Omegas and Inflammatory Balance – A Deep Dive Into Factors Influencing Their Biochemistry

Interview from Emerson Ecologics blog.

When it comes to essential fatty acids’ effect on inflammation and human health, context is everything, says Dr. Paul Anderson, NMD, CEO of the Anderson Medical Group, former chief of IV services for Bastyr Oncology Research Center, and a past professor at Bastyr University.

In this extensive interview with Emerson Ecologics Medical Educator Lisa Murray, RDN, LD, Anderson explains how the actions of omega-3 and 6 fatty acids are influenced by other nutrients and antioxidants, the contexts which influence their role in inflammation, and strategies to support optimal benefit from omega 3 supplementation.

Lisa Murray: In the past five years, there has been some conflicting research published about omega-3 fatty acids, particularly in the areas of cardiac and cancer research. Some people are now confused as to whether or not omega-3 supplements are beneficial. Can you shed some additional light on this subject?

Paul Anderson: Yes, whether it’s omegas or anything else, when researchers start to look retrospectively at instances of disease, and the nutrient intake versus supplement intake, or they pick out one particular isolated nutrient and look at it like a drug—a single variable that would change an outcome—I think that’s where we get the most confusing papers coming out. The researchers publish their findings, which are probably reasonable findings, but that doesn’t mean those findings necessarily relate to how either a supplement or the food source of the nutrient might be used in an integrative manner, let alone in real life.

There’s a summary paper from 2016 that does a nice job at looking at a lot of the more controversial studies. You’ll have one study saying omega-3 is good for prostate cancer, and one saying it’s bad for prostate cancer. It’s very, very confusing, so you have to look deeper and see what the researchers were really looking at. Context becomes the biggest thing in all of those individual studies.

Sometimes the context is they were looking at people with “X” disease, and then they looked retrospectively at their diet and dietary sources of, in this case, omegas. Then sometimes they look at the same disease, and they look retrospectively at supplementation with fish oil or something of that nature. You’re really looking at two totally different data sets there. And this is true any time you have something that seems paradoxical—either there’s a context that’s just really unusual or there’s something about the way the design was, or the data collection was, that just plain doesn’t work out in real life.

Murray: Let’s talk about the relationship between omega-3s and inflammation, and if, why and how omega-3 supplements help reduce inflammation.

Anderson: I think that the first thing to remember is that the omegas fall into three series. There’s more, but to keep it to the biggest biological actors, there are three series.

Series one is the omega-6 fraction. Also known as linoleic acid, it comes from lots of seeds, and nuts, and vegetables. They tend to be a higher quantity in most people’s diets, and that’s actually okay—it’s just that modern diets maybe have overdone it. But if these omega-6s are left alone, and they’re allowed to process through their whole biochemistry, they actually can turn into anti-inflammatory series-one cytokines.

Most people think of omega-6 as inflammatory, but that’s actually only partly true. The plain omega-6 that goes over to gamma-linolenic acid, and then DHGLA, or di-homo-gamma linolenic acid—if they’re left alone without other actors, they actually turn into a stabilizing prostaglandin thromboxane leukotriene series one, which generally are anti-inflammatory.

Murray: That explains why studies show omega-6 can be helpful for inflammatory skin conditions for some people, but not others. It really depends on a person’s diet and his or her metabolism, stress level, and general state of health?

Anderson: Exactly. For example, I think on the supplement side of things you see evening primrose, or borage or black currant oil—those are high series one; they’re high omega-6, and we use those for all sorts of things. But the thing with series one and omega-6 is that, depending on other factors, like how inflamed you are or other chemistry we’ll talk about later, it has an alternate pathway it can undergo. And that’s really where the trouble comes from. It’s not the omega-6 itself that’s the problem; it’s the rest of what’s happening in your body.

Murray: So there are three series of omegas, and we discussed the first series—omega-6. Let’s discuss the other two series.

