Thursday, October 29, 2015

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

File:Choline metabolism-en.svg 

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...

Monday, October 12, 2015

The migrating motor complex: Housekeeping system for the digestive tract

Have you ever felt a rumble in your tummy when it's been a while since you've eaten anything?  Do you know what it means?  While most people think it's a signal that they need to eat, it's actually the migrating motor complex, the mode your digestive system goes in to when you are in a fasted state.  The purpose of the migrating motor complex isn't to inform you that you are hungry, that's what your appetite is for.

The migrating motor complex

The migrating motor complex is actually housekeeping mode for your digestive tract.  The basics of it are simple.  Throughout your digestive tract, particularly the stomach and duodenum, there are receptors that detect nutrients.  When these receptors no longer detect nutrients and pressure in the duodenum increases through light contractions of the smooth muscle, the migrating motor complex is initiated.  Serotonin builds up in the duodenum and causes secretion of the hormone motilin.  Motilin causes strong contractions starting in the stomach that work their way down the digestive tract to the end of the small intestine, called the ileum. If you're interested in the hard, dirty science of it, the schematic below should help:

These rhythmic contractions of the digestive tract occur during interdigestive periods to move undigestible material, leftover particles of food, and unwanted bacteria from the stomach and small intestine in to the colon where they can be eliminated in feces, a process known as peristalsis.  During this process, there is also an increase in enzymatic secretions that aid in cleansing the digestive tract by breaking down undigested food particles and killing bacteria.  It is interesting to note that people with small intestinal bacterial overgrowth(SIBO) have a defective migrating motor complex.  Unfortunately, this is a classic chicken or the egg scenario so we don't know if it's cause or effect, but it's likely both.

There are 4 phases in the migrating motor complex, phase 3 being the most important as it is the period of greatest motor and secretory activity.  When you feel that rumbling in your belly, those are phase 3 contractions of the stomach.  Phase 3 lasts between 5-15 minutes and occurs roughly every 90-120 minutes.  Since this is the migrating motor complex, and the end goal is to move contents of the digestive tract to the end for eventual elimination, phase 3 contractions do not all happen at the same time.  The contractions typically begin in the stomach and move progressively through the beginning(duodenum), middle(jejunum), and end(ilieum) of the small intestine.  Sometimes the phase 3 contractions can bypass the stomach and begin in the duodenum or jejunum, but the vast majority begin in the stomach.

Factors that affect the migrating motor complex

Multiple factors have an impact on the migrating motor complex.  The primary factor regulating it is the presence of food in the digestive tract.  Once food is consumed, phase 3 contractions cease no matter which part of the digestive tract they are happening in.  This is because the types of muscular contractions that occur during digestion are distinct from those of the migrating motor complex.  While the contractions of the migrating motor complex are meant to clean and move food out of the digestive tract, the contractions that occur during digestion are meant to mix and grind the food you eat, which occurs in a distinctly different fashion.

Another factor is stress.  The digestive tract contains its own, fully functioning nervous system called the enteric nervous system.  The enteric nervous system can function on its own without input from the central nervous system, but the central nervous system does interface with the enteric nervous system and imparts some control over it through the autonomic nervous system, your stress management headquarters.  Specifically, the vagus nerve and prevertebral ganglia interface with the enteric nervous system.  While this control is not necessary, it is certainly optimal as the vagus nerve controls acid secretion and motility of the stomach.  Specifically with regard to the migrating motor complex, stress delays phase 3 contractions in the stomach and likely impacts gastric acid and pepsin secretion.

The final factor we will discuss that impacts the migrating motor complex is sleep.  Sleep slows down the migrating motor complex.  This is unfortunate because the vast majority of people spend most, if not all, of their time fasting asleep. This means that, in most people, digestive housekeeping more like Animal House and less like Grandma's house.

Modern eating patterns are no good for a clean GI tract

If you think about it, the eating patterns of most people probably doesn't lend itself well to this entire housekeeping process, including those that are living a "healthy" lifestyle.  If you eat 5 times a day with the first meal being as soon as you wake up, exactly when do these interdigestive periods begin?  It takes approximately 2-6 hours for food to leave the stomach and an additional 3-5 hours for food to leave the small intestine.  Given the fact that each migrating motor complex takes, at minimum, 90 minutes to complete, you'll likely get no full cycles during the day.  This means you are leaving the entirety of the housekeeping process to the times when it is least active, at night.

In my opinion, 5 meals a day really serves no purpose.  For one, the thermic effect of food, the energy demanding process that would be impacted by what you eat, isn't even dictated by how often you eat, it's dictated by how much you eat.  Those same receptors in your stomach that detect nutrients use that information to determine how much digestion needs to take place, how many types you eat doesn't even factor in to the equation.  Even eating 3 times a day may be too much because there really isn't an interdigestive period during the day.  In certain circumstances it may be necessary to ingest smaller meals, particularly if you have poor digestion.  However, this may not be optimal and a better approach may be to ingest digestive enzymes with your food until your digestion gets back on track.

Probably the most effective way to get all you can out of this housekeeping process without drastically changing your lifestyle is to withhold ingesting anything with calories until at least 3 hours after you wake up.  Notice I didn't say eating, I said ingesting anything with calories.  You can drink coffee, just stop dumping butter or coconut oil in it.  Black coffee has a stimulative effect on peristalsis and may increase gastric secretions because caffeine blocks the breakdown of acetylcholine.  This would, in theory, improve the effectiveness of the migrating motor complex by strengthening contractions and enzymatic secretions.  To fully optimize the process, withhold eating anything at least 3 hours before you go to bed.

How can I tell if it's working?

A great way to see if your migrating motor complex is working is to pay attention to what your stomach is telling you.  That rumbling in your belly is a good thing.  If you aren't getting that rumbling, something isn't working properly.  There is really no way to know for sure, but, in my opinion this whole process is likely controlled by bacteria in your gut.  The synthesis and secretion of serotonin and acetylcholine, two neurotransmitters that are used heavily in the migrating motor complex, seem to be modified by the bacteria in your gut.  If this is the case, what you eat is probably as important as how often you eat for efficient housekeeping of the digestive tract, something we may cover in a future blog.