Oral Tolerance Part I: Sensitive to multiple foods and not getting better? Here’s why
If you’re managing your autoimmune disease, chronic health disorder, or brain health, then you’re probably familiar with the autoimmune paleo (AIP) diet, also known as the leaky gut diet or autoimmune paleo protocol. Prior to its rebranding online, functional medicine practitioners called it the “elimination/provocation diet,” which I introduced in 2010 in my thyroid book as one tool to better manage Hashimoto’s hypothyroidism.
The diet has helped many people understand which foods trigger inflammatory or autoimmune reactions in them. Many people follow a customized version of the diet to successfully manage their condition. Some people, however, follow it religiously and do not experience sustainable improvement. In fact, they may develop sensitivities to new foods and even see their symptoms worsen.
This can be caused by loss of oral tolerance, the term researchers use to explain the immune system’s ability to appropriately tolerate foods while protecting the body from bacteria and other harmful compounds.
There are other types of tolerance. Chemical tolerance is the ability to appropriately tolerate the many chemicals in our environment without an immune reaction. Loss of chemical tolerance means a person reacts to a chemical or heavy metal the way they might react to gluten or dairy.
Self-tolerance is the immune system’s ability to respond appropriately to the body. Loss of self-tolerance leads to autoimmune disease, in which the immune system erroneously attacks and destroys healthy body tissue. A popular example of this is Hashimoto’s hypothyroidism.
When you lose one type of tolerance you’re likely to lose other types of tolerance as they have similar underlying mechanisms. Loss of tolerance is an exploding problem affecting an increasing number of people.
Does this mean you should abandon the AIP diet if you are just starting out on your health journey? No, identifying inflammatory triggers is still a vital introduction to managing autoimmunity.
The AIP diet was always meant as one of many functional medicine tools, not as a solitary approach to a complex health condition. If your health is not improving after removing inflammatory foods from your diet, that means you need to look for other factors.
Also, it is common in our busy lives to eat the same foods over and over, which can promote loss of oral tolerance. To maximize the potential of the AIP diet, it’s important to regularly vary the foods you eat and focus primarily on fresh produce.
In this article and in my online oral tolerance course, I will explain current understanding of what causes loss of oral tolerance and how to improve it.
Leaky gut repair as part of a larger oral tolerance protocol
One of my primary goals with the oral tolerance protocol is to show you how a one-size-fits-all approach to leaky gut doesn’t consider why a person gets leaky gut. This is why many people who follow the AIP diet for long periods of time either do not get better or may even get worse. The AIP diet is designed as an anti-inflammatory short-term introduction so you can determine which areas of your diet need adjusting.
This article does not get into the specifics of leaky gut — please refer to my books Why Do I Still Have Thyroid Symptoms? and Why Isn’t My Brain Working? and articles on DrKNews.com for more information on diet, lab tests, and protocols for addressing leaky gut.
A reminder about cross-reactive foods, such as gluten and dairy
It’s often necessary to eliminate certain foods from your diet, particularly gluten and dairy, that cross-react with tissue in the body. The proteins in these foods not only trigger an immune reaction to the food, but also to a specific tissue in the body. For instance, gluten cross reacts with neurological tissue in some people, thyroid tissue in others, and so on. Eating gluten will cause the body to attack those tissues in the body. Cross-reactivity also applies to other types of food proteins, such as dairy.
However, with loss of oral tolerance you may develop food sensitivities to foods that are not cross-reactive. Improving your oral tolerance may help you reintroduce these foods to your diet.
Don’t forget about gut autoimmunity
Another thing important to consider is whether you have gut autoimmunity — an autoimmune condition attacking tissue in your digestive tract. Gut autoimmunity can produce a wide variety of symptoms and digestive disorders that may be beyond the scope of leaky gut or oral tolerance protocols alone. When symptoms are very stubborn or irresolvable, gut autoimmunity is something to consider.
Understanding what causes loss of oral tolerance and what to do about it
Understanding the immune system mechanisms behind loss of oral tolerance and multiple food sensitivities will help alleviate the mystery and frustration many people experience. Please keep in mind that functional medicine is about translating new research into evolving clinical protocols but does not offer cures, magic supplements, or guarantees. Human physiology is complex, highly individualized, and affected by many factors, some of which we are still learning about or don’t even know yet.
Dendritic cells: Key players in loss of oral tolerance
Dendritic cells are immune cells that roam the small intestine. They have long arms that sample different proteins and determine whether the immune system should react to them.