Anderson: So series two are the real pro-inflammatory omegas like arachidonic acid, that sort of thing, and we’ll leave them alone for the moment. Then series three are the omega-3s. Flaxseeds are a good source of omega-3s, and then fatty fish have EPA and DHA omega-3s, and they become true anti-inflammatories as well.

I think there are a couple of things to mention before we get into this switching of the chemistry of these omegas. The first step in the series one, the omega-6s, and the series three, the omega-3s, is delta-6 desaturation—which is necessary in order to turn these omegas into a type of fat more usable by the body.

There are actually a number of things that affect delta-6 desaturase. One is your genetics—some people are genetically insufficient in the coding for delta-6, so they don’t get as much omega-6 and omega-3 out of vegetable sources as other people do. Some people just don’t convert omegas well, and that’s an important clinical point. It’s why for some people, and I’ve seen this for years clinically, you give them flaxseed and they’re not getting very much traction, so you move to an EPA/DHA supplement and suddenly everything changes. It’s probably because their delta-6 is slow.

It’s also important to remember that delta-6 desaturase is blocked by trans fat. That means that omega-6s and omega-3s from vegetarian sources in the presence of trans fats can’t convert to anything. You can eat all the seeds and nuts you want, but in the presence of trans fats they don’t go anywhere. They’re practically useless at that point. That’s been known in biochemistry for 30 years, and it’s just become cool in the last 10, but it’s actually one of the reasons why trans fats are so nasty.

Murray: So what’s your response when people say we should be focusing on food sources of omegas rather than supplements?

Anderson: Sure we should. But if people have a blockade of these desaturase enzymes, and they’re not getting food sources that are as close as possible to the end product, they’re not going to metabolize these fats properly, and the fats aren’t going to work.

And here’s another interesting bit of biochemistry. Delta-6 is also blocked by all of your stress hormones. When people are under higher stress, they actually down-regulate their ability to make anti-inflammatory cytokines, so that’s a direct correlation.

During inflammatory diseases, especially cancer, delta-6 also becomes down-regulated, which is very interesting.  And, delta-6 has very important cofactors, which tend to be cofactors for a lot of other good things. The big ones are B6, magnesium, and zinc. If delta-6 is slow, these nutrients are good to add—but de-stressing is good too, as well as avoiding other inflammatory things like trans fats.

Just to get the seeds, nuts, and veggie sources of omega 6 and 3 moving downstream we have to be less stressed, less inflamed, and have enough nutrients. I used to joke with my patients and say: “Well you could drink a bottle of flaxseed oil, but you’re so inflamed and stressed out it’s not going to do very much for you!”

Here’s a reason I think that may be a piece of the puzzle with some of the cancer studies where they looked at associations with omega-3s. Because cancer throws off all the enzymes that are required for processing these oils that in itself could throw the data off.  Do you think the majority of the population who has cancer is getting really good advice about nutrition, about stress, about trans fats and all these things? Probably not. If you look at the average group of people who have cancer, they may not process these things appropriately, but it’s not the fault of the omega-3 oil—it’s really the fault of the disease and not taking care of the rest of their system.

Murray: Are there other ways stress and diet influence omegas’ effects in the body?

Anderson: I remember back a long time ago, when we didn’t understand the way we do now, that omega-6 is actually anti-inflammatory.  It had a bad rep. But, what happened was they figured out that omega-6s can actually convert to series-two pro-inflammatory cytokines—that they can be stolen. That’s the other desaturase in the system, called delta-5.

Delta-6 is a helpful desaturase that moves vegetarian oils downstream into good cytokines. But delta-5 is used by your body if you don’t have any sources of arachidonic series two, which is necessary for immune function. Your body has a backdoor way in to take the post-GLA oil, the DHGL, and convert it into series-two cytokines substrates. Delta-5 is in there as a backup in the absence of animal fats, etc. That’s how vegetarians do it, which is a natural and necessary thing.

