Hashimoto’s and Oral Tolerance (Part 1 of 2)

As many of you know, for the last several years I have focused solely on treating people with Hashimoto’s.

This has given me a tremendous opportunity to explore this health issue in considerable depth. I have had the honor and the privilege to work with over 1,000 people with Hashimoto’s and I’ve been privy to some cutting edge research from colleagues like Dr. Datis Kharrazian and Dr. Izabella Wentz.

Dr. Kharrazian first introduced me to the concept of oral tolerance and I’ve spent a good deal of time combing through the medical literature learning about it’s significance with regard to Hashimoto’s and reactions to foods.

In doing so, I recently had an epiphany and it has changed my way of thinking about how we can use diet to heal this disease.

In this post, I’m going to go deep into what I have learned about oral tolerance and it’s relationship to Hashimoto’s, autoimmunity and the Autoimmune Paleo Diet.

You Can’t Get Better Without Addressing Diet

One thing I have learned is that diet is the foundation of success. And the reason this is true, in my opinion, is that the digestive tract is ground zero for autoimmunity.

An estimated 70% of the immune system is found there, and a breakdown of the gut and the intestinal lining leads to the systemic inflammation that is at the root of diseases like Hashimoto’s.

Ground Zero for Autoimmunity is the Intestines

According to Dr. Alessio Fasano, MD, an expert on the origins of autoimmunity, the cause of this disease in the intestines.


In a paper published in the Clinical Review of Allergy Immunology February 2012 , he noted that,

“Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens.

Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur.”

What that means in plain English is that the breakdown of the barrier of the intestines is the pathway to autoimmune disease.

Not The Whole Story

This is by no means the whole story. Yes, the breakdown of the intestinal lining is a causative factor for the development of autoimmune disease, however, it’s just the gateway.

This is kind of like getting a view of the door, but there is an entire landscape of immune reactions that go on beyond that door.

And what lies beyond the doorway is what we are going to explore here today.

Autoimmunity is the Loss of Self Tolerance

What’s happing with autoimmunity? Our immune system has lost the ability to differentiate between our own cells and foreign invaders, like bacteria, viruses and other pathogens.

And this confusion leads to our immune system attacking our body’s own proteins. This is caused by our immune systems losing the ability to have tolerance to our own tissue (made of these proteins).

The entire digestive tract is made up of multiple little ecosystems and these ecosystems are always battling with this problem of tolerance.

Because the gut is, essentially, one long open tube and lots of pathogens in the form of bacteria, viruses, fungi and parasites pass though there along with proteins that we need to ingest and get nourishment from.

An important part of this process of the ebb and flow of tolerance is something called “oral tolerance”.

Oral Tolerance: The Holy Grail of Autoimmunity?

Oral tolerance is defined as your immune system NOT REACTING locally and systemically to antigens such as food proteins.

In other words, oral tolerance is when you eat a certain protein and you become tolerant to that protein.

We can think about this in terms of our own evolution. If you are eating something (a protein) all the time, it would be a really good thing for you to develop a tolerance to it and not attack it.

If we’re only eating certain kinds of foods, we‘d be more likely to survive if we could build tolerance to them.

Proteins are the things we are most often exposed to. (They’re the building blocks of life, after all.)

And it turns out that tolerance to ingested proteins is also really important for the barrier function of the intestines i.e. to prevent leaky gut.

As we saw above, when this tolerance breaks down, chronic diseases follow; like celiac, Crohn’s, ulcerative colitis (these all occur locally in the intestines) and other systemic autoimmune disease like Multiple Sclerosis and even Hashimoto’s.

In other words, oral tolerance is a kind of dimmer switch, it turns down the attack. Both in the intestines and in the rest of the body.

When you have oral tolerance, your immune system doesn’t attack as aggressively.

When you lose oral tolerance you wind up with things like celiac disease (which is an autoimmune disease – not just a food intolerance).

How Does Oral Tolerance Work?

We don’t fully understand this, yet.

However, what we do know is that oral tolerance works by deactivating T and B cells that target our tissues – either by clearing them out and getting rid of them or by making them not respond to proteins anymore with something know as “anergy”.

Anergy is the lack of a normal immune response to a particular antigen or allergen.

Oral tolerance also works by Tregs directly suppressing these cells.

Tregs is another name for regulatory T cells (also called suppressor T cells). They are T cells which modulate the immune system, maintain tolerance to self-antigens, and discourage the development of autoimmune disease.

Can We Improve Oral Tolerance?

Of course, with autoimmune disease this may be a really important thing to achieve, if possible.

