Thursday, February 27, 2014

The human's guide to being human: The problem with gluten

Gluten is a component in our food that seems to make it's way in to the headlines every day.  What is gluten?  Should you eat gluten?  Is gluten really that bad?  How can someone eat gluten for years with no problem and then all of a sudden begin reacting to it?  These are all really good questions that deserve answers.  Unfortunately, people know little about what gluten is, even those that have pulled it from their diet.  In this blog we will take a look at gluten using the principles we have discussed in the "Human's Guide" series to help determine if gluten is really as bad for you as it's terrible reputation implies.

What is gluten and why is it problematic?

Gluten is a protein found in wheat that gives dough it's elastic qualities.  What most people don't know is that gluten is a catch-all term that refers to storage proteins found in wheat, barley, rye, and other grains that are called prolamins(1).  While not everyone reacts negatively to these storage proteins, they can often become problematic because humans cannot digest them.  Over time, this can cause people to suddenly begin reacting to gluten as well as other difficult to digest proteins such as the casein in milk or the globulins in legumes which are essentially their storage proteins.  This is why gluten sensitivity is likely a progressive issue and also why people with gluten tolerance issues tend to react to other problematic proteins.

This is not to say that some gluten containing foods can't be part of an otherwise healthy diet.  There are a couple of reasons that gluten seems to be causing issues in more people.  For one, the dosages we are exposed to day in and day out have increased dramatically over the last few decades.  Some of this is due to the fact that almost every meal we are exposed to contains gluten in some way.  Eating breakfast cereal or bagels in the morning, sandwiches and pretzels for lunch, and pasta for dinner are about as American as apple pie.

Another reason we are exposed to larger doses is because genetically modifying wheat causes it to make more proteins, including gluten.  A recent study found that people with irritable bowel syndrome who were given grain products made from an ancient form of wheat experienced an improvement in digestive symptoms while those who continued to eat modern grains did not(2).  Finally, with the rise of heavily processed foods and a sharp drop in fruit and vegetable consumption, the American diet is about as diverse as a Ku Klux Klan meeting.  These factors are all likely having a dramatic effect on our microbiome.

Protein digestion and gluten

Proteins are long strings of amino acids that are broken in to smaller peptides by our stomach acid and pepsin, a protein enzyme secreted by our stomach, as well as other protein enzymes in the small intestine.  In order for protein to be absorbed, it must be broken up in to it's constituent amino acids or peptide chains of no more than 4 amino acids.  Any protein that is not broken down in to small enough parts in the small intestine will make it to the large intestine where they are free to interact with the resident bacteria there.

Prolamins are long proteins that are high in the amino acid L-Proline.  What is interesting about this is that the human gut makes very little post-proline cleaving enzyme, an enzyme that helps break up larger proteins that contain L-Proline.  Since our guts do not make a lot of this enzyme, we have a difficult time breaking up proteins that contain high levels of L-Proline.  Since these long proteins are not broken down, we don't absorb them.  This is where they become problematic, if we don't absorb them they make their way through our digestive tract in tact.  When they make it to the large intestine, they can interact with bacteria there and wreak havoc on our microbiome.

In addition to reacting with the bacteria that make up our microbiome, gluten can interact with the intestinal wall which causes the release of a protein called zonulin.  In turn, zonulin causes areas between cells of the intestinal wall called tight junctions to dissolve, increasing the permeability of the intestine to the contents within it.  This allows the contents of your digestive tract to react with the immune system, 80% of which is located in the gut.  This causes you to begin reacting to larger proteins that are not meant to enter your bloodstream, as shown below.

The research of Dr. Alessio Fasano, the man who identified the protein zonulin as the cause of "leaky gut" and a major contributing factor to celiac disease and gluten sensitivity, notes that when gluten interacts with the intestinal wall of all people, it causes the release of zonulin(2).  In a healthy person, the tight junctions are resealed very quickly, in a person with celiac disease or gluten sensitivity, it takes much longer.  Dr. Fasano believes that gut dysbiosis, aka an altered gut microbiome, is a potential cause of this delayed sealing of the tight junctions.  There is indirect evidence that continually assaulting the microbiome with undigested proteins, particularly ones high in the amino acid L-Proline, may be able to trigger gut dysbiosis over time.  To illustrate this, let's take a look at just one of the thousands of species of bacteria that makes it's residence in your gut.