But here’s what people leave out of that story a lot of the time. Delta-5 desaturase, in addition to being stimulated when you don’t eat meat, is supremely up-regulated in the presence of insulin. Insulin is a very pro-inflammatory cytokine, and one of its many pro-inflammatory effects is that it turns delta-5 desaturase on, and it literally will steal your omega-6 and not let it go anywhere other than into the inflammatory cascade. And, 40-50% of people are at least dysinsulinemic, if not insulin resistant.

So is there anything else that can help slow delta-5 downActually, omega-3 EPA and DHA will slow delta-5 desaturation down as well.

Murray: Yes, we all know sugar is inflammatory, but I’m sure many of us don’t remember the mechanisms.

Anderson:  I think there are maybe like 10 people that seem to remember that; it’s easy to forget!

Of course, insulin has a million other inflammatory jobs it does, but this is another contextual thing. When looking at omega-6, if it’s left alone, it’s just fine to have around. But a standard North American diet tends to have a lot of insulin-triggering foods in it, and a lot of omega-6. So omega-6 becomes more of a danger—not because it’s omega-6, but because of other factors, it can be stolen and put into the arachidonic pathway. People eating higher-carb, more insulin-heavy diets don’t realize they’re turning their omega-6s into inflammatory stuff, and that’s a piece of the puzzle too. But people can cut back on insulin stimulation, getting more fiber and less sugar, and all those goodies that we can do.

Murray: So, what do you think is an optimum ratio of omega-6 to omega-3 in the diet?

Anderson: Generally speaking, if you look at most of the papers where they say there’s probably a benefit in having an omega-6 to omega-3 ratio of 2, 3 or 4 on the omega-6 side, to 1 on the
omega-3 side. And the reason a 2 or 3 or 4 to 1 is healthier is probably because it feeds the pathways more like they evolved over time. I think that’s a huge, huge thing.

But let’s step out for a moment and look at what we are getting in our diet. Let’s say for the sake of argument that we’re not eating trans fats, and we are getting our B vitamins and our minerals that are cofactors for delta-6. Also, for the sake of argument, we’ve got our stress hormones balanced and we’re not inflamed. If we can eat in a way—whether it’s from vegetarian sources or from fish or other animal sources—that’s 2, 3, or 4 omega-6 to 1 omega-3, we probably have just about the right amount of balance.

But this is in comparison to the average North American diet with an omega 6 to omega 3 ratio of about 20:1. The North American diet is almost like a funnel going straight down to all the inflammatory cytokines. That’s why so many people are so inflamed.

Murray: Once again, a clean, natural diet is really key for helping restore proper inflammatory balance, but if we’re not there yet, how can we best utilize omega-3s and other supplements for maximum benefit?

Anderson: I think it follows along with this discussion of metabolism, and how metabolism requires cofactors and getting rid of inhibitory stuff, and all of that.

I’ll use this example because I hope it makes the point the best. I would often get calls or emails, or a question or something from a practitioner, and they’d be saying, “Well, I’ve got this patient, and they have X or Y inflammatory process going on. I’ve been giving them all this omega-3, and it’s been two, three months, and nothing’s happening. I don’t understand, because the omega-3 is supposed to go in there and be anti-inflammatory.”

In a sense, what’s going on there is that the practitioner using the omega-3 is forgetting that it has to work in a context that involves a lot of other biochemistry. So if the practitioner is giving EPA and DHA which are right next to being the active form, the EPA/DHA really ought to do something by three months. If not, then we would back up, and I would ask what are you doing to stabilize the step before that?

Murray: And what would the answer be?

Anderson: There’s two steps, really. One is what we talked about with the desaturases.  But the other, which is more important, is the overall oxidative reductive balance in the whole body, so that when you put good omegas into a system, they can go into the cell membrane. With the oxidative reductive balance we run every minute of every day to keep us having a good redox, if the necessary cofactors are missing from your treatment protocol, you’re putting one super-large amount of good stuff in, and it gets kind of one shot, or one pass through the system, and there’s nothing to keep it going. We see this with our very inflamed patients. Inflamed people tend to inflame more with certain treatments, even though those treatments are supposed to be “good for them.”

