Nutritional recommendations for MTR and MTRR polymorphisms.

Miles Nichols says, “Do you have any info
on MTR and MTRR polymorphisms? Are these clinically relevant? Do they warrant methylcobalamin supplementation
or injections? Are there other considerations like glycine,
choline and creatine that are important in the cases of MTR and MTRR mutations?” Okay, Miles, let me stop and give a little
bit of background for everyone. In the methylation cycle, I’ve talked a lot
about MTHFR, which helps finalize the methyl group of methyfolate. But then folate has to donate that methyl
group to vitamin B12 in order for vitamin B12 to donate it to homocysteine. In that process, that’s how you clear homocysteine
primarily in the fasting state rather than the fed state. It’s also how you recycle homocysteine to
methionine to use for methylation, again, primarily in the fasting state rather than
the fed state. MTR is the gene for the methionine synthase
enzyme, which is the enzyme that takes the methyl group from folate, passes it to B12,
and then passes it to homocysteine. MTRR is a backup repair enzyme that repairs
vitamin B12 once it’s been oxidized. MTRR is not a normal part of the methylation
cycle. It is a backup enzyme. It’s kind of like a janitor. Only instead of coming in to mop the floors
every day, it’s like a cleanup crew that’s on call. Most of the time, you’re not using MTRR to
even a tiny fraction of your maximal capacity just because you don’t have a lot of damage
to the B12 molecule. About once every 200 or 300 cycles of the
methylation cycle, B12 will get damaged. This is an average. But once every 200 or 300 cycles on average,
B12 gets damaged. MTRR steps in and repairs it. The reason that Miles is asking this is because
I haven’t really addressed them very much in most of what I’ve written on methylation. There’s a reason for that, which is that—I’ll
address them in order. Methionine synthase, there’s a bunch of polymorphisms
in it. But the last time I did some research into
this, I couldn’t find very clear evidence on mechanistically what those polymorphisms
were doing to it. If I don’t know what the polymorphism mechanistically
is doing to the enzyme, then it’s hard to build a nutritional program around it. I came to the conclusion that the MTR is,
you can say some maybe things about it. I don’t know if the polymorphism lowers the
activity. If it does, then what that means is that no
matter how much methylfolate you have or how much methyl B12 you have, you’re not going
to be very good at remethylating homocysteine. So, it probably doesn’t make any sense to
inject methylcobalamin in that case. It probably makes zero sense because you can’t
use that enzyme. Now, it’s theoretically
possible that the polymorphism causes a defect in the methylfolate passing the methyl group
to B12 and causes no defect in B12 passing the methyl group to homocysteine. In which case, maybe injecting methylcobalamin
or oral methylcobalamin at high doses maybe would do something there. But I think that’s an extraordinary level
of speculation, and I think it’s rather bizarre to be injecting people with stuff on the basis
of that level of speculation. Now, my suspicion would be that if in fact
the enzyme doesn’t work very well, what you actually would benefit from would be number
one, doubling up on the choline just as you would—actually, most of my MTHFR recommendations
would make sense here. Choline would make sense because if you can’t
use the folate-B12 pathway, you’re going to rely more on the choline pathway to remethylate
homocysteine. So, if in fact that enzyme does anything,
it probably doubles the choline requirement like the MTHFR polymorphisms do. I was going to say it might make sense to
you, Sammy, but I take that back. I don’t know if it would. The other thing in the methylation protocol
that would make sense there is creatine because creatine would lower your methylation demand. However, I don’t think it would be as important
to put creatine in there, because in this case you don’t have a problem making methylfolate
if everything else is working fine, and theoretically you should be fine at using choline for supporting
methylation. The reason that I have the creatine in the
MTHFR protocol is because I’m trying to spare methylfolate as much as possible because methylfolate
is the off switch for the glycine buffer system. I want to reduce methylation demand so that
the system is not incentivized to use up the methylfolate that you put into it. Because when it does, you’re not very good
at regenerating the methylfolate, and the low methylfolate levels will cause you to
lose glycine. That’s why glycine is in the protocol. If your MTHFR is working fine, then the creatine
is much less relevant, and the glycine really isn’t that relevant. Glycine is still important for everyone, but
it’s not specifically relevant because of the genetic variations. With that said, I do think that because some
tissues rely more on folate and B12 than they do on choline that there might be some tissues
that would benefit from supplementing creatine, so you could play around with it. I supplement creatine, and I don’t have any
problems. I mean, there’s no harm in trying out the
creatine. Now, moving on to MTRR. My MTRR looks like a nightmare. I’m homozygous for one of the polymorphisms
that reduces the activity three to fourfold, and I am heterozygous for another polymorphism
that also reduces the activity three to fourfold. I don’t know exactly what that adds up to,
but my MTRR might be five to six to seven times lower function than normal. Does that matter? Well, the way it would matter if it did matter
would be that when I am exposed to oxidative stress, my B12 would get damaged at a higher
rate than normal. And when it does get damaged, my MTRR would
not be up to the task of fixing it. The reason the MTRR polymorphisms that lower
the activity three to fourfold are so common is because either they’re advantageous or
they don’t matter that much. I believe the reason is that they don’t matter
that much. They do matter when you are exposed to higher
than average oxidative stress. In my view, there’s no blanket recommendation
for someone with MTRR polymorphisms. What I say is because in theory you will be
bad at repairing B12 when your B12 gets very damaged, you should thoroughly look at your
B12 status at least once. Then every time you enter a new health era,
you should monitor your B12 status again. What I mean by health era is your health changes
or your developmental stage changes in a way that could impact your health. So, change in health eras, and I’m making
this term up, this is not a medical term, but the change in health eras means you get
sick with a sickness you never had before. That’s a change in your health era. Or you go through puberty. That’s a change in your health era. You go through menopause. That’s a change in your health era. Or you go on birth control. That’s a change in your health era. Any time where you say, “I have good reason
to think things might be different for me now than they were before,” measure your B12
status again. When I say thoroughly look at your B12 status,
I mean look at your serum B12, look at your homocysteine, and look at your urine or blood,
preferably both, methylmalonic acid, aka MMA, not mixed martial arts. Look, my MTRR, as I said before, looks terrible
on paper. But when I was at the peak of my mold and
barium crisis, and when I went on an antifungal drug that interferes with the methylation
system in the fungus where there’s a case report of someone with, I think it’s MTHFR,
getting neurological problems from using it, and I thought I was getting neurological problems
from being on the antifungal, I measured everything I could think of about my B12 status, and
everything looked fine. I’m not talking about just serum B12. I’m talking about all the functional markers
too. They looked just fine. That just reinforced my belief and the observational
data that these things are so common. If these things dramatically impacted your
B12 status in a very negative way most of the time, not many people would have the polymorphisms. And yet, they’re very common. Those are huge reductions in activity. They’re very, very common. So, I think it’s ridiculous to make a generalized
nutritional protocol around either of those. MTR, it gives you a couple ideas you can experiment
with. MTRR, be proactive about monitoring your B12
status. All right. Thank you for your question, Miles.


  1. Coronavirus has a patent on it

  2. My daughter has the same MTRR polymorphism status as you do, and she is vegetarian, so I'm thinking that has to be something which historically wouldn't have been so prevalent as it is now, and might make the polymorphism more relevant/problematic?

  3. Hey Chris, I've been following on your AMAs on itunes (and read your stuff going back to WAPF days). This one was particularly informative. Great work.

  4. That was a great explanation…..your best ever!☺

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