The question is this: If you can establish or re-establish or at the very least improve oral tolerance, can you remove or at least diminish the autoimmune attack?

Some researchers believe the answer is “yes”. There is some evidence that this may be an achievable goal.

If So, What Should We Improve Tolerance For?

That’s a very, very important question. Because this is potentially a dangerous game. By no means is this a easy, risk free process.

For example, should we attempt to establish oral tolerance to things like gluten and dairy? (Dietary proteins with tremendous destructive potential.)

In my opinion, the answer is a resounding NO!

They have been implicated in the destruction of brain tissue such as cerebellar tissue and myelin. (I’d like to keep my brain for as long as possible, wouldn’t you?)

So what does that leave us with?

A lot, actually. (More on this in Part 2 of this post).

But before we attempt to answer that, another thing the research has shown us is that simply establishing tolerance alone is not enough.

We must also do other things like reduce inflammation and strengthen the regulatory part of the immune system and work to calm and/or eliminate stress, restore integrity and balance to the ecosystem of the gut, etc. while we do this to achieve the best results.

So first, let’s look at the big picture.

What are the steps to first calming the immune system and then, secondly, trying to improve oral tolerance?

Steps for Influencing and Improving Oral Tolerance

First off, if you’re looking for a quick and easy solution, click away. This isn’t quick and it isn’t easy.

This is a long term project that may take several months and it may be riddled with unexpected outcomes (welcome to the immune system).

That being said, it can also yield profoundly positive long term results.

Step 1: The Elimination Diet Also Known as Autoimmune Paleo or Lectin Avoidance Diet.

If you are just starting out this is the place to begin.

The Autoimmune Paleo/Lectin Avoidance Diet removes the following foods:

Grains, nuts, seeds, legumes, nightshades, gluten, dairy, soy and eggs.

I’m not going to spend time on the how or the why of this diet in this post, but this is a very effective approach for reducing systemic inflammation and for calming the immune system.

In addition, in many cases with Hashimoto’s this will yield improvements in virtually all important thyroid markers including antibody levels, TSH, etc.

And it often results in a (sometimes dramatic) improvement in weight, brain fog, mood and energy.

With my patients, I also assess all the other systems of the body and when it is called for we work on healing the gut (almost always called for), detoxifying the liver, healing the adrenals and reducing inflammation in the brain while we are on this diet.

This is also beyond the scope of this particular post, but suffice it to say that this is a systemic, multi-organ problem and we need to heal every part of the body that is impacted if we hope to get this into remission.

Also, the fact is that being on this diet provides a tremendous opportunity to aggressively reduce inflammation and to clean up the liver, heal the gut and calm compounding factors.

Clinical Pearl: One thing I have observed with some people who tried the Autoimmune Paleo Diet (myself included) is that it can actually increase your sensitivity to foods that you are sensitive to.

A food that you had a reaction to in the past (like gluten) will often cause a much more severe reaction once you have eliminated it for a prolonged period of time.

And in some cases, the elimination can increase sensitivity to foods across the board. (And I have observed it seems to increase not decrease with time. Meaning the longer some people are on the strict elimination diet, the more sensitive they become.)

One theory is that what may be happening here is that the elimination of these antigens can lead to a decrease in oral tolerance.

This makes logical sense because oral tolerance requires exposure to the antigens ( in this case, dietary proteins).

Eliminating Foods Can Increase Food Reactions

And there is some evidence of this in the medical literature. Some researchers claim that the elimination diet is a potential cause of anaphylaxis or a severe and life threatening allergic reaction.

And many researchers and health professionals are now questioning the wisdom of NOT exposing children to things like peanuts in early childhood because the LACK of exposure can lead to a massive immune response when they do get exposed.

The question is, why?

If this is the case, what is the mechanism that could lead to the decline of oral tolerance?

I think the simple answer is that elimination of multiple immune stimulating antigens changes the entire landscape of your immune system. It has a major impact.

And while some of this is really good and, arguably, absolutely necessary, (especially in circumstances like autoimmunity) it may have some unintended consequences.

This is also a great illustration of the complexity of the immune system. It has multiple parts that move in multiple directions, all the time. And overly simplistic linear thinking doesn’t work when trying to understand and balance the immune system.

Increasing Food Sensitivity Is Very Stressful

Another important observation about this process is that having to worry about food all the time and having an increasingly smaller and more restricted diet is very stressful. It makes it difficult (if not impossible) to go out with friends and relatives. It can create anxiety over what to eat and it can make you feel further alienated and frustrated.