Candida Albicans: A day in the life of a commensal organism

Candida Albicans is a commensal organism, it lives in the human mouth and digestive tract and typically causes no problems to the human it benefits from.  However, Candida Albicans is able to convert back and forth between a yeast and a fungus depending on the environmental conditions it is in.  In it's yeast form, it is basically benign and may even provide some benefit to the host.  However, under certain environmental conditions, it changes from a yeast to a fungus where it can cause major problems and invade tissues.  In this way, what makes it's way through your digestive tract is critically important to the state of Candida Albicans because it affects the environmental conditions that it lives in, and thus affects the genes that are expressed.  But what causes Candida Albicans to morph from it's benign yeast form in to it's problematic fungal form?

Under alkaline conditions, such as those found toward the end of the large intestine, both the yeast and fungal forms of Candida Albicans contain a transport system for the amino acid L-Proline(3, 4).  L-Proline uptake induces the conversion of the yeast form of Candida Albicans in to the fungal form(5, 6).  Other amino acids do as well, including L-Glutamine, but L-Proline has the greatest effect.  In addition to free L-Proline, Candida Albicans is able to bind to the L-Proline found in larger proteins(7) that make their way to the colon undigested, which likely includes gluten.  Since Candida Albicans contains the enzyme L-Proline aminopeptidase, it is able to break L-Proline from these larger proteins(8) and induce fungal transformation.

Under more acidic conditions, such as those found at the beginning of the large intestine, Candida Albicans remains in it's yeast form as the change from yeast to fungus is blocked or reversed in acidic conditions(6).  However,  as a byproduct of amino acid fermentation, fungal Candida Albicans secretes ammonia which allows it to alkalinize the environment it is in(9).  This could allow fungal Candida Albicans to work it's way back up the digestive tract in to areas where it formerly couldn't convert in to it's fungal form provided enough amino acids and L-Proline are provided to promote alkalinization and fungal conversion.

A major factor of genetic expression that is determined by which form Candida Albicans is in is the gene for hyphal wall protein 1(HWP1).  HWP1 gene expression is very high in the fungal form of Candida Albicans but either not present or present in low amounts in the yeast form(10, 11).  HWP1 allows Candida Albicans to bind to the intestinal wall of it's host as well as tissues inside the body if it enters the bloodstream.  This could allow the fungal form of Candida Albicans to set up shop at the end of the large intestine while providing a continuous supply of undigested proteins high in the amino acid L-Proline from gluten could allow fungal Candida Albicans to alkalinize it's environment enough to work it's way back to formerly uninhabitable regions of the large intestine.  Ironically enough, fungal Candida Albicans has been implicated as a trigger for celiac disease as HWP1 has protein structures similar to the ones found in gluten that trigger an adaptive immune response(11).

Fungal Candida Albicans and gastrointestinal health

Fungal Candida Albicans can negatively impact digestive health in many ways.  In order to better understand how, we first have to take a look at what the beneficial bacteria are doing in your gut to promote gastrointestinal health.  There are thousands of different types of bacteria in your gut, but some of the best studied belong to the genus BifidobacteriumBifidobacteria ferment undigested carbohydrates such as soluble fiber and resistant starch in to short-chained fatty acids(SCFAs) such as butyric acid, acetic acid, and propionic acid.

These SCFAs have several important roles in intestinal health.  First, butyric acid is the preferred fuel for the cells of the digestive tract.  Butyric acid has been shown to improve peristaltic action by increasing contraction of the smooth muscle in the large intestine(12), but acetic acid is just as effective at a lower dose(13).  It is important to note that constipation, a common complaint of people with GI problems, is effectively a defect of intestinal peristalsis.

SCFAs, particularly butyric acid, have a direct effect on intestinal permeability.  Butyric acid increases the expression of tight junction proteins in intestinal cells whose tight junctions have been dissolved, re-sealing the intestinal wall and decreasing intestinal permeability(14).  SCFAs also indirectly reduce intestinal permeability through reducing inflammation in the digestive tract by promoting anti-inflammatory gene expression(15).  Increases in intestinal inflammation lead to an increase in systemic inflammation that increase intestinal permeability, allowing the contents of the intestine to react with the immune system.  When you get diarrhea, increased intestinal permeability fills the large intestine with water to flush it out.

