Many researchers hypothesize that, under the right conditions, the translocation of food proteins from the gut (facilitated by a compromised intestinal barrier) into the blood stream can contribute to the pathogenesis of MS in predisposed individuals.
Using this model, I demonstrate how that might happen.
The Intestinal Barrier and Intestinal Hyperpermeability
The intestinal mucosal barrier (also known as the "gut barrier") is made up of three physical components: a layer of mucus, a layer of epithelial cells, and a porous basement membrane. This barrier separates the contents of the gut (called the lumen) from the lamina propria, which is a layer of connective tissue that houses immune cells and capillaries.
The mucus layer offers a first physical line of defense against potential antigens in the lumen, preventing large particles and gut microbes from reaching the epithelial layer.
The epithelial layer offers a second line of defense. The epithelial cells are assembled in a row, bounds together by cell junctions that prevent the passage of large molecules while allowing the passage of very small molecules such as nutrients (e.g., amino acids, fatty acids, glucose) into the lamina propria.
Larger molecules (e.g., undigested proteins and bacteria) typically have a hard time getting past the mucus layer and the epithelial layer. When they do, they cause an immune reaction (i.e., immune cells attack them).
A compromised intestinal barrier (marked by a diminished mucus layer or relaxed cell junctions at the epithelial layer) therefore leads to chronic inflammation, which can contribute to the pathogenesis of MS.
Indeed, intestinal hyperpermeability is associated with a number of different chronic inflammatory diseases, such as Irritable Bowel Disorder (IBD), celiac disease, Irritable Bowel Syndrome, MS, rheumatoid arthritis, Type 1 diabetes, asthma, necrotizing enterocolitis, and autism spectrum disorder.
Things That Can Cause Intestinal Hyperpermeability
There are many ways that the intestinal lining may become compromised. Many of them boil down to these five categories:
- Infection; an infection by an external pathogen such as Vibrio cholerae or an overgrowth by a pathobiont (a usually harmless microbe that can cause problems when there's an overgrowth of it) such as Candida albicans can compromise the gut lining.
- Diet; gluten is known to disrupt the integrity of the gut lining in everyone (celiac patients, non-celiac individuals, human epithelial cells in vitro, and animals). Food-borne toxins may be a factor as well. Crops such as wheat, barley, oats, rye, and corn (and, to a lesser extent, rice, sorghum, and triticale) are prone to infection by fungi that produce a toxin called vomitoxin (lovely). Vomitoxin is known to induce a breakdown of the intestinal barrier. Diets high in fat have been shown to contribute to intestinal hyperpermeability as well.
- Lifestyle choices; Vitamin D has been shown to reinforce the intestinal barrier. Therefore, a Vitamin D deficiency (due to insufficient sun exposure) could result in less protection of the intestinal barrier (among many other things).
- Pharmaceuticals; NSAIDs such as aspirin, naproxen, and ibuprofen have long been known to damage the gut lining. Antibiotics, NSAIDs, and even medications such as Copaxone can hypothetically promote intestinal hyperpermeability by contributing to gut dysbiosis.
- Gut dysbiosis; the mucus layer of the intestinal barrier seems to depend on the presence of gut bacteria. An example is Bifidobacterium dentium, which has been shown to promote the production of mucus in the intestinal barrier.
Intestinal Hyperpermeability Can Lead to Food Sensitivities
The hypothesis that intestinal hyperpermeability can lead to food sensitivities is considered unproven, partly because:
- There isn't a consensus regarding what constitutes a food sensitivity
- There isn't a consensus regarding what biological processes are involved in food sensitivities
- There isn't a consensus regarding how to diagnose a food sensitivity
Let's dig in and try to get some clarity.
Characterizing Food Sensitivity
Unlike food intolerances (which generally have to do with the inability to digest a substance due to a lack of an appropriate enzyme) and food allergies (which involve IgE antibodies-driven immune activity that often quickly manifests into overt physiological symptoms), food sensitivities suffer from diagnostic unclarity.
Food sensitivities, which may be described as an abnormal physiological response to a food, often involve the immune system and are often driven by antibodies. A prime example of this is celiac disease, in which the body produces antibodies in response to the ingestion of gluten. Diagnosing celiac disease involves measuring the levels of particular IgA (Immunoglobulin A) and IgG (Immunoglobulin G) antibodies.
Evidence Supporting the Intestinal Hyperpermeability/Food Sensitivities Hypothesis
If we consider an elevated immune response against a food to be indicative of a food sensitivity, we can consider three pieces of circumstantial evidence that support the intestinal hyperpermeability/food sensitivities hypothesis:
- Intestinal hyperpermeability is associated with food sensitivity conditions such as celiac disease and non-celiac wheat sensitivity. There are both conditions that involve a known food antigen.
- Experimenters were able to induce a food sensitivity in mice by damaging their gut lining. The experimenters first infected the mice with Candida albicans. After confirming an increase in gut permeability, they fed the mice ovalbumin (the main protein in egg whites) over the course of 9 weeks. The mice developed marked sensitivities against ovalbumin.
(There is a question of whether or not Candida played a role in the results aside from damaging the gut lining, but the results of the experiment are certainly compelling.)
