Preterm Babies May Be Missing This Nutrient
OmegaMatters: Episode 53
Hosts: Dr. Bill Harris & Kelly Patterson
Guest: Dr. Simon Dyall
About this episode: In this episode, Dr. Bill Harris and Kelly Patterson talk to Dr. Simon Dyall, who received his BS in biochemistry from the University of Sussex and his PhD in neuroscience from Queen Mary University of London, where his research focused on neuroprotective roles of Omega-3 fatty acids. Dr. Dyall currently leads the Master of Science Clinical Neuroscience program at the University of Roehampton in Great Britain. His research sits at the interface of neuroscience, nutrition, neurobiology, and psychology, also known as nutritional neuroscience. Some of his current projects include exploring the role of polyunsaturated fatty acids and lipid mediators in perinatal health, and a neuroimaging study investigating the therapeutic effects of a high omega-3 fatty acid multi-nutrient supplement on stress and anxiety in young adults. For more information on OmegaMatters, visit https://omegaquant.com/omegamatters-broadcasts/.
SHOW TRANSCRIPT
Kelly Patterson: Today on Omega Matters, should we give preterm infants more arachidonic acid for brain development? That and more on fatty acids with Dr. Simon Dyall.
All right. Welcome to Omega Matters, where we talk everything fatty acids. My name is Kelly Patterson. I’m here along with Dr. Bill Harris, and today our guest is Dr. Simon Dyall. Dr. Dyall received his BS in biochemistry from the University of Sussex and his PhD in neuroscience from Queen Mary University of London, where his research focused on neuroprotective roles of omega-3 fatty acids. Dr. Dyall currently leads the Master of Science Clinical Neuroscience program at the University of Roehampton in Great Britain. His research sits at the interface of neuroscience, nutrition, neurobiology, and psychology, also known as nutritional neuroscience. Some of his current projects include exploring the role of polyunsaturated fatty acids and lipid mediators in perinatal health, and a neuroimaging study investigating the therapeutic effects of a high omega-3 fatty acid multi-nutrient supplement on stress and anxiety in young adults.
Thank you so much, Simon, for joining us today. So before we dive into the really research heavy stuff, will you tell us a little bit about how you got into this field and how you got interested in this area of study?
Simon Dyall: Thank you, Kelly. And thank you, Bill, for the kind invitation to talk today. Yeah, so I think I had quite an unusual background leading up to my work in fatty acids. During the late ’80s and ’90s, I used to be a personal trainer and used to teach aerobics and exercise to music. In the mid ’90s, there was quite a few popular books. One of them was by someone called Udo Erasmus. It was called Fats That Heal and Fats That Kill. And I think he kind of popularized this whole idea that Omega-6s were pro inflammatory and bad, and Omega-3s were anti-inflammatory and good. And we’re still having the fallout from that nowadays. But there was a real interest in nutrition and supplements and those kind of areas, and I wanted to learn more about it and I wanted to explore the field. So I decided to take a degree in biochemistry to explain what was going on.
And one of the highlights of the course for me is we had a lecture by Sir John Cornforth. He got the Nobel Prize for his work that elucidated the biochemistry of steroid synthesis in cholesterol. And I started to have this real kind of interest in lipids. And then I finished my degree and I was looking for something to do, I was looking for the next step, and there was this PhD advertised and it was looking at omega-3s in the brain. And I had no interest in the brain, but I was interested in omega-3s. So I thought, okay, let’s try for it. And I applied and the PhD was with Professor Adina Michael-Titus, who I think you had on a little while ago. And she was just starting to explore the role of fatty acids in the brain. And so we kind of started and we entered the field together.
So my first couple of years in my PhD was looking at developing lipid analysis, developing a fatty acid analysis, working out how to analyze things. Nowadays, we just send our samples and get it done. But at the time, it was a really nice grounding for me because we started with nothing. I worked with a really talented analytical chemist called Robin Welton, and we developed this process for analyzing fatty acids, for separating them. And this kind of really gave me an understanding of working with these fatty acids and how sensitive they are and how to measure them, how to analyze them. And my project was working with old rats. And basically we fed these old rats MaxEPA, which is an omega-3 supplement, and then we found out what happened at the end of the trial. We identified some really interesting changes in the levels of certain receptors and effects on neurogenesis, effects on neuroplasticity.
And at the same time, Adina was starting her work on spinal cord injury. So it was a really great time to explore the field. And it’s kind of gone from there, just started to move into more human trials. So yeah, it was just a transition from being in the fitness industry, having an interest in supplements, and then working out that I really enjoyed pathways and how the mechanistic side of things. And now I’ve been working in the field for 20-odd years.
Bill Harris: Oh, fantastic. So where is Roehampton?
