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Understanding Oral Tolerance in the context of Functional Medicine

Updated: May 21, 2022

by Dr. Mitchell Rasmussen, DC, CFMP, FRC-ms

50k foot view– In order for me to be healthy, when I eat, my immune system must tolerate the substances introduced into my GI mucosal tissue. I must be able to adequately digest, absorb, assimilate, recirculate, and excrete what I eat.

At the same time, my GI immune system must also respond swiftly, adequately, and resolutely to anything that is disease-causing.

>> It is an ACTIVE regulatory immune response; not passive. <<

Oral tolerance can be summed up in 4 words: “Immune Inclusion”, and “Immune Exclusion”.

oral tolerance functional medicine view

The GI Immune System

The surface area of the intestinal epithelium is huge. In the small intestine alone, we are looking at roughly the surface area of a tennis court (or maybe half a badminton court)!

Although surface area heavy, this tissue is merely a single layer of cells. And the largest collection of lymphoid tissue in the body is right next to it. The outside world is separated from our lymphatic system by a single layer of tissue.

The GI immune system needs to somehow manage all this area. It needs to be able to distinguish ‘self and non-self’, while coexisting with trillions of bugs.

When this system is working well, the GI tract remains tolerant to dietary antigens, while having the ability to defend effectively against pathogenic material.

The research calls this balance between tolerance and defense “controlled/physiological inflammation”.

When working, the tolerance generated in the GI tract will translate to a more generalized immune system tolerance. Therefore, we MUST address the gut inflammatory triggers if we hope to keep autoimmune relapses at bay.

Enter Food Sensitivities.

What Are Food Sensitivities? Are they inflammatory?

When we lose oral tolerance, we develop food sensitivities. Persistence of food sensitivities leads to chronic immune system burden.

This becomes another source of inflammation. Pathological.


It becomes systemic inflammation and will ALWAYS eventually lead to the brain. Brain fog, headache, fatigue, anxiety, depression, body aches. Or some combination, probably.

Let’s talk a bit about the process.

Dendritic Cells (DCs) – These cells are pretty unique; and are very much a bridge between the innate and adaptive arms of the immune response. They act quickly and they also speak with the slower, more elaborate immune responses, helping us by their orchestration of these events.

DCs are critical for the adaptive immune response.

They help us defend against invading pathogenic organisms and they also influence the behavior of our immune system known as ‘tolerance’. Tolerance of tissue is necessary to be able to integrate ingested food into our cells, to not develop autoimmune disease, and for our bodies to not over-react to non-harmful viruses/bacteria/etc. that we need as part of a healthy human eco-system.

dendritic cells in oral tolerance food sensitivities

DCs are immune cells with long projections. In the Immunology world, we think of DCs as “Professional Antigen Presenting Cells”. They are specialized for this function; and serve other functions, albeit less adeptly.

DCs are immune system sentinel cells, situated throughout our tissues. They stay positioned in some areas (such as the lamina propria of our GI tract, where 70% of our immune system hangs out) and they also circulate in the blood to be rapidly deployed to areas of immune insult. They “look for” potential problems and are constantly reaching out and grabbing something to analyze.

Essentially – DCs are always sampling conditions around them. They collect potentially antigenic material (a fragment of debris from either self-tissue, infectious agent, or food) and bring it to nearby lymph nodes for presentation to T and B cells there.

Interestingly, inflammation is a big controller of DC movement. More inflammation allows DCs to move more. When DCs are more mobile in the tissue, they are more likely to grab a piece of our own tissue (self-tissue) and present it to a nearby T or B cell in a lymph node. This is a key piece in the development of autoimmune disease. And this is a key driver behind the rapid increase in autoimmunity in our country.

Speaking specifically about the immune system in the GI tract – DCs present food fragments to T and B cells in the tissue underlying the epithelia of the gut. In the absence of co-stimulation, these DCs promote tolerance to the food fragments.

When dendritic cells sample food contents and are not co-stimulated by another immune signal, there is a promotion of tolerance to the tissue flowing through. No big deal.

Diving Into Digestion...

Ideally, food (and the microbes that came with it) has been properly chopped up (digested) in the acid bath that is our stomach. We chewed our food and were able to utilize digestive functions from salivary and pancreatic enzyme release.

Microbes primarily reside in the colon (far from the small intestine) because we are pooping every day.

We aren’t chronically stressed, so our Vagal Nerve tone is proper, and because of this, we have good down-going intestinal motility.

>> All these factors create a small intestinal environment ready to tolerate what we eat.


This means, under ‘healthy’ gut conditions, your immune system can recognize this food as non-harmful and will not respond with any further aggressive immune reactions. The T cells will become unresponsive and undergo Anergy and eventual controlled and non-inflammatory death (apoptosis).

Your system will tolerate that food protein.

The digestive system at work in functional medicine

Food Variety and Oral Tolerance

Let's Talk About “Co-stimulation”

Co-stimulation is a signal capable of eliciting a further immune response. It is not “all bad”. We need it when there’s pathogen burden. We don’t want so much of it when we are having a food sensitivity reaction or during an autoimmune disease flare.

Co-stimulation can happen because the food fragment was too big due to poor digestive function (i.e. low hydrochloric acid, impaired pancreatic/salivary enzyme production) or because the fragment sampled here was pathogenic.

