Hacking methylation: 2 key nutrients to support the methylation cycle

Image result for choline cycle

Taken from: http://geneticgenie.org/blog/2013/10/21/acetylcholine-deficiency-in-chronic…

Finding out that you have an MTHFR polymorphism drives most people crazy.  Normally it’s something you know nothing about until you begin to experience poor health and start digging and digging until you end up on 23andme.

Granted, a polymorphism in this gene can be problematic.  But most people look at it from the wrong angle.  They look at it from the point of view that the folate cycle is the end-all-be-all for methylation.  This couldn’t be further from the case.

Sure, creating methyl groups is a part of the equation.  But you also have to take a look at what processes increase demand for methyl groups.  If there are ways to lower demand for methyl groups, you don’t need to create as many to lower your methylation needs.  This lowers the burden on the MTHFR enzyme to create methyl groups.

Let’s take a look at both sides of this equation.

Creating methyl groups for methylation

A single run through the folate cycle creates one methylfolate(5CH3 THF) that donates its methyl group to homocysteine.  The methylfolate then becomes folate(THF) and the methyl group gets used to convert homocysteine in to methionine.

Image result for folate cycle

Taken from: https://openi.nlm.nih.gov/detailedresult.php…

A full run through the choline cycle also makes a methyl group to conver homocysteine in to methionine.  But, it doesn’t use MTHFR to do so.  It also makes 3 methylenetetrahydrofolate(5,10-CH2THF) which gets converted to 3 methylfolates by MTHFR.

Betaine methyl groups

Taken from: http://www.biochemj.org/content/472/2/135

It’s easy to look at this and think that it means that the choline and folate cycles are a push.  They both make 1 methyl group so it makes sense, but it’s more nuanced than that.  The choline cycle plays an even bigger role in the methylation cycle by using up methyl groups.  Let’s take a closer look at the choline cycle.

Choline cycle: The whole picture

On the surface, the benefits of consuming adequate choline are to donate methyl groups to the methylation cycle.  However, we use up a lot of phosphatidylcholine to make cell membranes.  When you don’t eat enough choline or phosphatidylcholine(PC), you must synthesize PC from phosphatidylethanolamine.  This process uses up 3 methyl groups.

Not getting enough choline reduces the number of methyl groups you generate via the choline cycle.  But you also have to take in to account the phosphatidylcholine that’s used to form cell membranes.  The cell membrane has a phospholipid bilayer, 50% of those phospholipids are phosphatidylcholine.

Image result for cell membranes phosphatidylcholine

Taken from: https://metabolichealing.com/pemt-gene-mutations-choline-phospholipids/

Every time your cells divide, they need phosphatidylcholine to form stable membranes. This is a big factor throughout the body but particularly in cells that replicate often.  This incudes the cells in your gut.

Instead of going through the creating methyl groups, this phosphatidylcholine forms cell membranes.  If you aren’t eating adequate choline or phosphatidylcholine, you make it from phosphatidylethanomamine.  This uses up 3 methyl groups and creates none,  a net of -3.

Image result for phosphatidylethanolamine phosphatidylcholine methyl

Taken from: https://en.wikipedia.org/wiki/Phosphatidylethanolamine_N-methyltransferase

Notice how it takes 3 S-Adomet to convert PE in to PC.  The enzyme PEMT transfers methyl groups from S-AdoMet to PE and makes PC and 3 AdoHcy(Met=Methionine, Hcy=homocysteine ).

Guess which cycle needs to pick up the slack for this?  I’ll give you a hint, the one you aren’t good at if you have an MTHFR polymorphism.

This isn’t to say that taking methylfolate isn’t an effective way to improve methylation.  What it means is that taking methylfolate without addressing choline is kind of a lost cause.

Most of the increase in methyl groups will go to creating phosphatidylcholine.  Both DNA replication and phosphatidylcholine synthesis are essential to cell reproduction.  You need to cover both bases, not just one.

Getting adequate choline/phosphatidylcholine doesn’t seem like a difficult thing to do.  But, a study published in 2007 found that most women(>95%) don’t get the recommended daily intake of choline(450mg/day)(1).  Getting adequate choline/phosphatidylcholine should be on your radar if it’s not already.

Layman’s breakdown: You use up a lot of phosphatidylcholine to make cell membranes.  If you provide this in the diet you should be all set.  When you eat inadequate phosphatidylcholine, methylation demands are greater.  This will divert methyl groups away from other processes and towards creating phosphatidylcholine. 

Most of the phosphatidylcholine you need that you don’t eat uses 3 methyl groups.   These methyl groups could have otherwise gone to something else.  You also make fewer methyl groups via the choline cycle.  This puts a greater burden on your MTHFR enzyme which is sluggish if you have a polymorphism in that gene.