A key component of loss of oral tolerance and multiple food sensitivities is over reactive dendritic cells. They think practically everything they encounter needs to be attacked.
What causes dendritic cells to become overly reactive? Proteins that aren’t thoroughly digested due to deficiencies in stomach acid and pancreatic enzymes is one cause. Low SIgA cells, antibodies that are a first line of defense in the gut, are another. We can address hyper reactive dendritic cells by improving breakdown of proteins and increasing SIgA levels.
Over reactive dendritic cells: Improve breakdown of proteins
Many people digest foods poorly for a variety of reasons, including aging, poor brain function, poor diet, and more. You need sufficient hydrochloric acid and enzyme activity to break down the proteins as soon as possible so they don’t provide target sites for antibodies.
Supplement with hydrochloric acid. Hydrochloric acid (HCl) is the stomach acid vital for digestion of proteins. People with low HCl typically complain of not feeling well after eating meats. Supplementing with HCl when you eat meats will help break down the proteins better.
Supplement with digestive enzymes. Proteins are made up of chains of amino acids, the building blocks of protein. Enzymes are necessary to break apart these chains of amino acids so the dendritic cells don’t become overwhelmed by proteins that are not completely digested. Effective digestive enzymes include pepsin, bromelain, proteases, and more. Look for a high-quality, broad-spectrum digestive enzyme supplement.
Supplement with DPP-IV enzymes: Gluten and dairy intolerance is common among those with loss of oral tolerance. DPP-IV enzymes will help break down gluten and dairy proteins should your food be contaminated (they are not, however, able to neutralize the effects of purposely eating gluten and dairy).
Supplement with flavonoids. Certain flavonoids, which are beneficial plant compounds, have been shown to help block the immune response from dendritic cells. They include quercetin, luteolin, apigenin, and lycopene.
Avoid artificial food colorings. Artificial food colorings have been shown to bind to proteins, thus preventing their breakdown. Avoid artificial food coloring for this reason.
Over reactive dendritic cells: Boost SIgA levels
SIgA are antibodies in the lining of the small intestine that attach to a protein to tag it as a hostile invader, which alerts other cells in the immune system to remove it. They can prevent an immune response by surrounding immune reactive proteins before the dendritic cells attach to them.
This keeps the dendritic cells from becoming over active due to constant bombardment.
Low SIgA levels are common with adrenal fatigue, chronic infection, hydrocortisone or other steroid medications, or vitamin A deficiency.
Ways to boost low SIgA include addressing the underlying cause. This is not a quick and easy fix but it’s important. Do you have adrenal fatigue? Are you battling a chronic viral, bacterial, or fungal infection? Are you taking hydrocortisone or other steroid medication? Look for factors that may be chronically taxing your immune system.
Another strategy is to take Vitamin A. Vitamin A helps boost SIgA levels. Recommended dose is 5000 IU a day. Please note, this is retinol vitamin A and not beta carotene.
Regulatory T cells — key players in oral tolerance
Regulatory T cells (T reg cells) decide whether the immune system needs to mount an inflammatory response to a protein the dendritic cells have transported to the lymphatic system. Because the lymphatic system travels throughout body, this inflammatory immune response can cause inflammation anywhere in the body.
Fortunately, we can profoundly influence T reg cells to dampen the inflammatory response. Factors that can improve T reg cell function to prevent inflammation include:
- Glutathione: Glutathione recycling; s-acetyl-glutathione; reduced glutathione; oral and topical liposomal glutathione; and glutathione nebulizer, IV, or suppository.
- Vitamin D
- Omega-3 fatty acids: A healthy balance of omega-3 and omega-6 essential fatty acids is necessary for healthy T reg cell function. Most people get too much omega 6 oils through processed foods. A healthy dietary intake of omega-3 is 3500 mg for a person eating 2,000 calories per day. In addition to dietary sources, fish, emu, and algae oil are supplement sources of omega-3.
- Short chain fatty acids (SCFA): SCFA supplementation is good for those whose produce consumption is limited due to SIBO or other digestive factors. You may also want to supplement for additional benefit.
- Endorphins (from exercise, laughter, positive relationships, volunteering, etc.) are a way to dampen inflammation and modulate the immune system.
