MTHFR & Autoimmunity
19th May, 2022


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Wendy McLean (00:05): Welcome to Common Ground, a podcast series discussing new research and interesting projects in the field of complementary medicine. Hello, my name is Wendy McLean, Educator at is a digital platform, a health professional resource, and a distribution service all in one.

Firstly, I'd like to begin by acknowledging the Gadigal people of the Eora Nation as the traditional custodians on the land on which we gather here. I would also like to respect their elders, both past, present, and emerging.

There are at least 80 recognised autoimmune diseases, affecting as many as 1 in 20 people worldwide. However, the prevalence of autoimmune diseases has increased at an alarming rate over the past few decades.

While the causes of autoimmunity are not fully understood, patients with autoimmune diseases seem to have a genetic vulnerability to certain environmental factors that could trigger these conditions.

Today on Common Ground, I will be discussing the link between MTHFR gene variations (methylenetetrahydrofolate reductase) and autoimmunity with Carolyn Ledowsky.

Carolyn is a naturopath, herbalist and nutritionist who has Bachelor degrees in herbal medicine, naturopathy and economics. She has an Advanced Diploma of Naturopathy and a Diploma of Nutrition. She has also studied courses in genetics at Duke University and the University of Maryland, and she's currently completing a Bachelor of Health Science with Honours in Naturopathy.

Carolyn now sees chronically ill patients from all over the world, who have searched, sometimes for decades, to find the reason behind their ill health. Her strength lies in her ability to reveal layers of dysfunction and not give up until results are seen. Most of her patients have MTHFR mutations and/or associated methylation disturbances. Her key passions are fertility, anxiety, and depression. Her practice specialises in genetic susceptibility and how this contributes to biochemical dysfunction and chronic health conditions.

We're very pleased to have Carolyn share her knowledge and experience with us today on Common Ground. And we warmly welcome you Carolyn.

Carolyn Ledowsky (02:23): Thank you so much, Wendy. It's great to be here. I just have to add I actually did finish my honours and I'm actually now doing a PhD.

Wendy McLean (02:33): Oh, wonderful. Congratulations.

Carolyn Ledowsky (02:36): Thank you. I'm doing that with UTS, which is exciting, on my fertility side.

Wendy McLean (02:41): Fantastic. Well, I wish you all the best with that.

Carolyn Ledowsky: Thank you.

Wendy McLean: It's a big undertaking.

Carolyn Ledowsky (02:47): It certainly is.

Wendy McLean (02:48): Wonderful. That leads us right in then. Could expand a bit more on your background and how did you come to specialise in MTHFR?

Carolyn Ledowsky (02:59): Yes. Look, it's a funny story because I really liked to look at bloods and I still do. I think it can tell us a heck of a lot. And I used to test folate levels and I'd see half the people with high folate and half with low. And I'd think, what's the significance of that? There’s got to be a meaning in this.

And when I rang the labs, they said, oh, that's, you know…

I said, exactly what are you testing?

And they said, derivatives of folate.

And I said, but what does that mean?

And they couldn't really tell me, so I'd then go to my professors. I would go to GPs. I'd have meetings with specialists and I’d say, what's the significance of a high folate? And they all said, well, it's a good thing. They're eating leafy green vegetables. And I thought, no, that's not what I'm seeing. That doesn't really compute.

And I was at a conference in Adelaide and I'm literally going back 13 years. And one of the presenters said an off-the-cuff comment — MTHFR is related to folate in the blood. And I thought, wow. So I went up to her after the presentation and said, what is MTHFR?

And she said, it's a gene that regulates folate.

And I said, how do I find more info?

And she said, you just have to Google.

And so, I started, and I started Googling and I literally became obsessed because it led me into combinations of genes that affected folate. And then, at the time, we didn't even have methylfolate in Australia. So, I would bring samples from the US and put them in little plastic bags and give them to my patients if I saw that high level. And then I started testing MTHFR, because in those days you could do it with Medicare. And I started to see the levels coming down if I gave them a different form of folate and I thought, aha. And then they started to feel better and they started to fall pregnant and not have miscarriage. And I thought, wow. And then the more I delved into that, it got me into the other genetics and it has sort of expanded from there.