- It makes sense from a physiological standpoint.
The only cells capable of producing antibodies are B cells. Within the gut, B cells are present in the lamina propria, concentrated in the capillaries and in specialized regions called Peyer's patches.
In order for a B cell to produce an antibody against an antigen, it must come in contact with the antigen--either directly or by being presented a piece of the antigen by another immune cell.
A breakdown of the barrier increases the likelihood of both of those events occurring and therefore the likelihood of an antibody being produced for the antigen.
Due to ethical constraints, I'm not sure the scientific community will be able to accept that intestinal hyperpermeability (under the right conditions) does in fact lead to food sensitivities in humans, but the evidence that is available now seems strong enough to leave little doubt.
Food Sensitivity and Autoimmunity
Molecular mimicry and cross-reactivity pave the way to autoimmunity.
Molecular Mimicry and Cross-reactivity
At the molecular level, a part of a substance can be identical or very similar to a part of another substance. This principle is called "molecular mimicry."
Molecular mimicry can cause your immune cells to attack a substance other than the intended target.
This phenomenon is called "cross-reactivity" and is the reason why some people who are allergic to latex also have a problem with avocados.
Cross-reactivity is also "implicated in the pathogenesis of many of these autoimmune diseases including MS, spondyloarthropathies, Graves' disease, and diabetes mellitus" and may be why the prevalence of autoimmune disorders in non-celiac wheat (gluten) sensitivity individuals is higher than in the general population.
In MS, cross-reactivity can happen in at least two ways:
- Your body can produce antibodies that cross-react with other antigens.
When a naïve (uninitiated) B cell comes in contact with an antigen, it absorbs it and disassembles it into bits. It selects a bit (called an "epitope") that is meant to be representative of the antigen. Later, clones of that B cell will produce antibodies tailored to that epitope. Unfortunately, if the epitope happens to be molecularly similar to areas of your nerve tissues, the antibodies may bind to your nerve tissues and your immune system will attack your nerves.
- T cells, which take on various roles in the immune system, have antigen receptors on their surface called T cell receptors (TCRs). These receptors dictate what antigen the T cell is meant to respond to. Unfortunately, TCRs are much more forgiving than antibodies tend to be and will bind to a wider range of antigens. If a cytotoxic T cell that has been primed to destroy a food antigen binds to a neuron, it will attack the neuron.
If your immune system is dysregulated and you possess antibodies against a particular food antigen, consuming that food may trigger an acute immune response that may cause your immune cells to attack your nerve tissues (e.g., myelin).
Potential Food Antigens
Gluten and dairy have long been suspected of being triggers in MS. This is not a phenomenon that's unique to MS. Cow milk proteins seem to be a trigger in both Type 1 diabetes and celiac disease. And gluten is known to be the trigger in both celiac disease and gluten ataxia (which is remarkably similar to MS in several ways).
1. Gliadin (Gluten)
Gliadin May Be Autoantigenic
Gliadin, one of the two major classes of proteins in gluten, has been shown to "cross-react significantly with various neural antigens including asialoganglioside, synapsin, and myelin basic protein (MBP)" in "most patients with gluten sensitivity." In other words, gluten can cross-react with neuronal membranes, tissue in neurons, and a protein in myelin.
Gliadin has also been shown to cross-react with epitopes on a type of neuron called Purkinje cells in the brain. This type of cross-reactivity is a hallmark of both gluten ataxia and autism.
Additionally, gliadin can cross-react with glutamic acid decarboxylase-65, an enzyme that converts GABA (a neurotransmitter) to glutamate (another neurotransmitter), thereby contributing to glutamate excitotoxicity, a secondary issue in MS.
Gliadin May Cause Autoantigenicity of Other Substances
Gliadin is often tough to digest, particularly one peptide (fragment) referred to as the "33-mer." The 33-mer is very resistant to degradation by stomach acids.
Undigested gliadin peptides that pass the compromised intestinal barrier are cleaved by a type of enzyme called tissue transglutaminase (tTG), of which there are several isoforms (types).
From time to time, a phagocyte (a class of immune cells) may engulf the gliadin antigen just as it is being cleaved by tTG. When this happens, the phagocyte absorbs and breaks down both the gliadin antigen and the tTG attached to it. If the cell happens to select an epitope that belongs to the tTG enzyme instead of the gliadin peptide, your body can end up producing antibodies against tTG.
This is what appears to happen in celiac disease, which is marked by elevated levels of antibodies against tTG2. This is why consuming foods with "meat glue" (such as imitation crab meat, fish balls, and Chicken McNuggets) often causes problems for celiac patients--because celiac patients have problems not only with gliadin, but with tTG2 as well.
Gluten ataxia and MS are linked to tTG6. tTG6 antibodies have been found to be "significantly elevated" in MS (particularly PPMS and SPMS), and its expression (production) correlates with disease activity.
2. Dairy Proteins
Scientists have known for quite some time that there's a correlation between dairy consumption and MS. In more recent years, scientists have gone as far to say that "early consumption of cow’s milk may be a risk for the development of autoimmune diseases such as celiac disease, Crohn’s disease, Behçets disease, MS, mild rheumatoid arthritis in rabbits, and type 1 diabetes in humans."