And stress is a really big deal for people suffering from autoimmune diseases like Hashimoto’s. The body is already under a great deal of physiological stress, to add further daily stresses regarding what to eat and where to find the right food can be really counter-productive to the process of healing.

So, if we can tweak this process to make it less stressful, than that is a very valuable innovation.

Step 2: Reintroduction Phase

Once you have done the elimination phase of the Autoimmune Paleo diet (usually for 30 to 60 days), the next phase involves reintroducing foods, one food at a time to see if you react to them.

In some cases, people react to an awful lot of stuff, precisely because they have been so good at eliminating these foods and have accomplished some really good things with regard to calming their immune systems.

My understanding of this phase of the Autoimmune Paleo approach is that this is essentially a test to see what you can and can not eat.

Proponents of the Autoimmune Paleo Approach rationalize this increase in sensitivity by saying, essentially, this is part of the healing process. And they assert that once you heal your gut you’ll have fewer sensitivities.

But this isn’t always true, there are people who have spent several years healing their guts and still find that they are sensitive to a number of foods.

Obviously, everyone is a little different and some people do better than others. And some people find they can re-introduce all sorts of things, while others can introduce just a few and still others find their diets becoming more and more restrictive.

If you’re one of these people, this process can be really demoralizing because here you have worked your butt off to be super compliant and follow the plan and the end result is that your diet consists of fewer and fewer foods.

It’s the living embodiment of the expression, “No good deed goes unpunished.”

 “Re-Establishment of Oral Tolerance” Phase

What I have come to see is that instead of just eliminating and seeing what happens during re-introduction, what we have is an amazing opportunity.

And that is to work to re-establish or improve oral tolerance and create a much more hospitable immune environment.

How do we do that?

Great question! (And one that needs a good deal more experimentation and exploration than this one post can provide).

I’m not going to pretend to have all the answers on this, but here is what the research suggests.

In autoimmune disease research, the goal with oral tolerance seems to be to suppress the Th1/Th17 response (for most autoimmune diseases).

There are two ways that researchers have tried to do this.


The first is by giving a high dose of a protein once.  (This, obviously, is the heavy handed approach.) From an immune system standpoint, when it works this can result in a anergy or complete shutdown of both TH-1 and TH-2 responses.

Problem is that it doesn’t always work and obviously with autoimmunity the risk here is that you can cause a massive flare ups and discomfort.

The second approach is to take the protein at a lower dosage multiple times, which has been found to increase Tregs.

The multiple dose approach is gentler and from an immune standpoint, a lot better suited for autoimmune disease.

But You Can’t Just Re-Introduce Foods

Here’s the real difference in approach. You shouldn’t think of this phase as simply a testing phase.

It could be much more than that.

However, before you get all excited, understand that we are wading into uncharted waters and if we are going to challenge the immune system, there is bound to be some reactions.

And not all of them will be good.

In addition, maybe it’s time to view reactions differently. Maybe not every reaction is just simply “bad”.

And maybe total elimination of reactions isn’t totally “good”.

It may be a bit more nuanced than that.

That being said, there are two things to consider during this process:

1. What helps induce or improve oral tolerance? (This would include supplements, life style changes, etc.)

2. Which proteins do you want to create oral tolerance for? (This would include the approach to diet and reactions)

Both are important because we want to do everything we can to make this a successful experiment.

Actually, there is also a third thing to consider and that is, what can we do to minimize the discomfort and immune system flare ups during this process?

(I don’t know about you, but I prefer to suffer as little as possible.)

Mechanisms of Oral Tolerance

Before we look at what to do to improve oral tolerance, let’s take a look at some of the mechanisms for establishing and improving it.

IL-10 and Oral Tolerance: IL-10 is anti-inflammatory cytokine because it decreases various immune cells such as Th1 AND Th2 cells. It also inhibits NF kappa beta, which is important in destructive inflammation. It inhibits COX 2 and mast cells and it decreases insulin and leptin resistance. IL-10 is something we want to increase.

IL-12 and Oral Tolerance: IL-12 is part of the TH-1 family of cytokines and it can block oral tolerance in TH-1 conditions. It is responsible for helping cytotoxic lymphocytes, natural killer cells mature and it also supplies growth factor to help certain cells grow into the killers that they are.

IL-12 is also involved in turning on genes that result in attacks on specific organs and has been implicated as an important player in Hashimoto’s. IL-12 is something we want to reduce.

Tregs and Oral ToleranceTregs comprise ∼5%–10% of  T helper cells.