Wendy McLean (05:19): Wow. That's been quite a journey. So, you said for of 13 years since when you first heard about it.

Carolyn Ledowsky (05:24): Yes.

Wendy McLean (05:26): Obviously, a lot of research is coming out now. And so, can you talk a little bit about what exactly MTHFR is? What is the gene? What are the mutations?

Carolyn Ledowsky (05:38): Sure. MTHFR stands for methylenetetrahydrofolate reductase. And essentially, it's just a long word for a gene that encodes an enzyme that allows us to make methylfolate or 5-methyltetrahydrofolate (5-MTHF). Now there are many genes involved in that folate pathway, everything from dihydrofolate reductase right down to MTHFR being the last step. And they're all involved in our ability to recycle our folates, to create methylfolate. But because the rate limiting step is MTHFR, those people that have homozygous or two copies of a gene polymorphism, they can have up to 65% reduction in their ability to make methylfolate. And as we know, methylfolate is then instrumental to get that into the methionine cycle to make SAMe, our universal method donor.

There's actually about 30 MTHFR polymorphisms, but there's two significant ones mainly in the research and that's the C677T and the A1298C. Now, if someone has, or your parents Wendy, randomly gave you one copy of each, you don't know. But let's say your parents both had one copy of the polymorphism. You would get randomly one from mum, one from dad. Now you could get two copies that are both mutated or polymorphic. You could get one or you could get none with that scenario.

And so, what we look at is what is the deficiency amount with each of the polymorphisms? And therefore it gives us a really good idea. So, if someone's trying to fall pregnant and they've had multiple miscarriages we can understand why, because not only MTHFR but a lot of the other genes in that folate pathway are not working sufficiently. And if you can't methylate your DNA, you can't successfully have a child because you are going to miscarry. And that applies to dad as well because the male equally donates 50% of the DNA. So, you've got to be assessing their ability to create methylfolate. And that's what my PhD clinical trial will be doing, it will be looking at how effective 5-methyltetrahydrofolate is versus folic acid in women or couples with recurrent miscarriage.

Wendy McLean (08:29): Wow. That's fantastic. That research has been needed. It's well overdue.

Carolyn Ledowsky (08:34): It is. And it then takes us to the folic acid story. And its part and parcel of this MTHFR discussion because your folic acid is the synthetic manmade version of folate. It can't actually be used by the body unless the body decides that it can use it. And we find that there is a limit to the amount of folic acid that can be used. And studies say that roughly 200 to 300 micrograms a day is all that can go through that dihydrofolate reductase enzyme. So, if it doesn't go through and people are having more, which we know they are, because originally when fortification came into Australia in 2009, it was meant to only be bread. But it's now gone out to almost every product on the supermarket shelf. And when you think about kids, they are getting up and they're having breakfast; they're having cereal for breakfast, it's fortified with folic acid and they go off to school and they have a lunch with sandwiches, and then they have something out in a packet for morning tea or afternoon tea. And the list goes on and on. So, we're getting from fortification a lot more than we ever thought we should.

And the research says that over a certain amount we get what's called unmetabolised folic acid. So it's not going anywhere. It's just building up in the blood. And there's been certain studies that have linked that with natural killer cell activity or reduced natural killer cell activity, autoimmune disease, cancer, all sorts of different. It's prevalent in almost all breast milk if women live in a fortified country.

Now some researchers suppose that it is downregulating the MTHFR gene. So, it's almost like a feedback inhibition system where its saying folate levels are too high, let’s inhibit MTHFR. But that's having a catastrophic effect, not just from a fertility standpoint, but you think about anxiety, depression, immune function, detoxification, they're all potential issues. And we don't know the full implications of this yet. And that's why these studies are really important because we have to know. And unfortunately, Australia has one of the highest fortification rates of any country in the world. The US fortifies with a hundred micrograms per a hundred milligrams of flour. We do 200 [micrograms per a hundred milligrams]; we're double. So we absolutely need to understand if this is an issue or not.