Although there is speculation that a milk-borne bacterial agent might be to blame, dairy proteins might be a more likely culprit.
Casein, another milk protein, can cross-react with gliadin and has been shown to underlie the incidence of milk sensitivity in some celiac patients. In 2014, researchers studied blood samples from 400 donors of unknown health status and found a significant correlation between elevated levels of casein and butyrophilin antibodies and elevated levels of antibodies against MOG and MBP (constituents of myelin).
Putting It All Together
To summarize what we've demonstrated, here's what could happen:
- As a result of various factors (e.g., infection, diet, lifestyle choices, pharmaceuticals, and gut dysbiosis), your intestinal barrier becomes compromised
- More food antigens pass through the epithelial layer and elicit an immune response
- Due to dysregulated immune tolerance, your body produces antibodies against the food antigens
- Due to molecular mimicry, the antibodies attach themselves to nerve tissue in the central nervous system (brain, spinal cord), flagging them to the immune system for attack
- Cytotoxic immune cells attack the nerves
While we can prove that each of these steps can happen individually, we aren't able to conclusively prove that each step causes the next step to occur.
So What Should I Do?
Eliminating dairy and gluten from your diet for at least a month may be a good choice to see if it has a positive effect on your condition. So long as you're careful to avoid nutritional deficiencies, eliminating dairy and gluten is safe and relatively easily to do, thanks to today's ingredient labeling requirements and the fact that it seems like everyone has some kind of food sensitivity these days.
Immune cells don't live forever (in fact, effector B cells don't live very long at all), so the longer you go without coming in contact with a food antigen (e.g., gliadin, casein), the less immune activity you are likely to have against tissues that cross-react with it (e.g., myelin).
There is anecdotal support as well. There are many prominent individuals who purportedly "reversed their MS" largely by making dietary choices such as removing dairy and gluten, including Palmer Kippola and Terry Wahls.
On a personal note, my wife's postprandial (after a meal) GI symptoms (which had seemed to culminate into her neurological symptoms) disappeared very quickly after she gave up dairy, gluten, and a few other potential food antigens. Her neurological symptoms went away as well and she hasn't had another flare-up since. (You never know how things will go, but we're hopeful!)
What Medical Practitioners May Push Back On
Argument #1: There's no proof that a compromised gut lining is the cause of any issues in the context of MS; it may instead be the result of the underlying issue.
Rebuttal: As I've outlined, there's plenty of evidence that shows how a compromised gut lining could cause downstream issues. Even if there's no proof, it's certainly plausible.
And even if a compromised gut lining were a downstream issue as opposed to a causal issue, intestinal hyperpermeability is abnormal, can cause issues, and is linked to a number of GI and autoimmune disorders. There's every reason to believe that restoring the integrity of the intestinal barrier would be a good thing to do, regardless of whether or not it would help with MS symptoms or progression.
Argument #2: Plenty of people with intestinal hyperpermeability don't develop food sensitivities or autoimmunity, so that disproves your hypothesis.
Rebuttal: I don't argue that intestinal hyperpermeability alone is enough to result in food sensitivities or autoimmunity. As I mentioned in this article, dysregulated immune tolerance is needed. That can come from a Treg deficiency (like we also see in psoriasis) or from chronic activation of TLR4.
Argument #3: There's no proof that these issues are relevant in MS; the studies you cite are inapplicable because many of those studies were on other disorders, such as celiac disease.
Rebuttal: Of course there are differences diseases and between individual humans, but our biological processes are governed by the same principles at the cellular level.
That's why we are able to map out metabolic pathways in humans such as the Krebs Cycle. We are confident that this model of the Krebs Cycle applies to every human, and this model lets us predict and explain what happens as a result of an enzymatic deficiency that disrupts the cycle.
That's why the same FDA-approved MS treatments are given to patients irrespective of ethnicity, genetic mutations, geographical location, or biological sex, despite the fact that all of the pathogenesis and course of MS clearly are affected by these variables.
Another example: Activating CXCR3 receptors on epithelial cells induces the release of zonulin, which weakens the intestinal barrier. Although CXCR3 is upregulated in celiac patients and may partly explain the hypersensitivity to gluten in CD patients, this CXCR3/zonulin mechanism occurs in all humans and in animals, as demonstrated in in vitro and in vivo experiments. In this particular example, we're dealing with a difference of scale, not a difference of mechanism. Here's a video of Alessio Fasano (gastroentereologist at MassGen with 200+ published studies to his name) speaking about this: https://www.youtube.com/watch?v=te577-ssRr8&t=4m0s
The fact is that there are a lot of underlying commonalities (including genetic variations) that link MS with autoimmune disorders and with other neurological disorders, and if something is known to be a factor in a similar disorder, it's logical to consider the possibility that it's a factor in MS as well if there's a physiological basis for it.
When we say something has been "proven," that just means there haven't been sufficient studies to prove a hypothesis or a data point. MS is a complex disease. Some of the necessary data points don't exist simply because scientists haven't specifically looked for them in the context of MS.