Simon Dyall: So Roehampton… Tom Brenna, he always calls it the University of Wimbledon because it’s kind of Southwest London, and most people know where Wimbledon is. So Roehampton is Southwest London.
Bill Harris: Okay. Is that where Adina is too?
Simon Dyall: No. So Adina’s kind of East London. She’s at Queen Mary University of London. So the Queen Mary is East London, and I’m sort of Southwest London. So when I’m doing stuff between the two, I have to get on my bike and cycle across London to drop off samples and various things.
Bill Harris: Still an exercise enthusiast, sounds like.
Simon Dyall: Exactly. Yeah.
Bill Harris: That’s great. Well, I think it’s a great place to start. You have a real interest in what we call perinatal nutrition and fatty acid metabolism. You want to explain what perinatal means for people and then what kind of research studies you’re doing in that area?
Simon Dyall: Yeah. So this is an area that I kind of got into by complete chance. So I was running a master’s in clinical nutrition course at Roehampton, and we had a consultant neonatologist. So she looks at the very young babies. And she wanted to measure the fatty acid intake of extremely preterm infants, so infants that are born less than 28 weeks. So when we talk about perinatal, we’re talking about the early birth period. So during pregnancy and just after birth, just after the baby’s been born. And she wanted to measure the fatty acid intake of these extremely preterm infants and see how it allied with recommendations to see whether they were getting what they should have via recommendations. For extremely preterm infants, there are no real guidelines. In the UK, we follow the European recommendation, what’s called the ESPGHAN guidelines, and they don’t really apply to infants less than one kilogram, so there’s no real kind of context to put this in.
So what we did was we measured the fatty acid intake of these extremely preterm infants through the first six weeks. So we measured the maternal breast milk levels, we looked at donor milk levels, and we measured formula levels. And then we saw, how do these compare to the ESPGHAN guidelines. But as I say, the ESPGHAN guidelines are quite crude. It’s to do with body growth. And what we wanted to do was to see how would this relate to what they would’ve had in utero. So if they’d stayed in the womb in their last trimester, how does it relate to these, what’s called, accretion rates? And Professor Michael Crawford in the mid 1970s came up with this concept called bio-magnification and bio-reduction. And essentially in utero, the placenta bio-magnifies certain fatty acids and it bio-reduces other fatty acids.
And what he did was he measured maternal plasma levels, he measured maternal cord blood levels, he measured maternal liver levels, and he measured fetal brain levels. And you can see that certain fatty acids are reduced across this process and certain fatty acids are enhanced or bio-magnified across this process. And the long-chain PUFAs, the arachidonic acid and the DHA, are significantly magnified across the process, whereas the short-chain fatty acids, linoleic acid, is reduced. And he kind of says that the certain fatty acids, like the linoleic acid, is rejected, whereas the arachidonic acid and the DHA, these are conserved and preserved across the process. So working out…
Bill Harris: Is that a rejection or is that a synthesis of arachidonate from LA, lowering LA levels and raising arachidonate levels? It seems like it is… Why? Continue explaining this.
Simon Dyall: Yeah, so that’s one of the questions is… So what he’s looking at is, basically he’s saying that the linoleic acid isn’t needed, and then the arachidonic acid and the DHA is needed for the brain. So in the brain, as you know, DHA and arachidonic acid levels are around… So arachidonic acid in adult brain is around 10%, and DHA is around 12%, whereas linoleic acid levels are very, very low. So for brain growth and brain development, you need the arachidonic acid and the DHA, whereas for brain growth and brain development, you don’t need the linoleic acid. So that’s what he’s saying in terms of rejected. He’s basically saying for brain growth, you need arachidonic acid and DHA, whereas you don’t need linoleic acid for brain growth. Whether the linoleic acid can survive enough to be converted into arachidonic acid, that’s a separate question. But for brain growth, you need these particular building blocks.
You need arachidonic acid and DHA. So that’s what the bio-magnification is saying. For brain growth and maturation, arachidonic acid and DHA are the substrate for it, whereas linoleic acid isn’t the substrate for it.
Bill Harris: Does the placenta take preformed arachidonate or DHA out of the mother’s blood and transfer it, or the placenta’s actually creating or making DHA and arachidonate?
Simon Dyall: So essentially in the process, the arachidonic acid, yes, arachidonic acid is being produced and being distributed to the fetal brain. So that’s kind of the magnification at the placenta.
Bill Harris: Yeah. So again, it’s not just a stealing of preformed arachidonate from mom. It’s a making of arachidonate in the placenta and transfer it to the baby? Or does mom’s arachidonate drop, and DHA?
Simon Dyall: Yeah, so mom’s DHA levels will drop, and that may be a factor in postpartum depression. So we know that breast milk levels go down significantly in DHA, especially if you have twins or especially if you have pregnancies very close together. And interestingly, there’s some very interesting work looking at MRIs, looking at maternal brain shrinkage post-pregnancy. So we know that after birth, the maternal brain shrinks, and it hasn’t really been looked at as to whether if you have more DHA and arachidonic acid, you can preserve this to a great extent. So there is a brain shrinkage.