Wendy McLean (11:36): Yeah, absolutely. You've mentioned the role in immune function. And so, MTHFR is associated with not just fertility, but many health conditions as well. Are there any specific links between MTHFR mutation and autoimmune disease?

Carolyn Ledowsky (11:56): Yes, there are. And there's quite a few studies. They're not all 100% in terms of, yes, this is diagnostically absolutely the problem. But multiple sclerosis (M)S, lymphoma, thyroid autoimmune disease. Vitiligo is another one. Graves’ disease, rheumatoid arthritis, and systemic lupus erythematosus (SLE) are all associated with it. But it's more specifically, and this is where the research really comes to the fore, it's the reduction in DNA methylation that is the real trigger. And so, when we look at MTHFR because it does have such a significant effect on overall methylation levels because it's supplying SAMe or together with B12 it is producing SAMe. And so it's more that this abnormal DNA methylation is the major concern.

Wendy McLean (12:58): I understand that there's a direct effect of this hypomethylation on the T-cell response. Can you talk a bit about that?

Carolyn Ledowsky (13:05): Yes. And it's quite interesting because they've looked at certain drugs that inhibit DNA methylation and they've given them to mice and they've said, okay, what is the effect? And what they see is if methylation is inhibited, it decreases in our CD4+ T cells. They become responsive to normal stimuli. And so that induces self MHC class II cells, and that then sets off this autoreactivity. And researchers have, as I said, researched this in mice where this change in methylation status and the effect of the CD4+ T cells, did lead to development of a lupus like disease.

What happens is this whole process overactivates our CD18, or it used to be called LFA-1, it overactivates these, and they play a critical role in the regulation of our immune system. So as a result, we get this autoreactivity, we get these inflammatory conditions, and we can get things like inflammatory bowel disease, psoriasis, diabetes, and arthritis. And we are getting a lack of methylation, which causes this overreactivity and then the T-cells become autoreactive and that induces autoimmunity. It's quite interesting, the studies. And obviously it's the DNA methyltransferase 1 that is critically important here.

And as we age, you know, methylation is less. Then there’s stress. And as you said in the introduction, autoimmune disease is increasing. There's no question. And I must wonder whether it's a lot of these things that we're talking about. Like is it the folic acid fortification that's affecting our methylation? Are we now so stressed that we are using methyls that we can't replace? I read an interesting article that MTHFR polymorphisms are becoming more prevalent, there's more people with them now because of the epigenetic change that we are seeing.

Wendy McLean (15:46): Yes, with all these environmental exposures to these toxins, your phthalates, your endocrine disruptors.

Carolyn Ledowsky (15:53): Exactly. And toxicity is key because methylation is hugely affected and vice versa. If methylation is deficient, then you're going to be having problems with toxicity, particularly things like oestrogen dominance. And I don't think there's anyone in the world now that doesn't have some level of oestrogen dominance.

And I think what really interests me is that we are seeing these floods and we know how we have an epidemic of people affected by mould in this country. Mould creates an oestrogen dominance because the glucuronidation pathway is reduced when there's exposure to mould, because that's the pathway, the phase two pathway, that we use to eliminate mould out of the system. So, you think about all these potential people that are affected, and today we've got floods, you know, it's most of this country that is affected by it. And unfortunately, so many people don't even realise, and I wonder if this is all going to be a trigger for immune problems going forward.

Wendy McLean (17:09): Yes. I think the same as well. I see mould as a huge issue. You know, I was up in the flood zones early on for a couple of days. And that was one of the main things; in people who could go back to their homes, they were trying to clean this mould and you know, not necessarily having gloves to wear or the correct masks. So, I feel that there's going to be an epidemic of mould illness as well.