There are two types of Tregs: ‘induced’ (iTregs) and ‘natural’ (nTregs).  Both types are anti-inflammatory.   Induced means that they are created outside the thymus.  (There are 2 kinds of induced Tregs: (Th3 and Tr1). Natural means that they are part of the cells naturally produced in our thymus gland.

Tregs calm and suppress  Th1, Th2, Th17 cells and their cytokines, as well as many other immune cells and proteins such as, basophils, eosinophils, mast cells, and IgE and they also influence migration of inflammatory cells to tissues.

Tregs inhibit immune activation by direct cell to cell contact.  This means that they are directly anti-inflammatory.

Tregs need to be ‘activated’ in order to have their suppressor functions. Exposure to a dietary protein or an antigen is one of the ways that they get activated. Obviously, increasing Tregs  in a balanced way is a good idea with autoimmunity.

But, as with all things, if you do this too aggressively, there is the risk of becoming less able to defend against some infections. And unfortunately, one of those infections is a viral infection like herpes and Epstein Barr. (You can read more about the herpes/Hashimoto’s connection in this post.)

Mucous in the Intestines and Oral Toleranceresearchers have found that mucous plays an important role in maintaing the barrier of the gut and in modulating homeostasis (or balance) in the gut. Having a healthy amount of mucous in the gut is also a good idea.

Dendritic Cells and Oral ToleranceDendritic cells (DCs) are antigen-presenting cells(also known as accessory cells) of the immune system of mammals. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

Dendritic cells are important for immune tolerance because they can adapt to proteins or enhance the attack on them. At low levels these proteins help dendritic cells to adapt, but if proteins become excessive and aren’t cleared this can result in dendritic cells attacking and consuming the protein (and in some cases our own tissue). With dendritic cells we want to encourage as much variety as we can and make sure that intestinal transit and protein clearance is functioning well.

cAMP and TolerancecAMP is a signaling molecule that relays messages to T cells to not respond and proliferate to a protein. This, essentially, trains the immune cells to not respond. Increasing cAMP may be beneficial.

Intestinal Health and ToleranceA healthy ecosystem in your gut, with good blood flow, motility and transit time and healthy amounts of enzymes, bile and stomach acid are all important for improving oral tolerance. A healthy gut ecosystem is extremely important.

Commensal Bacteria and ToleranceOral tolerance is dependent on good bacteria in the gut. The more we learn about intestinal bacteria, the more valuable they become and the more irresponsible excessive antibiotic treatment becomes. Gut bacteria should be treated like an endangered species and be tended to and watched over carefully.

High protein diets and Oral Tolerance: This was a very interesting finding in the research. Diets that are lower in protein reduced both TH-1 and Th-2 and were effective in helping promote oral tolerance. Reducing dietary protein may help to reduce sensitivity.

Things that Cause Declines in Oral Tolerance: There are a number of things that may lead to declines in oral tolerance. Obviously, these are things we want to avoid:

  • Alcohol : Sorry, booze fans. Alcohol has been shown to reduce intestinal mucosa and to disrupt immune regulation in the gut resulting in a decline in oral tolerance.
  • Appendectomy: Recent research has shown that the appendix is a repository for good bacteria. So, it comes as no surprise that removing it can negatively impact oral tolerance.
  • Citrus pectin :Pectin occurs naturally in the cell walls of most plants and especially concentrated in the peel and pulp of citrus fruits (lemons, limes, oranges, and grapefruits), plums, and apples.Recently, scientists have been able to modify and  break down pectin’s long, branched chains of polysaccharides into shorter, unbranched lengths of soluble fiber molecules that dissolve easily in water.The result, modified citrus pectin(MCP), is a substance that is rich in galactose residues, which are easily processed by the digestive system and absorbed into the bloodstream. It has shown promise in some cancer treatments. It has also been found to inhibit oral tolerance to certain types of proteins.Note: A potential dark side of increasing oral tolerance is that it may also make your immune system more tolerable to cancer cells. Obviously, another reason why balance is critically important.
  • H Pylori : Heliobactor pylori is a bacteria that can cause declines in stomach acid and can lead to ulcers and GERD.  It has also been linked to lower oral tolerance.
  •  Medium Chain Triglycerides: Made popular by the Bulletproof Coffee craze, these “healthy fats” were found to increase sensitization and lead to anaphlaxis by stimulating absorption into Peyer’s patches and by stimulating TH-2.( There are always physiological consequences to doing things.) This may be one of the reasons the Basic Bullet Proof Diet advocates lower levels of protein.
  • Retinoic acid: Used to treat acne, this metabolite of Vitamin A, was found in one research study to induce inflammation with IL-15. Interesting because Vitamin A has been found to increase oral tolerance.
  • Skin sensitization: This was also interesting. In mice models, using skin sensitization to try to create tolerance actually had the opposite affect on oral tolerance.