Bill Harris: Does it recover after birth? Ask Kelly.
Simon Dyall: So there’s a recent MRI study that went on for a couple of years and the brain was still shrinking, so the brain was still smaller. So part of it is to certain empathy areas are enhanced. So it’s to do with empathy with the child. So there is some very profound work or very consistent work that maternal brain does shrink after pregnancy or after giving birth.
Kelly Patterson: I think any mom with little kids would confirm that finding, would tell you that they have experienced that phenomenon in real time.
Bill Harris: Wow. So what’s your work then in this area? What are you trying to…
Simon Dyall: So essentially what the work is is that we found that in these extremely preterm infants, they had very, very low intake levels of arachidonic acid and DHA far below the estimated accretion rates. So what would happen is that their blood levels would drop. So over the time in the neonatal unit, their DHA levels and arachidonic acid levels would drop. And this, Camilia Martin and others have shown that there is increased risk for sepsis and other kinds of things associated with these lower levels. So my work in this area is to try and maintain and increase DHA and arachidonic acid. So we’ve looked at working with… So preterm infants get their nutrition from a range of sources. The preferred source is maternal expressed breast milk. However, for a range of different reasons, the mothers may not be able to express. So therefore, donor milk is a recommended alternative. So I’ve been working with donor milk banks to try and preserve the fatty acid content of donor milk.
So we’ve looked at, for example, UV protecting the bottles to prevent light damage. We’ve looked at developing nutritional guidelines for donors to get them to try and eat more fish and try and take more supplements because breast milk is very, very responsive to DHA intake. And one of the other things is a continuation of one of your studies, Bill, where what we’re doing is we’re giving the donors feedback on their breast milk fatty acid levels to see if this enhances their nutritional status and enhances their intake. So we’ve been trying to…
Bill Harris: Donor moms?
Simon Dyall: Yeah. So we’re giving the donor moms… Yeah. So we’re giving the donor moms their fatty acid DHA levels in their breast milk to see if this motivates them to follow nutritional guidelines more. And this is a study that we’ve just started…
Bill Harris: You’re paying more for higher DHA milk.
Simon Dyall: I think there’s ethics around paying the donors, but…
Bill Harris: Oh, come on.
Kelly Patterson: Donor is the…
Simon Dyall: Yeah.
Kelly Patterson: And this is particularly important for the preterm infants because of that. They’re missing out, especially the early preterm, because they’re missing out on that third trimester. That’s where the accretion of those fatty acids, it kind of accelerates during that third trimester.
Simon Dyall: Exactly. So the third trimester is the period of maximal fat deposition. So if you’ve ever seen the extremely preterm infant, they’re very, very lean. They’ve got no body fat. It’s also the period of maximal brain growth. So it’s the period of maximal brain growth, period of maximal fat deposition, and if they’re born extreme preterm, then this that would be happening in the womb, it’s happening in an incubator. And in an incubator, the neonatal nutrition, neonatal environment is very, very different. And we’ve just published a paper with some really great authors, so Susan Carlson, Tom Brenna, Michael Crawford, Norman Salem. We published a paper recently developing this concept called the preterm PUFA gap. And this is the gap between the PUFAs that the neonate would’ve received in utero versus the PUFA that the neonate receives in the incubator. So this is the gap that they are not having by being born early. And it’s this gap in arachidonic acid and DHA levels that they would have, and they’re having much higher levels of linoleic acid than they would have in utero.
So it’s trying to think about how to address this gap. And we know that preterm infants are at risk for short-term health conditions such as retinopathy of prematurity, necrotizing anticolitis, but they’re also at risk for later life conditions. So later life conditions in terms of increased risk for neurodevelopmental disorders, increased risk for memory delay, increased risk for other kinds of things. So is this later life risk and early life risk related to the PUFA gap? And that’s something we’re kind of exploring. And if we can provide nutrition that’s more aligned with what they would receive in utero, does this decrease these associated risks of being born early?
Bill Harris: Yeah, they’re incredibly important. So we know the DHA levels in milk are very responsive to mom’s intake of DHA. How about arachidonic?
Simon Dyall: Yeah. That’s a great question. And Tom Brenna did a really nice review a few years ago looking at, trans nationally, looking at different populations to see… And DHA levels were highly responsive to different populations. But arachidonic acid seems much more constrained. It seems much more tightly regulated. And unfortunately, there’s very limited research in this area. We did a systematic review a couple years ago, and we only found one trial that was specifically feeding arachidonic acid to see a response, and that was at a very low dose, too low a dose to actually see an effect. So observationally, it appears that arachidonic acid is much more tightly regulated than DHA, but experimentally, we don’t have the evidence yet to definitively say how responsive it is to dietary intake.