Carolyn Ledowsky (17:37): A hundred percent. We have to stop this rain, Wendy.

Wendy McLean (17:42): We do. So, you've talked about the impact of stress as well. So there's a stress in our environment that potentially can interact with these genetic mutations. So how would you test for the MTHFR mutations, especially when you mentioned there's 30 different types?

Carolyn Ledowsky (18:06): We've got a test kit on our website — You can just jump straight in. You can also go through your doctor, but it's not Medicare rebated now. So, there's a variety of different ways. Or you can do, genetic testing — Ancestry DNA® will pick it up. Many of the test kits in Australia will also have it as stock standard now.

And predominantly they will test the two, the C677T and the A1298C. The other variants they're really not testing at the moment just because there's not enough research to substantiate the fact that they're polymorphic and there's a problem.

Wendy McLean (18:50): I understand. So, what can someone do that has an MTHFR mutation? Are there specific nutrients or dietary interventions that you would recommend and particularly thinking about it in this aspect of autoimmunity and detoxification?

Carolyn Ledowsky (19:07): Yes. And it's interesting. If we go back to the rheumatoid arthritis picture, there are also drugs. I think it's important to remember that there are drugs that specifically reduce our folate pathway, like methotrexate.

Wendy McLean (19:26): Yes. That's a great point.

Carolyn Ledowsky (19:28): Yes. So, and you have things like Procainamide which is an antiarrhythmic that is a DNA methyltransferase inhibitor. Methotrexate inhibits dihydrofolate reductase. So unfortunately, it's not just, I think we've got to remember, that there are drugs that are specifically reducing these folate pathways. And I think in the case of cancer… have we seen any studies that implicate 5-methyltetrahydrofolate in cancer? And the answer is no. So if you've got someone with rheumatoid arthritis though, and they're on methotrexate, you have to ask yourself if that is the best fix. Because if we are saying that autoimmunity is progressive because of a reduction in DNA methyltransferases, then what are you doing with methotrexate?

I mean, essentially you are reducing methylation, you're stopping it. I think we've got to look at the autoimmunity side. I understand in cancer we just don't have enough information yet, but I think in autoimmunity and when we're given drugs like methotrexate, I think we have to consider that maybe it's not the right strategy. Because you can improve their autoimmunity. And from my patient's perspective, we try and improve the methylation component. I mean, in conditions like psoriasis, also autoimmune, you can get people have a bit of a flare if you push the folate too hard, but you've just got to start the process going and get all the underlying biochemistry. So, it's a long way of saying what you've really got to do is understand why they've got the problem in the first place.

And it could be many different factors. For example, it's not just MTHFR. For us to use methylfolate we need good levels of B12. B12 is what makes us uptake our folate. If someone is vegan or vegetarian, not eating meat, then they are going to have a methylation deficiency. Creatine is one of the best methyl backups we have. Sixty percent of all SAMe production daily goes towards making creatine. If someone isn't eating meat or they are not getting creatine from their diet, because of gut issues, then are they potentially going to be deficient? The answer is yes. There are so many different factors that we need to consider; the diet. The key factors for methylation are obviously folate, B12, B6, keeping homocysteine levels under control, choline. They're all incredibly important. And I think you've got to look at diet. It must be one of the first things. Moderating stress levels, because the way that we are so stressed, particularly with all this COVID business and now the floods and everything else, people are in that flight or fight mode. And that's creating really big issues apart from the fact that it is decreasing your B12 because your hydrochloric acid levels go down. I mean, there's so many knock-on effects, but stress eats and chews up methyls. So if you’re homozygous MTHFR and you've got a 65% downregulation of your ability to make it, what stress does is put you in a deeper hole and your ability to climb out of that hole, Wendy, is just not good enough.

Wendy McLean (23:49): Yes. It's so complex. And so you've got the person sitting in front of you, you're not only having to deal with this mutation and the methylation and all those biochemical cycles. You've got to deal with that stress as well. And so would there be certain other nutrients or herbs that you would use for that?