The reason usually is that the practitioner has forgotten about the actual base that circulates between your cells and your blood and your cell membranes and maybe it’s not being cared for. But that’s pretty simple, thankfully. You have two water-soluble compartments that use primarily water-soluble antioxidants to keep them balanced, and one group of fat-soluble compartments, which is actually where the omegas go. But there are antioxidants required for all three compartments. The cytosol—the inside water-soluble compartment of the cell—primarily uses glutathione as the primary antioxidant. But as we know, they cycle, so in the water-soluble compartments, whether it’s plasma or the cell, we normally use vitamin C to recycle glutathione, and vice versa.

The other thing is that in the fat-soluble membranes, that’s where the vitamin E family like tocopherols and tocotrienols get in the game. They’re the same way—they’ve got one cycle and then they’re oxidized, so they need something to help them recycle. That’s usually vitamin C, and vice versa.

So we surround the cell, and the cell membrane where the omegas are going to go, with this kind of three part-oxidative reductive support system that is always recycling. If we’re low in one of those—vitamin C, glutathione substrates, or tocopherols—then the whole thing slows down.  We wind up with all these great omega-3s just sitting there in the cell membrane but it’s so oxidized that they can’t really do anything in the presence of all that oxidation. People need to have appropriate dietary or supplemental support for their redox system, or else they’re not getting a good home for the omega-3s to go to that’s going to work very well. I think that’s very important to point out.

Murray: The need for vitamin C and vitamin E is just so basic and foundational we can forget about it. What are your recommendations for how much people should take every day just to stay healthy?

Anderson: Yes, it’s like vitamin C is so ubiquitous, we assume that everyone must be taking it. And then you find out people aren’t taking it because they think: “Vitamin C, yeah that’s so low tech, why do I need that?” But we all do! It’s probably one of the most important things to keep us running.

Because vitamin C is water soluble and very safe, I would start with 500 to 1,000 milligrams with each of your meals, which is plenty for most people, because that kind of keeps you at a steady state. If someone is really inflamed and I feel like I want to get the levels up faster, I would double that if they can do so without loose stools. And if you have just come off of having the flu, or getting surgery or something, you’re going to require a lot more because you’ve burned it all off.

Murray: Can you use buffered C with the same effect?

Anderson: Buffered C is just as useful—you get the same effect either way. There are two times when I generally favor using an electrolyte buffered form. One is if people have very sensitive stomachs—because with some people, ascorbic acid and their stomach just don’t get along. The other is in your very inflamed folks, or people with cancer, etc. Sometimes for them the buffered forms are helpful on the pH side of the body, in a way that actually helps the vitamin C get where it’s going without disrupting a lot of the other processes.

Murray: Your discussion of tocopherols brings to mind the whole controversial vitamin E issue, which has been around for longer than I can even remember.

Anderson: And I would say it’s a lot like the omega story, where every study shows you a different outcome. I think there are two reasons for that.

One is vitamin E itself. If we go back to that idea of glutathione, vitamin C, and then vitamin E, they really do work together. So if you take an inflamed person who has no water-soluble antioxidants, and you just put a bunch of vitamin E into them, you’re imbalancing the system on the fat-soluble side.

The other reason is that a lot of times in the studies that don’t turn out so well, the form of vitamin E they’re using is also imbalanced. It’s either a single isomer, or it’s the synthetic form, only part of which is going to work anyway.

So there are lots of issues around vitamin E. What I have found over time that works the best is to look at how vitamin E comes to us in nature, because it’s more complex than, say, glutathione or vitamin C—pretty simple molecules there. In nature, vitamin E is actually a spread of tocopherols, which are the fat-soluble forms, but then there’s also the close cousins, tocotrienols, which are one step more complex than tocopherols. They’re actually a stronger antioxidant.