Bill Harris: No, interesting. Interesting.
Kelly Patterson: My question really is, how come we don’t hear about arachidonic acid being as important for brain development? We hear about DHA being super important for brain development in that third trimester all the time, and I think probably it has to do with most people are not consuming nearly enough DHA or arachidonic acid isn’t as much of a concern. Obviously in this population it is. Why do you think that is? So we don’t know as much about that.
Simon Dyall: I think a lot of it is this kind of fear around arachidonic acid being pro inflammatory and as a bad thing. We’re still living under that. As I say, I mentioned earlier, the fats that heal, fats that kill. But arachidonic acid is just as important. The arachidonic acid… So Manuela Martinez did some seminal studies in the early 2000s where she looked at autopsy samples and measured the levels of these fatty acids in autopsy samples across different ages. And the accretion rate, so the uptake rate of arachidonic acid, slightly earlier than DHA, it was just as much. So arachidonic acid is very important for brain development, it’s also important for cardiovascular function, for immune function. So all of these areas, arachidonic acid is key. And Tom Brenna did some really nice work looking at the conversion of arachidonic acid to adrenic acid. So adrenic acid is the next one on the pathway. And around 16% of the labeled arachidonic acid that was fed to baboons was converted to adrenic acid.
So arachidonic acid is not just important in of itself, but also as a source of adrenic acid. And adrenic acid is called adrenic acid because it’s got high levels in the adrenal gland, so it has important functions there, but it’s also important for myelination, it’s also important for oligodendrocytes. So we know that DHA has its roles, but arachidonic acid is just as important in terms of brain structure, in terms of brain function, in terms of immune function, cardiovascular function, because the first thing you check in a fetus is the heart rate, is the heart. So is that working? And arachidonic acid is very important for endothelial function and as a source for adrenic acid. So when we’re talking about neonates, we can’t separate the two. Arachidonic acid is just as imperative as DHA for brain development.
Bill Harris: Yeah. And giving more linoleic acid to mom does not produce more arachidonate for the baby, right?
Simon Dyall: No. So Norman Salem did some work looking at whether the preemie infant could convert linoleic acid to arachidonic acid, and it converts slightly better than adults, but nowhere near sufficiently. And unfortunately, we’re giving too much linoleic acid to preterm infants for that.
Bill Harris: Okay. So the infant itself cannot… It doesn’t make enough arachidonate from linoleic acid.
Simon Dyall: Exactly.
Bill Harris: Does the placenta? But the placenta is, I assume, a machine that will make fatty acids, elongate linoleic and make arachidonate.
Simon Dyall: I’m not sure any work that’s been done looked at the efficiency of conversion, looking at that process. That’s something that we need to explore. But the focus of my work is what happens outside the womb, in the incubator. What can we do in the incubator to maximize brain uptake.
Bill Harris: Yeah. And you say you’re trying…
Simon Dyall: There were some really nice studies… So in the 1990s, Maria Makrides and others… So in the 1990s, it wasn’t compulsory for formula to contain DHA, and you can see very, very different… So it’s kind of this quasi experiment. So you can see differences in brain levels of DHA and arachidonic acid between those that are fed formula and those who are breastfed. And so the conversion isn’t there. So you get lower levels of these fatty acids with the formula at the time that didn’t have these long chain PUFAs compared to breastfed infants.
Bill Harris: And nowadays, DHA is mandated or just allowed in formulas?
Simon Dyall: So it’s different… So generally, DHA is mandated, so there has to be DHA, whereas the arachidonic acid now is more moving towards the remit. So what the manufacturers want to do rather than being mandated. So there is a drive towards…
Bill Harris: We’ll have…
Simon Dyall: I’m not aware of any formulas that don’t have it at the moment, but it’s not mandated anymore.
Bill Harris: Okay. Okay. And you talked about accretion rates into the brain. And so how do you measure that and then compare that to what’s in your formula? How do you measure accretion rate?
Simon Dyall: Yeah. So accretion rates is a very contentious area, shall we say, because there’s no way to actually quantify it. So it’s done on… Basically, you look at levels and then you calculate re-oxidation because there’s the amount that’s actually in the brain versus the amount that’s actually needed to do this. So there’s lots of different formulas based on whole body oxidation, levels in fats, levels in muscle, all these different areas. So they’re at best estimates, essentially. So it’s the best estimate for what the brain would need in this situation. So there are… I think Coopers was the most recent one, but there is going to be a confidence interval around that. So it’s best estimates for brain uptake.