Other polymorphisms in the choline cycle

There are also polymorphisms in the choline cycle that can impact the methylation cycle.  Polymorphisms in the phopsphatidylethanolamine methyltransferase(PEMT) and choline dehydrogenase(CHDH) genes also impact the methylation cycle.

PEMT makes phosphatidylcholine from phosphatidylethanolamine.  You can circumvent a sluggish PEMT enzyme by eating or supplementing with lecithin/phosphatidylcholine.

CHDH is a little trickier.  CHDH makes betaine from choline, which is a necessary step in creating methyl groups.  Supplementing with betaine can skip past this step and help meet your needs.  If you also have a polymorphism in PEMT you want to supplement with phosphatidylcholine as well.

As you can see, a lot of this is specific to the individual.  For example, I’m heterozygous for MTHFR C677T so I don’t make methyl groups through the folate cycle well.  I have no issue with PEMT, but I do have a polymorphism in CHDH that lowers my ability to make betaine from choline.

For proper methylation via the choline cycle I should eat/take betaine.  However, since I have a fully functional PEMT, I also have to supply phosphatidylcholine.  Otherwise, I’ll use most methyl groups created via methlyfolate and betaine to create phosphatidylcholine.

The basic takehome message here is adequate choline is essential.  Taking methylfolate or not, choline/phosphatidylcholine deficiency will have a huge impact on methylation needs.

It’s hard to nail down what percentage of methyl groups generated get used to create phosphatidylcholine.  This is dependent on the amount of phosphatidylcholine one consumes.  It also differs based on the genetic differences mentioned above.

A recent paper estimated that the methylation demand for creating phosphatidylcholine may exceed that of creatine(2).  Creatine just so happens to be next up in our discussion.

Layman’s breakdown: You likely need more choline/phsophatidylcholine than you are currently eating.  Creating PC from scratch uses up a lot of methyl groups and most people don’t eat enough..  There are also genes with polymorphisms in the choline cycle that dictate what you should eat or supplement with.

Creatine synthesis and methylation

Another significant user of methyl groups is the synthesis of creatine.  Creatine helps supply energy to cells by storing excess phosphates.

Energy is stored in cells as adenosine triphosphate(ATP).  ATP holds energy until it breaks in to adenosine diphosphate(ADP) and a phosphate.  This liberates energy to be used in biological reactions.

Image result for ATP

Taken from: http://education.mrsec.wisc.edu/nanoquest/molecular_motor/

ADP gets recycled back to ATP when a phosphate gets donated back to it.  ATP can then provide energy as it once did.  This recycling happens over and over continuously.

Creatine holds on to phosphates to donate back to ADP and recycle it back to ATP.  For this reason, creatine is called creatine phosphate or phosphocreatine when holding a phosphate.

Image result for creatine ATP

Taken from: http://eng.aesirsports.de/index.php/2015/07/09/creatine-dosage-to-load-or-not-to-load/

As you can imagine, this process is constant.  Over time, creatine is converted to creatinine and lost in the urine.  Therefore, it needs to be resynthesized or consumed in the diet.  Creatine synthesis uses up quite a bit of methyl groups, accounting for 40% of total methylation(3).

Just like phosphatidylcholine, the amount of methyl groups needed to synthesize creatine is dependent on how much of it you consume in your diet.  Supplementing with creatine can be a useful strategy to lower methylation requirements and make up for poor MTHFR efficiency.

Creatine is exclusively found in meat which I’m not necessarily against eating, but people with methlyation problems need to keep meat intake relatively low due to the high methionine content.  In these cases supplementation may be necessary until you re-balance methylation demands.

Layman’s breakdown:  The synthesis of creatine uses up approximately 40% of the methyl groups you generate from the methylation cycle.  Supplying it in the diet can reduce methylation needs and will almost certainly increase energy levels due to its ability to recycle ATP from ADP.  Both creatine and phosphatidylcholine synthesis use upwards of 80% of your methyl groups.

Methylation and the gut

Methylation needs are high in tissues with high cellular turnover.  When cells replicate, they require methyl groups directly for DNA methylation and phosphatidylcholine synthesis.  This supports cell differentiation and building of the cell membrane.

The epithelial cells in the gut turnover quickly, approximately every 3 days.  Not only does this increase demand for methyl groups for DNA methylation and phosphatidylcholine, but it uses a lot of energy.  This puts a burden on creatine synthesis as well.

With poor methylation status cells won’t differentiate properly, their cell membranes won’t form properly, and energy levels will be low.  This can lead to damaged, unhealthy cells making up the intestinal barrier.  An additional factor that has been studied is the energy demands of regulating the intestinal barrier.

