Methylation and the folate cycle: You're on the wrong path(way)!

 

The picture above represents the methylation cycle and the pathways that help power it.  On the right side in grey you have a partial representation of the folate cycle while on the left side we have a mostly complete representation of choline metabolism.  Both of these processes intersect the methylation cycle at the same point, a critical point where homocysteine is recycled in to methionine.  High homocysteine levels are a bad scene as homocysteine is toxic, so having efficient conversion of homocysteine to methionine is important to prevent this scenario.

The folate cycle and choline metabolism balance each other out

Many people are aware of how the folate cycle impacts methylation, many are even aware of gene polymorphisms they have that negatively impact this point of the methylation cycle.  However, few realize that having a defect on one side is typically compensated for by the other side.  In other words, when the folate cycle doesn't run well, choline metabolism can pick up the slack with respect to the methylation cycle and convert homocysteine to methionine, and there are studies that show this(1, 2).  It's important to understand the opposite to be true as well, when choline metabolism doesn't work well the folate cycle can pick up the slack with regard to the methylation cycle.

The problem is that most people with polymorphisms related to the folate cycle focus on getting more folate or increasing methyl-B12 in the hopes of improving methylation.  This is a fool's errand as the primary polymorphism occurs in the MTHFR gene, which is the rate limiting step and occurs prior to the step in the cycle where homocysteine is recycled to methionine.  This isn't to say that you shouldn't get adequate B12 and folate, just that this pathway will always be inefficient at recycling homocysteine to methionine.  Why focus on it then?

Dietary choline vs. choline synthesis

Looking at the choline side of the equation we have 2 pathways to ensure adequate choline, dietary intake and synthesis from phosphatidylethanolamine(PE).  As you can see from the figure, in order for phosphatidylethanolamine to become phosphatidylcholine(PC) which can then become choline, you have to use SAM-e which then becomes homocysteine.  To be precise, you use 3 SAM-e so you make 3 homocysteine molecules.  This pathway is obviously not ideal if you wish to lower homocysteine levels as it also increases them, so adequate dietary intake of choline is the optimal pathway.  In someone with polymorphisms in the genes that negatively affect the folate cycle, choline intake is very important as a poorly functioning folate cycle increases choline requirements(1, 2).  Ingesting choline in the diet decreases homocysteine because it provides an eventual methyl group to convert homocysteine to methionine AND it prevents the generation of homocysteine through choline synthesis from phosphatidylethanolamine.

Choline is not considered an essential nutrient in the United States by definition because people who get adequate methionine can make it and people with adequate folate intake need less of it.  The problem with this definition is that inadequate choline increases the demand for both methionine and folate and it does not take into consideration polymorphisms, such as MTHFR, that increase choline requirement.  This caused the Institute of Medicine to reclassify choline as an essential nutrient. 

The recommended intake for choline is set at 425mg/day for women and 550mg/day for men, but people vary in their need for choline.  People with MTHFR polymorphisms as well as pregnant women need higher intakes of choline.  Foods that are high in choline include eggs, oysters, fish, poultry, beef liver, cruciferous vegetables and peanuts.  Supplementing choline in the form of soy or egg lectithin, choline bitartrate, or phosphatidylcholine is also effective and well tolerated.

Signs you need more choline

One of the easiest signs that you need more choline is that you are a human, living in the United States.  Only 10% of older children and adults get adequate choline in their diet and not all show overt clinical symptoms(3).  Fatty liver and muscle damage are common, but these symptoms tend to be subclinical in nature so most people would have no idea they are experiencing this until something significant happens.  I would suspect that most symptoms of choline deficiency would primarily center around functions that rely on methylation or the neurotransmitter acetylcholine.  Since most people who are currently trying to improve the function of the folate cycle are familiar with symptoms associated with poor methylation, I'll focus on the symptoms associated with low acetylcholine.

Acetylcholine is formed when the enzyme choline acetyltransferase turns acetyl CoA and choline in to acetylcholine and coenzyme A.



Many executive functions such as sleep, stress, digestion, GI motility, and memory all rely on sufficient acetylcholine.  In regard to sleep, acetylcholine is very important for REM sleep, the stage of sleep where dreams, and potentially memory consolidation, occur.  Within the autonomic nervous system, preganglionic nerves of both the sympathetic and parasympathetic branches use acetylcholine as well as postganglionic nerves of the parasympathetic branch.  Symptoms of acetylcholine deficiency in the autonomic nervous system would likely include anxiety and mood disorders.

During digestion, acetylcholine is responsible for the secretion of enzymes in the stomach as well as motility throughout the digestive tract.  Impairments in these functions can lead to IBS, SIBO, or poor nutrient status due to problems in absorption.  An interesting side note is that both caffeine and nicotine, which tend to increase GI motility, work by increasing acetylcholine levels or activating acetylcholine receptors.  Caffeine works by inhibiting the breakdown of acetylcholine and nicotine works as a substitute for acetylcholine by stimulating nicotinic acetylcholine receptors.  Linking digestion and the autonomic nervous system together, the primary neurotransmitter used by the vagus nerve is acetylcholine.  The vagus nerve is known as the conduit through which the brain and gut communicate with one another.

Finally, with regard to memory, acetylcholine is very important for the formation of new memories and deficiency can impair working memory(4).  This would most likely present as brain fog.  Further underscoring the importance of acetylcholine for memory, the class of drugs most used for Alzheimer's disease work by inhibiting the same enzyme that coffee inhibits and people with Alzheimer's disease produce less acetylcholine and have dysfunctional nicotinic acetylcholine receptors(5).

So, it's as simple as supplementing with choline, right?  If only it were that simple...