Bill Harris: And you’re trying to figure out a way to provide that externally to get…
Simon Dyall: Yeah. So what we’re trying to do is we are trying to provide as close as we can or to understand what would be needed as close as we can and then to provide this. Unfortunately, with preterm infants, there is not the… About one in 10 infants are born preterm, but there’s not really, should we say, the money behind developing formulas for preterm infants. There’s not a big enough market for the specialist area. So the big manufacturers are not as keen to develop specialized products for this particular patient group. So we’re trying to… So again, it’s trying to work out… So there’s been lots of trials giving DHA. So there’s been lots of trials doing DHA interventions to see whether that benefits preterm infants, but very few have actually given arachidonic acid and DHA at sufficient levels. And there’s a recent study by Molti that provided 100 milligrams per kilogram DHA and 50 milligrams per… So 100 milligrams per kilogram arachidonic acid and 50 milligrams per kilogram DHA. So really good levels.
And she used a technique called diffusion tensor imaging to measure white matter maturation, and she found significant difference in white matter formation between those that were supplemented versus those that weren’t. And one of the problems we have in the field is that the indices of cognition in neonates is very crude, there’s kind of the Bailey scale and things like that, which aren’t very good at sensitively looking at improvements. So that’s one of the issues we have is the intervention trials, is that they tend to focus just on DHA. And when you’re measuring cognition, you’re using a sledgehammer to see subtle differences in cognition. So Robert Gibson and Maria Makrides did a study a little while ago that showed DHA supplementation increased the risk for lung disease, chronic lung perceives, BPD, but they did a follow-up five years later and found a significant benefit in terms of IQ for those that were in the intervention trial versus those that weren’t, suggesting that you may have short-term adverse effects, whereas the long-term benefits are more profound. But that was just the DHA trial.
So it’s moving the intervention trials to appreciate the importance of arachidonic acid and developing sensitive indices to quantify benefit. And it may be you need to look five years, six years, eight years to actually see how profound these benefits are.
Kelly Patterson: The real impact is longer.
Simon Dyall: Yes.
Kelly Patterson: Interesting.
Bill Harris: Can you back out and give us a high level view of the importance of DHA? We’ll stay in the preterm world, but in terms of the longer term outcomes, what’s the state of the art now in terms of the benefits of giving higher amounts of DHA to preterm infants in terms of their growth development and mental development?
Simon Dyall: So there’s this kind of debate in the clinical field, there’s this focus on DHA, whereas what we are saying is you’d need the arachidonic acid as well. So a lot of trials were just given DHA, and I think that’s limited the beneficial effects, is that you need to have higher levels of arachidonic acid, higher levels of arachidonic acid than DHA. And when these are given, there is indication that it decreases the risk of things like ROP, retinopathy of prematurity, as it increases white matter maturation. So that’s where the field is going, that the field is looking towards more physiological levels, so higher doses, but having a lot of arachidonic acid and less DHA, and then looking at longer-term effects on this.
Bill Harris: So what we’ve seen with DHA alone is a little cloudy, maybe because we’re not giving arachidonate as well.
Kelly Patterson: Missing an essential ingredient.
Simon Dyall: Yeah.
Bill Harris: Interesting.
Simon Dyall: Exactly.
Bill Harris: Yeah. Yeah. Golly, that’s amazing. So they must be fairly small trials. How many preemies do you have that you’re working on right now?
Simon Dyall: Yeah. So when we did the feeding trial, not the feeding, when we did the measuring the intake trial, we were looking at 20 or so. So it’s with all these things, it’s getting the support, getting the funding for it. So who’s going to fund it? Is it going to be the supplement manufacturers? You can’t patent arachidonic acid and DHA, so who’s going to fund these trials? And it’s getting… So that’s the big area, as we know, with all trials.
Bill Harris: Yeah. So you said something about 10% of kids are born pre… It seems awfully high. Why is that? Do you know? What are the factors that play into that?
Simon Dyall: So there’s lots of factors.
Kelly Patterson: I was going to say, that’s anything before 37 weeks, right? That figure?
Simon Dyall: Yeah.
Kelly Patterson: Okay.
Bill Harris: So 37.
Kelly Patterson: Okay. It’s…
Bill Harris: Not bad. There’s three weeks…
Kelly Patterson: There’s a variation in there that’s anywhere between 20, what, 24, 25 weeks and 37 weeks would be that category, right?
Simon Dyall: Yeah.
Bill Harris: Okay.
Simon Dyall: So that’s one of the big issues in the field, is that a lot of the research in this area groups them together. And obviously an extremely preterm infant born at less than 28 weeks is going to be developmentally very different to an infant that’s born at 36 weeks. And Maria Makrides has done some phenomenal work looking at DHA levels as a risk factor for preterm birth. And she’s done lots of great work in Australia trying to raise awareness of this. And Susan Carlson, again, has done some work in Kansas looking at the different demographics around this. So low DHA status is a risk factor for early preterm birth, and obviously that’s a modifiable risk factor.