Carolyn Ledowsky (24:11): Absolutely. And I think what we have is our practitioner training programs and this is exactly what we do. We say, okay, you've got the person in front of you. You've got 500 different tests. What do you do? And so we consider the genetic susceptibility. How much is that playing apart? What do we think are the holes in their ability to recover? Because let's face it. If someone is deficient with their methylfolate or deficient in folate, they're going to have a lifelong problem unless you plug that hole up. Then we say, is there anything environmentally that we think has influenced their methylation capacity? So the floods and the exposure to mould is a massive thing because mould and yeast inhibit the methionine synthase enzyme which allows you to use folate. So again, you can get autoimmunity, you can get problems with detoxification, you can get neurotransmitter issues.

Now let's look at our bloods and let's understand what the bloods are telling us. If you've got a low B12 it might be reflected in a continuing low white cell count. If your folate is low, it might be a high mean corpuscular volume. So there's varying things in the bloods. We need to look at thyroid function. We need to look at iron. We need to look at all the basics. And then we look at any other results that we think would be significant, like perhaps an organic acids test or whatever it happens to be, or a Dutch test to look at their hormones. And then we say, right, what is the key symptom that this person is presenting with and how do each of those influences affect that? And what's the first thing we need to do.

And for us mood and anxiety trumps all. So that will always be the factor that I will look at number one. I need to get the anxiety down. I need to get the mood up. And by understanding your B12 and your folate and what your dopamine genes are doing, and serotonin genes can give you massive clues.

So I don’t know if I've answered your questions.

Wendy McLean (26:46): Well, certainly you gave lots of good information there. I love that idea and that approach; that dealing with the mood and the anxiety is number one.

Carolyn Ledowsky (26:57): Yes, because then you can go on and look at if someone has then got rheumatoid arthritis or psoriasis or autoimmune diabetes or whatever it happens to be. Then you've got to approach that on an individual basis; particularly rheumatoid arthritis, I think it's a big one. Because if they are on methotrexate, I really want to work with their doctors getting them off it. And if I can dampen down the symptoms, look at their fat-soluble nutrients, their A, D, E and K and zinc and copper and everything else that we want and they start feeling better and you start to put a bit of folate in and they’re not hyperreactive, then that for me is a really good sign that we're on the right path.

And it's interesting too that for SLE the age of onset is 40 years of age. It's quite late. And I think it's probably at an age where we don't methylate as well as we should. You know, you've gone through your thirties, particularly as a female, you’ve had kids and often one after the other. What does that use? Folate. And so, you can be nutrient depleted too. And then if you've got MTHFR on top, then the ability to get yourself out of the hole is much harder.

Wendy McLean (28:22): Yes. And that would certainly seem to make sense, because we do see a lot of these autoimmune conditions having a dominance in females. Like you say, with SLE coming on at that later age.

Carolyn Ledowsky (28:35): Yes, exactly. And even the number of women we see who have autoimmune thyroid issues. You know, whether it's our subset of the population, but pretty well all our fertility patients particularly with homozygous MTHFR have autoimmune thyroid issues.

And they've got elevation in ANA antibodies and not so much the ENA [extractable nuclear antigen antibodies]. If we see the ANA and the ENA is not elevated, then we know that we can reverse that or at least get it to the point where it doesn't become a problem anymore.

Wendy McLean (29:17): That's interesting. Look, it's so important because people tend to have these clusters of autoimmune diseases as well. So if you can work out what's going on and if you've got any chance of dampening it then that's fantastic.

Carolyn Ledowsky (29:34): And I think inflammation, as you know, is key. And it's upregulating pathways that shouldn't be upregulated for long periods of time. And so you've got to also look at, I think the environmental factor is massive. Because if you've basically got inflammation, infection, or LPS, it's setting off inflammatory pathways that should not be set off for months and months and sometimes years. And then you get the histamine side effects and everything goes awry because histamine is a signaling molecule. Nitric oxide is upregulated, it's a signaling molecule. So these signaling molecules are all doing the opposite of what they really need to be doing. And they're offsetting other things and taking the focus away from methylation.

