putting this stuff in my mouth just makes me sick. So my question is, is hydrolyzed collagen different from glycine? If so, what should I be using?

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          • I would try the glycine. I’ve heard lots of strange reactions to gelatin/collagen. So it’s worth trying straight glycine to see if you get the benefits without the strange reaction.

  2. I use bone broths in food preparations probably every other day and have done for at least three years. Am I likely to be deficient in glycine?

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  3. Joel, do you have any references or links regarding a connection of type 2 diabetes and glycine deficiency? Would the glycine need of a diabetic be greater than average to overcome the chronic inflammation associated with insulin resistance?

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  4. Of course whole foods give the complement of associated amino acids and other nutrients, but it is true that glycine alone has the anti-inflammatory effect. Hence, it is useful as a supplement where a radical change in diet is not envisioned. (As for Ray Peat, clearly he and I are largely on the same wavelength.) As for other amino acids, serine, in particular is almost as good as glycine, owing to its easy metabolic conversion to glycine in the liver.

    As to bone broths’ being consumed several times a week, it’s a good bet that that would prevent one’s being glycine deficient. Of course it depends on the quantity consumed, relative to muscle meats and other foods high in methionine.

    As for type 2 diabetes, there was a clinical trial showing benefit with 15g/day supplemental glycine, done in Mexico City and published in 2008. (I have a pdf copy, rather than a link: Cruz et al., J Endocrinol Invest 2008;31:694-99). There was also a very interesting 2010 study by Gall et al (PLoS one, vol 5, No. 5 e10883. PLoS one is available free on line), who looked at the profile of hundreds of metabolites in a population of insulin resistant individuals v. normal controls. It is fascinating that in this long and detailed paper, they authors make no note whatsoever of the fact that glycine was the metabolite most reduced in the insulin resistant patients! That’s really the problem with what is called “data driven science”, new disciplines like genomics, proteomics and metabolomics. In my view, these are not really genuine scientific disciplines. Rather, they are sophisticated forms of biochemical data mining. Very useful, of course, because one can test different hypotheses much quicker and easier and more thoroughly than ever before. But it is “hypothesis driven science” that is real science, to me. You might say data driven science is to hypothesis driven science as trawling is to fly fishing.

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  5. How much glycine per day would you recommend? Say you eat 100 grams protein from muscle meats every day, would 10g/day glycine suffice?

    Reply
    • Sweetamine, the product I make and sell, contains 8 grams of glycine per daily serving. That seems to be enough for most people.

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  6. I guess the vegans deserve some credit for identifying the dangers of excess methionine years ago, although i don’t necessarily agree that ALL animal foods should be removed. P.S. is Jello an acceptable source of gelatin? I don’t like the taste of bone broth/stock, takes too long to make while having a very short shelf life, plus some say toxins accumulate in the bones of animals, especially CAFO ones.

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    • The trouble with Jell-O is that is high in sugar (or artificial sweeteners) and also expensive. (Each 4-oz. serving gives you about half a gram of glycine, so it can get pricey, compared to a product like sweetamine, with 8 grams of glycine per serving. If you prefer jello, however, I would recommend just buying unsweetened gelatin and boiling it up with your favorite fruit juice. I have actually used it to get 10 grams per serving by using gelatin and boiling it up with sour cherry juice, then adding 8-10 grams of straight glycine powder per serving. It comes out pretty good (although again, a bit pricey).

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      • Hi there, I’ve taken gelatin off an on for a while. I went to look at buying Sweetamine but couldn’t find an ingredients list on the site. I prefer to take supplements that are food based and don’t have excipients (particularly magnesium stearate)Is there anywhere I can read the ingredients list for Sweetamine?

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        • Sweetamine contains glycine, L-serine, taurine and natural stevial extract. That’s it.

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    • “I guess the vegans deserve some credit for identifying the dangers of excess methionine years ago,although i don’t necessarily agree that ALL animal foods should be removed”

      Obviously not since A: methionine is an essential amino acid, and B: We now know that the ‘dangers’ of excess methionine are conditional on a deficiency in glycine…and animal foods are also the best source of glycine.

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  7. Would glycine be beneficial to those with scleroderma since the body is producing excess amounts of collagen?

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    • I would not expect glycine supplementation to have any effect on collagen production generally. Even when glycine deficient, the body has enough to make collagen. Protein turnover is way slower than the turnover of the free, soluble glycine. That being said, it is possible that scleroderma–an autoimmune disease of unknown etiology–might be one of those conditions that results from glycine deficiency. One would have to try it.

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  8. Hi Joel,

    Very interesting article.

    But I think there is one very questionable assumption here. You said “And we all know that, contrary to healing, the inflammation inhibits healing, which is why we have to put ice on the injury, to suppress inflammation.”