What we find, and there’s even a little bit of cancer research going on around this, is that you’re better off doing a lower dose of vitamin E with a broad spread of tocopherols and tocotrienols. Like the one I personally take has about 40 IUs of tocopherols, but then it’s got about 100 mg of tocotrienols. For maintenance, that’s a reasonable dose because the tocotrienols are so much more potent.

But again, if I have somebody who comes in and they’re in a flare of an inflammatory illness, just like with vitamin C I might go a little higher with vitamin E in the beginning. They might get three or four times what I’d use for maintenance, for a month or two, to kind of calm the fire down a little bit.

Murray: So, back to the basics of supporting cellular health. I know you like to supplement glutathione. Now that there are stable, clinically effective glutathione products available, are those preferred over using precursors like N-acetyl cysteine (NAC)?

Anderson: Here again, it can become individually kind of skewed. NAC is a good precursor for glutathione, and you can also use supportive things like glycine and glutamine, which are also part of glutathione, as precursors. There’s nothing wrong with that.

Now, one thing that you do see, and it’s kind of the same as I was saying before, is that there are some people that you can give a lot of NAC to, but the enzymes to help it convert over are slow or maybe genetically injured. So then using a liposomal glutathione or acetyl glutathione as a supplement gets them moving faster.

The other thing you have to think about with glutathione is that it requires lots of trace minerals and a few B vitamins to keep it cycling and adding alpha lipoic acid (ALA) is helpful too.

Murray: So would a good multivitamin with trace minerals be enough to keep glutathione adequately cycling, or do you need to use an additional trace-minerals supplement?

Anderson: If you’ve got a really good-potency multi that’s got a broad spectrum of trace minerals and B vitamins, that’s fine for maintenance. But if a person comes in and they’ve got neuropathy or some other reason why we feel their glutathione levels need to rise quickly, we might tell them that for a couple of months, on top of your multi, we’re going to add a trace-element formula, and maybe a few more B vitamins as well as ALA for support.

Murray: Finally, I want to ask you about the role of polyphenols. How do you use some of our favorites like curcumin and boswellia?

Anderson: They’ve been popular for a long time, and it seems like they’re getting more press nowadays. I often joke at conferences that you would think by reading the papers that all diseases would be gone by now if people just had enough curcumin and green tea.

But obviously that’s not happening. It goes back to the same issue, that taken in isolation, phenolic compounds give you a bump, or boost of inflammatory modulation, that can be really helpful. But you have to remember you’re modulating a very complex system. We use things like curcumin, green tea extract, boswellia—even the artemisinins and all these things that come from plants—as that extra therapeutic add-on to all of the base work we’re doing with supporting redox with the nutrients and the omegas. They are working around and in that whole system, so the better you are about feeding that whole system, the quicker they work.

Murray: When do you introduce phenolic compounds into a patient’s care?

Anderson: It’s getting more common that people come in and just want health maintenance, and they’re really not sick. In those cases, then we would tend to talk to them about getting a lot of stuff like polyphenols in their diet, etc., and then maybe a little supplementation.

But most people come in and they have a problem. What we have found is as long as we’re working towards these goals of the basic nutrients being covered, and looking at their diet for their fat balance, and maybe adding some omega-3s, then we can also start with the family of polyphenols right away, because their activities work in areas where these other things don’t get to as easily. They work in a lot of the immunochemistry of the body. It’s as if they’re saying, “OK, for whatever reason the body thinks it needs to be in a pro-inflammatory immune state. Let’s just bring that down a little bit and back off on the intensity.”

Curcumin, boswellia—those are really good acute agents. So we include them in the beginning with all of the other stuff just to put the fire down. Then we back off and see what the patient really needs long-term. It kind of goes back to the same thing with your essential fatty acids, where eventually maybe you could get to the point where you’re eating correctly enough that you’re getting most of them from your food. You can get a lot of polyphenols from food too. But if you’re sick, you need more help than what normally your food can provide.

Murray: You know what? We’ve really covered a lot of ground here, and I want to thank you so much for taking time to dive into the details.

Anderson: Good. Thank you for the opportunity to talk about this terribly important and meaningful subject.

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