Worried about MTHFR? Why your focus is dead wrong

In the world of health hackers and people trying to heal from conditions largely ignored by conventional medicine, there’s no more well known genetic SNP than that for Methyltetrahydrofolate reductase(MTHFR).  For good reason, around 40% of us have some form of the gene that decreases efficiency of the enzyme.

In the folate cycle, MTHFR converts tetrahydrofolate to methyltetrahydrofolate.  Methyltetrahydrofolate then lends a methyl group to convert homocysteine to methionine, an important step in providing methyl groups for methylation reactions.

Image source : http://www.fxmedicine.com.au/sites/default/files/photos/Fig.2.jpg

On the left is a small snippet of what most people feel is the methylation cycle.  You need the folate cycle to power this reaction or you’ll be sick, fatigued, and in poor health.  The problem is, you’re only getting a small part of the story.

The larger picture in methylation


Image result for Methylation folate cycle

If we just scoot out a little further, we can see that the choline cycle can also power the methylation cycle.  In fact, from this figure it appears that it can make up for a sluggish MTHFR gene by powering the cycle just as well.

Once we get trimethylglcyine, it can lend a methyl group to the methylation cycle and become dimethlyglycine.  But again, this figure doesn’t show the whole picture.

Betaine methyl groups

I’ll break this one down for you.  Choline gets metabolized in to betaine which methylates homocysteine to methionine and becomes dimethylgycine(DMG).  This is the same process that MTHFR contributes to so it’s a push at this point.

Next, DMG gets converted to sarcosine, sarcosine to glycine, and glycine to carbon dioxide(CO2).  In each one of these conversions, THF gets converted to 5,10-CH2-THF.  5,10-CH2-THF is the direct precursor to methylfolate.

In a single run of the choline cycle, you’ve done the same thing as the folate cycle, and created 3 more “pre”-methylfolates to power it.  Research has validated that the choline cycle may be more effective at powering methylation than the folate cycle(1).

It’s important to note that if you begin the choline cycle with phosphatidylethanolamine (PE) instead of phosphatidylcholine(PC) you cancel out a methylfolate.  Fortunately, PE is more of a back up to PC than a way to synthesize it.  PC makes up the cell membrane of most things you eat so getting enough isn’t that difficult if your diet is diverse.

But is gets better, and it segues to the gut.

Bile, the enterohepatic circulation and phosphatidylcholine

Image result for enterohepatic circulation bile systemic

The crossroads between the methylation and choline cycles is planted squarely in the gut.  Enterohepatic circulation refers to the circulation of nutrients, hormones, and toxins between the liver and gut.  Most of the components of the enterohepatic circulation are also components of bile.  This includes phosphatidylcholine.

Bile is made in the liver, stored in the gallbladder, and secreted in to the intestine when you eat.  One of the primary roles of bile is the emulsification of fats.  This aids in the digestion and absorption of fats and fat soluble molecules.

Phospholipids are a component of bile secreted when you eat.  The primary phospholipid contained in bile is…phosphatidylcholine.  Phosphatidylcholine circulates within the enterohepatic circulation along with folate.

After going through the enterohepatic circulation, folate enters the bloodstream and gets distributed to the liver and other tissues.  In rats, interruption of the folate cycle can reduce serum folate levels by 30-40%, a much greater effect than a folate-free diet(2).

Diet and supplementation

Ideally, your diet should provide enough choline/phosphatidylcholine and supplementation shouldn’t be necessary.  Eggs, liver, and nuts are great dietary sources of choline.  If you want to cut to the chase, spinach, beets and shellfish are great sources of betaine which is trimethylglycine.  If you have a SNP in choline dehydrogenase which converts PC to betaine, betaine is your guy.

Of course, some people would rather be safe than sorry.  The great thing is, phospatidylcholine is cheap.  You can get a 2-3 month supply for $15 depending on if you get capsules or powder.  Sunflower and egg lecithin are your best options as they contain a compliment of other phospholipids including PE.

My personal choice is Now Foods Sunflower Lecithin granules.  The best part about the powdered form is that it acts as an emulsifier as well.  It’s great for shakes or adding to stuff like Trader Joe’s coconut milk that need better dispersal.


I wouldn’t necessarily ignore the folate cycle, but I wouldn’t concentrate the majority of my time on it.  Too many people have lower enzyme efficiency due to a SNP in the gene for it to have major health implications.  I am included in this group as I’m heterozygous for a couple of genes in the folate cycle.

Phosphatidylcholine should be something on your radar if your goal is optimal health.  Its participation in the methylation cycle and enterohepatic circulation put it front and center in gut health.


6 thoughts on “Worried about MTHFR? Why your focus is dead wrong

  1. amy baker says:

    Interesting article, definitely but what do you do when taking lecithin makes you feel worse? Out of this world tired, headache, brain fogged and what not.
    Oh and it’s not because I can’t tolerate sunflower seeds … I could eat those 24/7 with no issues whatsoever.

    • cincodm says:

      Hey Amy, it depends on how much you are taking. We were discussing this in the facebook group a bit ago. When you start something like lecithin you have to start very slow as it is an emulsifier and can speed up some processes that may be slow due to poor fat soluble vitamin status.

      I always like starting with food that contains the nutrients and then slowly ramp up supplemental doses if you plan on supplementing. Sometimes supplements come in doses that are way too high and it’s appropriate to take far less and slowly work up.

  2. Serotoni says:

    Hi! nice article! what suggest for overmethylated people ? (High serotonin, High Copper, Low histamine).


    • cincodm says:

      I suggest everyone begin paying attention to circadian rhythms, which you can find a number of articles on here with the search function. After you’ve been doing that for a couple of months, then you can begin to tease apart remaining symptoms. You have to adjust lifestyle to reflect how our physiology is supposed to operate in order to determine which effects are due to genetics and which are due to environment.

  3. Renae says:

    I found this so interesting that I went and bought the sunflower lecithin you recommended! Now I just want to ask about dosage…you say to start slow, so how slow? I’m assuming a lot less than the 1 tablespoon dosage they print on the label! I forgot you said to start slow and I feel like this supp is making my insomnia worse instead of better…perhaps a smaller dose would be the way to go!

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