Creatine kinase is the enzyme responsible for donating a phosphate from creatine phosphate to ADP to re-form ATP.  Inhibiting this enzyme decreases tight junction protein synthesis and induces inflammation(4).  Mice with IBD have low creatine kinase levels and supplementation with creatine resolves this inflammation(5).  It also improves tight junction protein synthesis.

Owing to the importance of methylation in the gut, both phosphatidylcholine and folate participate in the enterohepatic circulation.  This means that both circulate in the gut 7-10 times per day and help support the demand for methylation in the gut.

Layman’s breakdown: The rapid turnover of cells in the gut impose a high demand for methyl groups from the methylation cycle.  Getting adequate phosphatidylcholine and creatine decreases the demand for methyl groups to synthesize both of these important nutrients for gut health.

Without adequate creatine the high energy demands of a replicating cell can’t be met.  Without adequate phosphatidylcholine cell membranes can’t form an effective intestinal barrier.  Without proper DNA methylation, a stem cell can’t become the type of cell the body is calling for.  The combined effect of these 3 factors causes a leaky gut and increases inflammation there.

Special consideration: Vegans and vegetarians

Intake of both of these nutrients is extremely difficult for vegans.  Creatine is found exclusively in foods of animal origin and phosphatidylcholine needs may be hard to meet without animal-based foods.  Another consideration is that generating choline via PEMT is dependent on methionine which is also low in vegan diets(6).


While many people focus on consuming methylfolate to improve their methylation, there are two other options that may be more attractive.  Rather than increasing the number of methyl groups you make, ingesting these nutrients lowers the number of methyl groups you need to make.

Synthesis of phosphatidylcholine and creatine require a large proportion of the methyl groups created via the methylation cycle.  Getting more of both in your diet can reduce the demand placed on the methylation cycle.  Additionally, phosphatidylcholine can be used to make betaine which donates a methyl group to the methylation cycle to help meet methylation needs.

If you have an MTHFR polymorphism and are not seeing improvement by supplementing with methylfolate, you may want to take a look at phosphatidylcholine and creatine.  The combined demand for methyl groups for both could be close to 80% of total methylation.  Providing them in your diet could lead to significant improvements in energy levels and gut health.

Got questions or comments?  Pop them down in the comments section below.  There’s more kickass information where this came from.  Be sure to request to join the private facebook page here to have access to some of the stuff I’m not releasing in public blogs like this one.


11 thoughts on “Hacking methylation: 2 key nutrients to support the methylation cycle

  1. LT says:

    If you wanted to check your CHDH genes, which report would show them? Alternatively, which genes would you look up in the raw data (and what is normal for them)?

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  3. Anony Mousse says:

    Last year I decided to supplement with choline and inositol. I was doing well with methylfolate, methylcobalamin, P5P, and Sam-E. The weirdest thing happened with the choline supplement. Within 24 hours, it put me in the most depressed mood, which never happens to me. I get angry a lot, but never feel depressed. I had never felt like that before in my life, like nothing could make me happy. I knew it had to be the choline or inositol as I had changed nothing else. I switched to an inositol only supplement and within a day I felt normal again.
    I couldn’t figure out why though, because everything I read suggested as a methyl donor, choline should increase neurotransmitter production and mood. After doing a ton of reading, I found out that choline increases serotonin transport, and so if you’re a slow methylated, too much choline can make you get rid of choline faster than you can make it. I’m concerned about choline after reading this but I’ll never try supplementing it again. Instead I’m trying to eat more broccoli and peanut butter.
    Do you think a lecithin supplement in a small amount would work for me? How about foods that contain lecithin, should I be getting enough choline from them?

    • musiclvr says:

      I doubt you’ll see this years after the fact but choline is not just a methylating agent, it is also incorporated into acetylcholine. Ach has a close relationship with dopamine, the motivational neurotransmitter (among other things). When you say “nothing could make me happy” I know that feeling well: low dopamine. I counteract it with a small dose of tyrosine if I feel that flat affect low motivation feeling from taking too much choline.

  4. Mike says:

    Nice Article. One thing I learned recently is to simply make sure you have enough phosphorus. I had just done organic acids testing and serum/intracellular blood testing to see low phosphorus levels. I also had my readings done with an Oligoscan which confirmed the extremely low phosphorus (and all other mineral values matched as well!). Since adding phosphorous, I am able to tolerate supplements that never made a difference before such as simple B vitamins in higher amounts. Now that I have something to make more ATP (and I can feel it already), I can’t wait to apply what I just learned in this article with creatine, choline/phos-choline, and betaine. Thanks!

    • Rohit Sahdev says:

      Mike – How did you add phosphorus? Did you use phosphoric acid or trisodium phosphate. I guess many people would be low in phosphorus. I know that its a underappreciated mineral.

  5. cincodm says:

    Awesome, glad you got something out of the article. Make sure you pump up those mitochondria with time-restricted feeding and exercise. Thanks for reading!

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