    Bottom Line:

    In summary, you can see that many factors contribute to the development and maintenance of oral tolerance. And that it is critically important for dampening immune reactions.

    And the loss of loss or decline of tolerance may be an important factor in autoimmunity and in sensitivity reactions to dietary proteins.

    But, as with everything, carefully balancing oral tolerance is critically important when dealing with autoimmune disease and reactions to dietary proteins.

    In part 2 of this series, we’ll take a look at specific herbs, supplements, dietary and lifestyle approaches for improving and maintaining healthy oral tolerance.

Let’s talk! Schedule an appointment with me to discuss these and other health issues.  Click Here




http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578149/ Mechanisms of oral tolerance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376463/ Boosting IL-10

http://science.sciencemag.org/content/342/6157/447.abstract Mucous and oral tolerance

http://www.hindawi.com/journals/jir/2013/972865/ Dendritic cells and oral tolerance

http://www.sciencedirect.com/science/article/pii/S0008874996902749 cAmp and Tolerance


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27123/ Dendritic cells induce anergy in autoimmunity

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857757/ Model of Oral Tolerance: Suppress TH1 and TH-17, but not TH-2

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076704/ Keys to success

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http://www.nature.com/mi/journal/v5/n3/full/mi20124a.html Oral tolerance to food protein

http://www.nature.com/mi/journal/v2/n1/full/mi200875a.html Celiac disease as an example of the destructive potential of loss of oral tolerance.

http://www.hindawi.com/journals/ad/2014/437231/ Link between environmental factors and auotimmunity

https://www.drmcdougall.com/misc/2009nl/jan/ms.htm MS and dietary protein

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http://circ.ahajournals.org/content/129/Suppl_1/AP354 Lectin Avoidance study

http://www.nature.com/nri/journal/v9/n5/full/nri2515.html Microbiata shapes intestinal immune responses

http://cshperspectives.cshlp.org/content/4/6/a006957.full T cell tolerance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1628850/ Anaphlaxis during elimination diet

http://www.ncbi.nlm.nih.gov/pubmed/21333554 Intestinal tolerance requirements

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376463/ Boosting Treg function (IL-10)

http://www.ncbi.nlm.nih.gov/pubmed/15681753 IL-10 Creates Tolerance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222333/ Having Lots of an Allergic Protein will create tolerance

http://www.ncbi.nlm.nih.gov/pubmed/12026189 Low Protein diet induces tolerance, boosts IL-4

http://www.ncbi.nlm.nih.gov/pubmed/12887157 Low protein reduces Th-1 cytokines.

http://naglerlab.bsd.uchicago.edu/documents/Caoetal2014.pdf Role of commensal bacteria in oral tolerance

http://www.ncbi.nlm.nih.gov/pubmed/22339388 Skin Sensitization and oral tolerance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563838/?report=classic Medium Chain Triglycerides and tolerance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC187370/ H. Pylori’s impact on oral tolerance

http://www.ncbi.nlm.nih.gov/pubmed/17034584 Alcohol and oral tolerance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103798/ Apendectomy and oral tolerance

http://www.ncbi.nlm.nih.gov/pubmed/9921278 Palimate and oral tolerance

http://www.ncbi.nlm.nih.gov/pubmed/21307853 Retinoic acid and oral tolerance

About the Author Marc Ryan

So now, not only is it my profession, it’s my passion, and it’s personal. I’ve been joking with people lately saying it’s a blessing and a curse. A blessing because I really get it, and a curse because I really got it! ?

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Leave a Comment:

Mary Lyon says

Thank you Marc!
This is very detailed and interesting.
I was wondering whether it might be a case of a very very slow and almost imperceptible re-introduction of beneficial foods being persisted with until tolerated?

For example I seem to be able to tolerate small amounts of dairy eg a little organic milk in a very occasional cup of fresh ground organic coffee….whereas something with sugar in causes me to blow up and i’m full of gas!!!!!!!!

    Marc Ryan says

    Hi Mary,
    I think when considering re-introduction you should always forst consider the destructive potential of what you want to re-introduce. Some foods just shouldn’t be re-introduced in my opinion (like gluten and aspartame, for example). And these foods may not be the same for everyone. There’s some introspection and some trial and error that must be done.

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