    The research is far from conclusive that ice speeds up the healing process, and there are numerous studies that have found that icing (i.e. suppressing inflammation), does NOT speed up healing of the tissues. It hinders healing. (See below for some of the many studies showing this).

    I would be interested to hear how you can reconcile this with your theories (which are otherwise very interesting), but in general, I think your assumption that “of course, everyone knows we have to ice injuries to speed up healing” is not supported by the research.

    http://ajs.sagepub.com/content/32/1/251.abstract

    J Strength Cond Res. 2013 May;27(5):1354-61. doi: 10.1519/JSC.0b013e318267a22c.
    Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage.

    Am J Sports Med. 2013 Aug;41(8):1942-51. doi: 10.1177/0363546513490648. Epub 2013 Jun 5.
    Effects of air-pulsed cryotherapy on neuromuscular recovery subsequent to exercise-induced muscle damage.

    J Appl Physiol (1985). 2011 Feb;110(2):382-8. doi: 10.1152/japplphysiol.01187.2010. Epub 2010 Dec 16.
    Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats.
    Takagi R1, Fujita N, Arakawa T, Kawada S, Ishii N, Miki A.

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      • Very interesting, Matt. I had not seen that. Nice article.

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      • I immediately thought of that article when reading this one :D

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  9. Another excellent article.

    I’m curious: Do some people have metabolic abnormalities that result in more severe glycine deficiency?

    Thanks!

    Reply
    • Thanks for the kind words, K. And you raise a very interesting point, which actually brings up a pet hypothesis of mine: No doubt readers are familiar with the genetic disease known as cystic fibrosis (CF). Although there are now drugs and dietary regimens that can allow people with this disease to survive quite a number of years, they are plagued with severe inflammation that often affects the lungs. Thick, viscous mucus secretions make it difficult to breathe, spawn secondary infections, and inflammation causes so much damage that it has typically resulted in early death. (You may be familiar with a recent, highly publicized case in which our Federal HHS department initially refused to approve a lung transplant for a 13-year-old CF patient.)

      So it’s a no-brainer that glycine supplementation, by limiting inflammation, should be of some help. But there’s much more to it, I think. That’s because the actual genetic defect in CF is for a protein called “CFTR”, which is actually a cell surface membrane chloride channel. It is not a glycine-gated chloride channel, but my hypothesis is that, if one is not also glycine-deficient, the glycine-gated chloride channels may be able to compensate for the defective CFTR chloride channels, enough to maintain normal or near normal function. As you might guess, people with CF kids are naturally loathe to try anything new, unless it is something approved by their medical teams. Maybe some doctor somewhere will be interested in giving glycine a try. Wouldn’t it be cool if CF turned out not really to be a disease, but a genetic variant that only produces disease in the presence of a glycine deficiency?

      But while we’re on the subject of metabolic abnormalities, there’s also one in which the normal enzymatic degradation of glycine (into carbon dioxide and ammonia) is defective. Patients with this condition (called nonketotic hyperglycinemia, or NKH) are much worse off than those with CF. After birth, they progressively develop more and more siezures and other brain problems, as glycine builds up to toxic levels (almost impossible to do if you don’t have NKH). So, naturally the doctors put these kids on a low protein diet (to limit glycine intake), as well as the low-toxicity drug sodium benzoate, which binds glycine and helps the body to excrete it.

      My hypothesis in this case runs counter to this “prevailing wisdom” which I believe to be overly simplistic. First of all, there are other ways to clear glycine metabolically, one of them being by loading up with excess methionine (which requires glycine for its clearance). So for NKH people, methionine or SAMe would be excellent supplements, in my view (and NOT glycine, of course).

      But there’s another way to clear excess glycine I have not seen considered: In one simple step, the liver can turn glycine into the amino acid L-serine. Serine, in turn, can be converted (by a process called gluconeogenesis)into glucose, which is of course used for energy. In fact, gluconeogenesis normally happens at a high rate when carbohydrate intake is low or nil (like during prolonged fasting) or when on low no-carb diet, because the body needs a substantial amount of glucose in the blood at all times. But if you have a normal or even a high-carb diet (as in the low-protein diet recommended for NKH), the liver cannot turn glycine into serine, because gluconeogenesis is turned off, in favor of burning the dietary glucose first.

      So the bottom line of my hypothesis for NKH would be a low glycine but zero-carb diet, thus forcing the body to convert the excess glycine into glucose and burn it for fuel. So what would these kids eat? Well, chicken is probably the best source of high methionine/low glycine protein (just without the breading or the barbeque sauce), rather than mainly limiting protein, and then supplemental methionine or SAMe. NKH only affects about 1 in 60,000 individuals. But importantly, that means carriers for NKH would be much more common, about one in several hundred people. Such people would be normal generally, but their glycine levels would be on the high side, and some of the few people who report adverse effects with glycine supplementation may be carriers of NKH (and they likely do not have problems with chronic inflammation, either.)