Bill Harris: But for others that we know, they’re modifiable, even not modifiable risk factors for preterm.
Simon Dyall: So obesity, so smoking. Healthy lifestyle is a benefit for this, but there’s lots of different risk factors. Some of them are modifiable, some of them not. Interestingly, during COVID, preterm birth went down slightly. So stress may be a factor and other kinds of things.
Bill Harris: Oh, interesting.
Kelly Patterson: Really?
Bill Harris: Interesting. Yeah.
Kelly Patterson: That’s very interesting. Commuting maybe.
Bill Harris: Maybe so. Well, that’s great. Can you just briefly give us… I know you’re also interested in adult brain development, not just preemies, but what’s your bigger picture of other research interests that you’ve got?
Simon Dyall: So I think one of my biggest weaknesses as a researcher is one of my biggest strength, is that I’m interested in lots of different things. I don’t just focus on preemie infants. I don’t just focus on depression. I don’t just focus on aging. I’m interested in all of it. So my research spans from preemie infants right through to aging. But I think that also gives me a kind of nice perspective across the field looking at how these things interact because one of the things that… So I’m interested in depression, and one of the things, when we do our depression trials, is to ask people, do you know if you were born preterm? Because this can affect obviously brain development and alter risk for these different things. So I’m interested in depression and mood disorders, we’ve done a few trials in this area, but I’m also interested in brain aging and neuro-degeneration. So my early work with Adina in my PhD was looking at brain aging in rodents. So I’m leaning across the board.
Bill Harris: And you mentioned depression, and it always comes up, I’m sure you always get asked, EPA or DHA?
Simon Dyall: Yeah, so that question does come up a lot. The answer from the evidence… So if you look at the trials, so the trials suggest that you need to have a ratio of at least three to two EPA to DHA. So high EPA supplements appear to be more effective. Part of this may be related to the mechanism action. So I’ll talk about this. Part of this may also be that the research in just high DHA supplements is less, and that may bias the literature a little bit because there’s less trials looking at high DHA. But if you look at the existing trials that are there, the ones that are most effective have the high EPA supplements. So a ratio of two to one or three to two EPA to DHA do appear most effective. But that may be partly in artifacted literature and partly because mechanistically, this may be the way it works.
So with Omega-3s in depression… So it needs to be, from the evidence, high EPA to DHA. And I’m currently working with co-authors on a statement for ISSFAL, International Society for the Study of Fat Acids and Lipids. We’re looking at the literature to see when are Omega-3s most effective in depression. So we’re trying to look at the existing literature to see what recommendations can be made, if any. So we haven’t had final approval on this yet, so I won’t really talk about the statement yet, but I will just say that these are the conditions, based on the existing literature, that appear to show greatest efficacy. So high EPA to DHA. And the evidence suggests at the moment, if they’re used as an adjunct to existing treatments, so working with SSRIs and other things like that, a clinical diagnosis of depression, because depression is a highly heterogeneous condition, and if you’re looking at trials, you may have a range of different… It may be self-reported, it may be depression with other things. Whereas if you have a clinical diagnosis, it makes it a clearer, this is what we’re looking at.
It also appears that if there is no comorbid conditions, so cardiovascular disease, things like that. And yeah, basically… So high EPA to DHA, clinical diagnosis depression, around at least a gram of Omega-3s. That’s kind of the conditions where it appears to be most effective at the moment. Also, potentially if there is increased inflammation. So with depression, on average, if you have depression, then there is increased inflammation, but it’s only a subgroup that have this increased inflammation. So there’s a subgroup with major depression where there’s elevated inflammation. So it may be in this subgroup that the Omega-3s are having greater effect. So that’s one of the issues with the trials is that you have a trial, you just recruit people with MDD, major depressive disorder, and they’re a highly mixed population. And it’s identifying which particular subgroup is going to be most responsive to this intervention. So that may be why EPA is more effective because EPA may be related to more of the anti-inflammatory pathways and the pro-resolving pathways around that.
Bill Harris: Go ahead, Kelly.
Kelly Patterson: Can you talk a little bit more about that inflammation and what types of people or what other risk factors those people with inflammation may have? Do they have that inflammation, we think, because they’re low in omega-3s or is it coming from somewhere else?
Simon Dyall: Yeah, that’s a great question. So the early work… So Joseph Hibbeln did the early work looking at populations. In the Lancet paper, he nicely showed that populations that ate more fish had less depression, and that kind of set in the field. And then there was the blood work and there was a strong indication that if you had major depressive disorder or a diagnosis of depression, then you tended to have lower blood levels. So lower blood levels were associated with MDD. This may be because they had poorer diet. So these are other kind of factors. So irrespective of this is that we know that with depression, there is a, on average, greater inflammation, but this is a particular subgroup within it that may respond to Omega-3s. And…
Bill Harris: How do you measure inflammation in people like that?