Wendy McLean (30:26): Absolutely. And I think unfortunately people are just not aware of their environmental exposures and the cumulative of load that they're unwittingly exposed to. So I think a big part of our job is education and empowering these people to reduce their environmental exposure.

Carolyn Ledowsky (30:46): And as you very rightly said, the amount of toxin exposure that we have is far and above anything else that we've ever experienced. It's not just what we're eating, but it's what we're breathing in. And it's, the fumes in our house and the mould and the Lyme’s and whatever else we get exposed to. And with that comes then phase two detox issues, and phase three: the bile. I just did a webinar last week on fatty acids and bile. And I'm astounded by the amount of people who have the disturbed fatty acids. And it's because bile is just not moving. And even having CBS pathway issues where you’re not making taurine or having methylation issues where you're not making phosphatidylcholine, these all have knock on effects I think for our immune system. And the more toxins we have, the more off kilter our immune system gets.

Wendy McLean (32:00): Yes, absolutely. I'm just thinking air pollution is a big one that we're unfortunately becoming more and more exposed to. I'm also thinking our water and even when we think we're doing the right thing with bottled water, look at the endocrine disruptors in bottled water. It's quite alarming really.

Carolyn Ledowsky (32:22): Yes. And as I said, our detox pathways are just becoming so jammed. No wonder we're getting more people with multiple chemical sensitivities and autoimmune disease because they just can't get themselves out of it. And the immune system is completely overloaded. I was listening to an interesting show the other night that was talking about the pollutant levels in these dust storms. So because of the way that we are developing, not so much here, but in the Middle East where they get these huge dust storms, and the dust storms pick up toxins. And as they move across countries, they are picking up more and more pollutants. So when they actually hit, I think South Korea was where they were finally hitting, apparently the dust is so toxic the kids in schools walk around with masks all day, every day, and every classroom has to have multiple air filters.

Wendy McLean (33:29): Yeah. That's astounding. I've actually been reading about microplastic exposure in the air as well.

Carolyn Ledowsky (33:36): And the ocean

Wendy McLean (33:37): And the ocean. And our drinking water and food. It's quite alarming. And we still don't even have a basic understanding of what they could potentially do to our body.

Carolyn Ledowsky (33:50): No. And the problem is they last for so many years. Like, it's not as if you can just say, oh, I'm going detox that out of the system. Some of them are lasting in your system for a hundred years.

I think the answer to all our, you know, in terms of our wish list, we must detox. But the problem is, and this is another thing I'm teaching a lot of my practitioners, we have patients now, because if you think about five years ago, someone came and said, they didn't really feel very well. You know, you put them on a detox program, and they come back and say, you know what, Wendy, I actually feel really good now. I'm much better than I was. But you try and do that now? There are some patients where they can't take one supplement. They have a problem just drinking water. And so, these people, I think, are the ones that are jammed. Bile is jammed. They're not making taurine. They have insufficient methylation to make phosphatidylcholine. They just can't move toxins out of the body. Then you look at all the glutathione snips on top of that. You know, and glucuronidation, and all these pathways have to be supported. I'm such a fan of calcium deglucurate because I really think it's probably the number one priority. And particularly when you've got these super sensitive patients, because if that's jammed and you've got all these endocrine disrupting hormones, and you've got the oestrogen dominance, we really need that glucuronidation pathway working.

Wendy McLean (35:29): Absolutely. Well, Carolyn, that's been an insightful conversation. I think we went quite deep there. So I'm sure that our listeners will get a lot out of it. So thank you so much for your time today.

Carolyn Ledowsky: You're welcome.

Wendy McLean: And thanks for tuning into this episode today, we appreciate your support and feel free to leave us review. We'd love to hear from you. Thank you.