Candida Albicans and acid/base reactions

The roles of the SCFAs are important to know because ammonia effectively eliminates them.  We all had the chance to experience, firsthand, the effects of combining acids and bases when we were in elementary school.  For those of you foggy on the details, the pseudo-volcano many of us made in science class out of baking soda and vinegar is a prime example of an acid/base reaction.  Baking soda, with a pH of 8.3, and vinegar, with a pH of 2.4, react and cause the rapid fizzing that resembles a volcanic eruption when placed in a partially enclosed cylinder with the top removed.  Could this same effect be one of the causes of the bloating many people with gluten sensitivity experience when exposed to the proteins in gluten?  Could it also be why beans, containing both hard to digest proteins as well as fiber, tend to bloat and cause gas?  It is interesting to note that vinegar is made from acetic acid, one of the SCFAs our beneficial bacteria make, and ammonia has a much higher pH of 11.0 than baking soda, which would cause a greater reaction than baking soda.

Bloating aside, there is experimental evidence that ammonia has a negative effect on intestinal health.  Cells of the rat colon cannot effectively metabolize SCFAs in the presence of ammonia when glucose levels are low, as would be the case toward the end of the large intestine(16).  In the absence of a healthy microbiome or the fermentable fibers that these types of bacteria use, ammonia levels can climb and ammonia can react with the cells of the intestinal wall.  By lowering the pH of the large intestine, SCFAs can help regulate the amount of ammonia being created as many of the amino acid fermenting bacteria that create ammonia, fungal Candida Albicans included, are inhibited by SCFAs and the acidic environment they create(17, 18, 19).


While this blog has focused on the interaction between gluten and Candida Albicans in the gut, the intent is not to target any specific commensal organism as the culprit.  Candida Albicans happens to be one of the few commensals we know a lot about because it has been studied at length.  There are thousands of different types of bacteria in your gut, and we have data on very few of them.  Any of the bacteria in your gut that can ferment amino acids are likely to have a negative effect on gut health if they overgrow simply because it is likely that they create ammonia.  Ammonia is made from 1 molecule of nitrogen and 3 molecules of hydrogen, and protein is the only macronutrient that contains nitrogen.

This is not to say that protein is the devil or that this process was always bad.  High levels of protein fermenting bacteria are associated with inflammation, which in turn is associated with insulin resistance.  While this is not necessarily a good thing now that food is plentiful, going in to the leaner months insulin resistant when food was scarce was likely a beneficial thing.  Consider it a way to activate the "thrifty" genotype.  Since both grains and legumes keep for much longer than fresh fruits and vegetables and are an acceptable nutrient containing food source, they may have been necessary for our survival in northern climates and the shifting food supply caused by weather before modern technology made most food available year round.  There is, however, a distinct difference between doing this for 4-5 months out of the year and doing it chronically over the course of decades.
Many people who undergo long term low carb diets notice an increase in their blood glucose despite not eating any carbohydrates.  It has been postulated that this is due to gluconeogenesis, the creation of glucose from protein, and something called physiological insulin resistance, a way that the body spares glucose for the brain.  This may not necessarily be something that is orchestrated at the level of the individual cell or even within the body at all.  The brain and gut are connected by the vagus nerve which is a conduit for communication between the bacteria in our gut and the brain.  Much of this phenomenon known as physiological insulin resistance may be orchestrated in the gut by the resident bacteria.

Reducing the amount of undigested protein that enters the large intestine is likely a good idea over the long term, but that doesn't mean that bread or pasta can't be part of a healthy diet.  To the contrary, in the face of a highly diverse diet, I believe that these foods can be enjoyed in moderation.  In addition, I believe that one can reverse gluten sensitivity under the right dietary conditions.  I am currently working on a program for this, and I don't believe that people with non-celiac gluten sensitivity need to spend years fixing the problem provided they are manipulating the proper variables.  We'll see how it goes.

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