Simon Dyall: So in this population, it’s typically by high sensitivity CRP levels. So it’s just circulating levels. So it’s kind of a crude measure. So it’s CRP levels. And David Michelin did a really nice dose ranging study looking at MDD patients with obesity, because with obesity, they had increased inflammation. So this was identifying this inflammatory subgroup, if you can say, with obesity. So obesity is a risk factor for increased inflammation, and then he’s looking at this. And he found the greatest effects with EPA at over four grams as opposed to two grams or one gram. So he found quite high levels of EPA produced the greatest effect. And he did a nice follow-up study where he looked at the relationship between oxylipins, so mediators produced from these omega-3s, and he found a nice relationship between those with the higher levels of these omega-3 related oxylipins and effects on mood.
And there was some… So potentially… Yeah, so production of these EPA-derived oxylipins in reducing inflammation, having beneficial effects on… So you can link the pieces together. At the moment, it’s still kind of a little bit disparate, but you can link all the bits to the mechanisms to say that those with an increased inflammation may be more likely to respond to the omega-3 derived mediators.
Bill Harris: Yeah.
Kelly Patterson: Interesting. Interesting. Your recent paper, your mixed designs and mixed results paper, you talk about one of the issues with looking at a lot of these studies and this… That’s more focused on Alzheimer’s and cognitive function, not depression. But one of the things you mentioned in there is talking about the difference in dosing and why so many studies, that a lot of these studies are looking at very low doses. And I think that’s the case in a lot of the depression studies as well, that a lot of these clinical trials are done with very low doses. Why are these studies still being done with such low doses in a lot of the cases? If we know that a lot of these higher doses are more effective, why are so many people still studying low doses? What are your thoughts?
Simon Dyall: Yeah. Thank you. Yeah. So this paper came out, I think, last year. We originally planned to do one on depression as well, but so far we’ve just done it on the aging. So what we did with this paper was that we looked at what the trials actually do. So rather than just doing a meta-analysis and systematic review and just pulling together, looking at the fine details. So look at the dose, look at the duration, look at how they were given, look at the participant characteristics. So all of these factors. So nutrition trials are hard to do. It’s very hard to do a nutrition trial, a nutrition RCT trial, because it’s a foodstuff. It’s not like a drug where one group has it and one group doesn’t have it. You’ve got something that we have. Bill, from your Omega-3 Index trials, you know that no one has an Omega-3 Index of zero. So everyone has some circulating in the blood. So all we’re doing is we’re giving a little bit more to people and then hoping that they’ll respond to it.
So we looked at this and we looked at the actual papers to see… So you mentioned dose, but we looked at duration and endpoints, et cetera. What was their rationale? Did they have a actual specific rationale for this dose? Was it based on mechanistic understanding? And we found that… So we did a systematic review. I think we inluded 27 of 28 trials, and no true trial was remotely similar. And yet when you do a systematic analysis, a systematic review and a meta-analysis, you pool them together. But we couldn’t find any characteristic across these trials that was consistent across them in terms of dose, duration, endpoint, systemic characteristics, stats, all of these kinds of things, sample sizes. So to do a meta-analysis when you’ve got this complete heterogeneities, no wonder you’re getting mixed results and confusion. But with your idea about dose, so we looked at what was the rationale that studies gave for their dose, and it was really, really interesting.
Some of them, it was because that was what the manufacturer recommended. Some of them was because this relates to what the standard intake is if you were to eat fish. Some of them was, “This was what was effective in a young population.” But there was no real mechanistic, “This is what’s needed to increase tissue levels by X amount. This is what we’re trying to do.” And I think that’s the problem is that people think an Omega-3 trial is easy. All you do is you just have two groups of people, and you give one group fish oil and one group you have placebo, and then you just see what happens. But there’s so much methodological complication with an omega-3 trial.
And I think that’s one of the big issues, is that what I would recommend is if you are running a trial, get a lipid biochemist on board who can talk to you about the dose, the mechanisms, how it might work, is it going to get into the brain? Is it going to cross the blood-brain barrier? Is it going to affect CSS levels? What kind of levels are needed to do these kinds of things? And I think that’s one of the problems, is that people just think Omega-3s are like any other drug, you can just give one group something, another group placebo, and then see what happens without looking at the duration, the dose, the form, was it tricoglycerol, phospholipid? All this kind of stuff. For aging, should it be EPA and DHA? All of these kinds of things.