Maybe you have Small Intestinal Bacterial Overgrowth, so your DCs keep grabbing nice little samples of the critters meant to be in the colon. That is certainly enough to lead to co-stimulation.

You might say if the food is still recognized as ‘food’, there will be a higher likelihood of the immune system becoming interested in it. This becomes an immune food response that is destructive, not tolerogenic.

Persistent co-stimulation leads to persistent inflammation. These inflamed GI cells will make cytokines that promote Th2 dominance after a while.

This may yield diminished ability to deal with further pathogen burden over time. And it certainly won’t fix your ongoing GI inflammation situation.

Th2 dominance will make it more difficult for you to deal with your bacterial biofilms (up to 80% of all infections are associated with them!), will make chronic dysbiosis a sure thing, and will yield more tissue debris which is itself inflammatory. And you find yourself neck up in self-reinforcing loop mechanisms of inflammation.

Leaky Gut Functional medicine approach Denver

Keep in mind - It is necessary for our immune system to activate in some way every time we eat. This is vulnerability; we are taking the outside world into the inside-of-us world. And the tissue within the GI tract isn’t that ‘strong’ on its own. SO – our immune system is always checking in on what is going into us.

Oral tolerance is at the center of our health. Establishing it is a must.
Comprehensive Elimination Diet Guide

The Elimination/Provocation Diet is where we start. We need to get immune stimulating foods out; and give our GI tissue a chance to heal. The moment we stop eating things such as:






is the moment we at least stop the unnecessary burdens of inflammation through this tennis court sized absorptive surface protecting us from the bugs of the world.

>> The Elimination Diet gives us a start. A way to gain a few steps. <<

The elimination phase is meant to give a break to our immune system.

The elimination phase will lower GI inflammation. When food is added back strategically, we can immediately (3-5 days) understand how each type of food impacts our system.

Developing an understanding of which foods work for you now and which foods don’t is certainly a great start but often not the only piece of the puzzle.

These foods will change as you change. As your immune system calms down, as your tissue heals, as you gain the ability to better assimilate what it is you’re eating, you will be able to eat more foods with less food reactions.


As a note: There are other prescriptive eating plans that can get even more gut gentle, such as the GAPs diet, a low FODMAP diet, 2 weeks of the Physician’s Elemental Diet, or the Autoimmune Protocol. There IS a perfect eating plan for everyone. And it will change over time. Feeling Stuck? Schedule a Consult to discuss Individual Functional Medicine Consultation at The Facility.


Your health will come back.

To what degree?

For some – 100% improvement. For others, it is more modest. And when it is more modest; this is when we really get digging into your physiology.

Often, with Functional Testing, we will find a concurrent gadolinium toxicity or mycotoxin illness. We will find a reactivated viral infection or a severe manganese deficiency.

>> There are always going to be “other things”, and never do we find a single solution to your complex problem set. <<


What we want to make understood is this:

Often, eating in a “system-friendly” way is not the actual treatment; but without eating in that way, no other type of treatment would make a dent.

It is fundamental. So goes oral tolerance goes your health.

There is too much surface area there for it not to affect the body. That makes sense now.

What are our takeaways?

  • Oral tolerance is an active immune response.

  • We eat and that food becomes us because of our oral tolerance.

  • The GI tract has a ton of surface area and is where most of our immune system hangs out and operates.

  • The process of oral tolerance involves numerous immune system mechanisms and signaling molecules.

  • Dendritic Cells sample fragments of food or critter in the intestinal mucosa and present these fragments to effector molecules of the adaptive immune response.

  • If there is co-stimulation from that fragment being something foreign, the immune system will mount a response against that food.

  • This response is destructive and inflammatory, and we can call it a food sensitivity.

  • Co-stimulation is not always bad.

  • Immune exclusion is how we avoid foodborne illness; and we need stomach acid to get that party started.

  • Immune inclusion is the active immune process involved in being able to eat foods and not have inflammatory reactions.

  • Food sensitivities never only affect the gut. This inflammatory response triggers systemic inflammatory responses and we know that eventually, systemic inflammation leads to brain inflammation via all the reasons we are now inflamed.

  • Inflammation begets inflammation.

  • Establishing proper oral tolerance is going to be key. The Elimination/Provocation diet is a great starting point.

  • Your food reactions will change as you regain control of your body. As your gut heals and your inflammation calms down, your gut can begin to tolerate more foods.

  • Getting your eating to agree with your body on a day-to-day basis is necessary for anything else to work well. It isn’t usually the only ‘cure’, but we know that you will never get well if you don’t ALSO address this factor.


KeyPoints_Oral Tolerance
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Mitchell Rasmussen Functional Medicine Doctor Denver Colorado

Dr. Mitchell Rasmussen, DC, CFMP serves as Director of Functional Medicine at The Facility in Denver, CO. He sees patients in-person and via Telehealth to get to the root cause of dysfunction and restore a state of well-being using nutritional intervention, supplementation, and lifestyle change.


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Want to work with a functional medicine doctor to run labs and assess nutrient status? Struggling with hormone imbalance, IBS, weight gain, mood changes? Let's look at BIOCHEMISTRY. Read more about Functional Medicine at The Facility here.

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CLICK HERE to schedule a FREE 15-Minute Consult with Kate to determine your best course of action!

Or reach out by email


What Is Oral Tolerance


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