      Reply
      • That is very interesting!

        When my nephew was born at the beginning of this year, he started getting very sick at 2 days old and then went into seizures. They found out he has OTC deficiency (an issue with the urea cycle I think?). My sister did genetic testing and found out she is a carrier and the one who most likely gave it to him (it’s passed along on the x chromosome from the mother).

        When boys get it, they get very sick and can die. When girls get it, they become carriers and can have some more mild symptoms of having the gene. My nephew had a liver transplant (he ate a very, very low protein diet until then), will most likely have to have a kidney transplant, and has to be on long term meds.

        Now, although my sister is a carrier, her body can use proteins alright.

        Does OTC deficiency have anything t do with excess/not enough glycine?

        I still need to get the genetic testing done, but haven’t yet because it’s very expensive AND it’s tricky to find a clinic that will use the lab orders I already have.

        Thank you! And thank you for your articles!

        Reply
  10. I have a hard time believing anything that Joel Brind says, since he spent so many years claiming that abortion leads to breast cancer. I believe he still asserts that, in spite of all the scientific and medical evidence to the contrary.

    Reply
    • …and I have a hard time believing anything that anyone claims to know about “all the scientific and medical evidence” about anything, especially when they are engaged in ad hominem attacks. All are free to read my writings on all areas of research in which I have engaged, and to make up their own minds. On these comment strings, I intend to limit my writings to the subject at hand.

      Reply
  11. This is a good point, Ari. I may have given the wrong impression that I was advocating icing, although my intention was really to talk about the typical need to suppress inflammation in blunt injury, for example, where there is no infection to fight. Ice is of course a very crude way to suppress inflammation, because it also suppresses blood flow necessary for healing. In that way, it is rather like anti-inflammatory drugs, which are also crude. That’s what’s most important about glycine: It does not really suppress inflammation, but rather, completes a healthy, natural cellular environment in which inflammation occurs only in an appropriate manner and measure.

    Now perhaps you also think that my assertion that inflammation is an unnecessary and inappropriate response to blunt injury is a “very questionable assumption”. It may well be as yet unproven (with a large N and peer-reviewed, published trials), but it is a reasoned conclusion–not an assumption. It is based on my formal studies of human biochemistry, physiology and immunology, which have given me a framework for interpreting not only experimental results in the lab, but also personal experiences (and a growing number of experiences of family, friends and customers).

    I will have two more posts on this blog on this subject coming up, wherein I will flesh out the important role of the other key nutrients involved in inflammation, and finally, on the key pathways of one-carbon metabolism, where the balance between glycine and methionine plays a central role.

    Reply
    • Very interesting, Joel. I look forward to hearing more of your thoughts.

      Reply
  12. I sometimes experience inflammation that doesn’t seem to have a cause (like injury or over exercising), so I’m enjoying this series of articles and looking forward to the next two! :)

    Reply
  13. I wonder how much glycine is in a 5oz bag of Haribo Gold-Bears?

    Reply
    • It’s pretty easy to calculate: There are 3 servings in each 5 oz. bag (I happened to have one handy:-), with 3 grams of protein in each serving; 3 servings per bag, so there are 9 grams of protein, all of which is gelatin. Gelatin is 22% glycine, so there are 22% of 9, or about 2 grams of glycine per bag.

      I have a friend whose grandson has cystic fibrosis. The kid craves gummies (Welch’s fruit snacks, which also have a similar quantity of gelatin). After I told my friend about glycine, his mom tried an experiment and switched to gummies with no gelatin. The kid started wheezing within a couple of days, so she switched back to the fruit snacks with gelatin, and the wheezing stopped. That’s one bit of anecdotal evidence supporting my hypothesis about CF I mentioned in an earlier comment.

      I also hypothesize that what hospitals do more than anything else (except surgery when needed, of course) that actually helps patients get better is to feed them Jell-O for dessert after every meal. Jell-O provides about half a gram of glycine per 4-oz serving.

      Gummies, Jell-O, bone broths, sweetamine: It’s all good:-)

      Reply
      • Wow… that’s more than I suspected. That’s good to know then. A bag of Gold-Bears is a little over 500 calories of sugar and gelatin goodness. Makes me smile.

        Reply
        • Sounds like your gummy bear “addiction” is really craving a nutrient you need. Not that you necessarily need all that sugar, of course.

          Reply

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  1. diet and inflammation - […] my last post—Part 2 of this diet and inflammation series—I discussed the cells—called macrophages—which actually […]
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