It’s taking a step back and think, mechanistically, what am I trying to improve and what is needed to benefit this? And I think one of the other issues is that people think the Omega-3s are this magic bullet and they’re suddenly going to make people smarter and cleverer and stronger and all these other kinds of things. But you’ve got to think, in your population, over time, your control group, your placebo group are going to get gradually worse through just natural aging. If they’re MCI, they’re going to progress more dramatically, but they’re going to get worse. Do you want your intervention to preserve cognition? Do you want it to decrease or affect the rate of decline, or do you want to make them better and make them cleverer than they were to begin with? And then you need to have appropriate statistics to do this. It’s unlikely that you’re suddenly going to make them smarter by giving them fish oil for six weeks, so therefore what you’re trying to do is you’re either trying to preserve or you’re trying to affect the trajectory of the decline.
And you need to appreciate how steep is the decline in your placebo group such that you’ll see a difference in your intervention group. And the LipiDiDiet trial was a great example of this. So they did a trial… So it was an Omega-3 with multi-nutrient, so it had B vitamins and phospholipids, et cetera. And at two years, their placebo group hadn’t really declined. So they didn’t see an effect at two years. But they extended it to three years, and at this point, their placebo group started to decline and they started to see a difference between the two groups. So if you’re not running your trial for long enough in an aging population, if your placebo group isn’t declining rapidly enough, you’re not going to see an effect because what are you expecting the Omega-3s to do? Are you expecting them to preserve or to affect the rate of this trajectory?
And that’s one of the issues is that people say, “Oh, it’s an Omega-3 trial that failed,” Because you’re not really thinking about what you’re expecting it to do. You’re not giving enough dose. There’s a couple of studies that measured CSS levels as opposed to circulating levels. It doesn’t show whether it’s incorporated in the brain, but it shows whether you’ve enriched the brain environment. And these were fortunately a couple of the highest doses. So one gave two grams of Omega-3s, one gave 2.3 grams of Omega-3s, and the two gram one enriched the plasma phospholipid levels by 200%, but the CSF levels were only enriched by 38%. So you’ve got these levels that massively increase the circulating levels, but they’ve got to get into the brain. Richard Bazinet and Stan Rapoport did great work looking at the brain uptake. It’s about three and a half milligrams a day.
So you’re trying to have an effect in getting things into the brain, so you need to have sufficient dose for sufficient duration for the placebo group to manifest getting worse, but to also have a conservation. And that’s one of the big problems with the trials is that they don’t have enough people to last long enough to follow them for sufficient period. If you’ve got 50 people per group and you’re measuring them for three years, how many are you going to have at that three years? How many are you going to follow to that period? So there needs to be sufficient numbers to be powered at the end of the two years, three years to have an effect. And that’s kind of the reason people are dismissing Omega-3s because they’re not giving them the appropriate opportunities to work.
Bill Harris: Right. See, I mean, you suggested this, but can people increase their brain DHA by taking DHA supplements, adults? The index goes up, red cells, heart, other tissues, but is brain unique that it does not respond to additional supplement?
Simon Dyall: I remember at ISSFAL a couple of years ago you asked this question in one of the sessions, and essentially, we don’t know. That’s the big question. People are a bit averse to having biopsies. For whatever reason, they don’t want to have biopsies to measure… Yeah, exactly. So without that, we are kind of guessing. So we know what the half-life is, is about two years. Their brain turnover is about two years for DHA. And we know that certain regions of the brain are susceptible in aging, so certain levels will decrease. But we don’t know, if you give a supplement, does it increase your brain levels? So we don’t have that data. We can measure red cells, we can measure all of that stuff. And animals you can look, but animals… Rats have a very different metabolism to humans in terms of this. So the short answer is we don’t know. We don’t know. If you take this two grams of Omega-3, does it increase your brain DHA levels? We can’t measure it.
Bill Harris: Okay. Okay. Fair enough. I mean, that’s good. We know it does a lot of other good things around the body, and we’ll assume it’s also helping…
Simon Dyall: It may not need to. In order to preserve cognition, it may not need to incorporate. So we know that DHA is highly enriched at the synapse. It’s not just found in the brain, it’s found in specific regions. So there is at the synapse, the connection between stuff, and it’s involved in synaptic communication. So it may be that bathing DHA around the synapse involves reuptake and is beneficial in different ways. So it’s kind of a black box. We give the supplements, we measure cognition, we can measure these things, and we get improvements in cognition and certain measures, but whether it needs to incorporate into the phospholipids in the brain or whether it’s the environment, these kind of factors are more complicated. But as you say, it has lots of beneficial effects around this.
Bill Harris: Right, right. It’s probably a great place to wrap this up. Really a nice overview from the preemies all the way to dementia. This is good stuff. So thank you, Simon. Really good to have you on the show. Appreciate your expertise in this area. And I know we’ll be on some panels here in the coming days on dementia. I’m looking forward to that. And thanks again for being on the program. And Kelly, I’ll let you wrap it up.
Kelly Patterson: Yeah. Thanks for joining us today, Simon, and thanks for everyone joining us to talk about all things fatty acids. We’ll see you next time.