Liver function plays a key role in oral tolerance
The dendritic cells also carry proteins to the liver. There, “Kupffer cells” can trigger inflammation if the liver is toxic or has poor detoxification function. For some people, managing loss of oral tolerance depends on supporting liver function and detoxification. Supporting liver detoxification pathways may help reduce inflammation. I talk more about how to do this in my brain book and thyroid book, or you can read more here.
Diversity of gut flora essential to healthy oral tolerance
One of the pitfalls of going on a very limited diet is you lose your diversity of gut bacteria. Research has shown a rich diversity of gut bacteria is essential to maintaining oral tolerance. Eat a diet that consists primarily of vegetables and vary the vegetables you eat; just don’t eat vegetables you noticeably react to. A diverse array of fruit is important, too, but be careful you don’t spike your blood sugar with too much fruit or overly sweet fruits.
An ample amount of diverse produce daily increases the diversity and amount of gut bacteria, which in turn produce short chain fatty acids (SCFA). SCFAs help regulate T cells (T reg cells) to dampen inflammation.
Lesser known inflammatory triggers to watch out for
In addition to an anti-inflammatory diet, it’s important to also be aware of lesser known sources of inflammation.
For instance, excess salt has been found to be an inflammatory trigger in those with autoimmunity. Westerners eat about twice the recommended amount of sodium of 2300 mg, the equivalent to one teaspoon.
Those who have low blood pressure may consume extra salt in order to raise blood pressure. In this case, trial and error may be necessary to see what works. Glycyrrhiza, a compound in licorice root, may also be effective in raising blood pressure.
Another potential inflammatory trigger is BPA, or bisphenol A, a chemical most commonly found in plastics, fire retardants in furniture and sleepwear, store receipts, and many other products. BPA has been shown to cause loss of tolerance in infants and have a huge impact in general on immune tolerance. Minimize your exposure as much as possible.
Tame histamine reactions to improve oral tolerance
It’s not uncommon for people who have lost oral tolerance to dietary proteins to experience histamine reactions.
Symptoms of a histamine reaction can vary but some of the more common include:
- Sinus issues and congestion
- Seasonal allergies
- Redness and inflammation of the skin
- Joint pain
- Emotional instability
Histamine reactions occur when antibodies that tag a protein as immune reactive also activate mast cells, the immune cells that release histamine.
Foods that commonly trigger a histamine response include aged and fermented foods, smoked foods, fish, and seafood (especially canned). Natural compounds that calm a histamine reaction include quercetin, butterbur, stinging nettle, and mangosteen.
Lab testing for loss of oral tolerance
Food sensitivity testing can help you in your quest to restore oral tolerance.
I use food immune reactivity testing from Cyrex Labs as these tests are extremely sensitive and consistent. They also test foods in the state they are normally consumed, such as raw versus cooked. This is because proteins change from raw to cooked state and you may react to a food in its cooked state but not its raw state. For instance, sensitivity to bacon increases ten times when it is cooked versus raw.
Also, some people react to foods when they are eaten together but not individually. The Cyrex Labs Array 10 Multiple Food Immune Reactivity Screen tests for a few of these.
Cyrex Array 10 also tests things such as thickening gums and artificial food colorings.
I use this testing to determine which foods may need to be eliminated. I also retest to determine whether your oral tolerance protocol is working.
For example, if you tested positive to 120 out of 180 foods tested on the Cyrex Labs Array 10, this is a strong indication of loss of oral tolerance. However, I do not tell patients to remove all those foods from their diet.
Instead, remove the foods to which you clearly react and begin a protocol to restore oral tolerance. Then test again. If you see fewer foods come back positive for immune reactivity you know you’re on the right path with the protocol.
I usually don’t see patients entirely resolve their food sensitivities. Instead, we look for a trend toward improvement.
Please note: If you clearly have loss of oral tolerance but your test comes back with few to no positive markers for food sensitivities, you likely have a depressed immune system. In this case, you need to follow strategies to boost SIgA levels.
You can screen for low SIgA prior to your Cyrex test by ordering a total immunoglobulin (IgG, IgA, and IgM) test.
Hormone imbalances and loss of oral tolerance
If a person follows the oral tolerance protocol and does everything right but still isn’t improving, one avenue to investigate is hormone function. Hormones impact inflammation and every step of the oral tolerance pathway. This includes not only the sex hormones, but also thyroid and stress hormones.
Good hormone function is necessary for the gut lining to regenerate, to keep inflammation in check, and to ensure the brain communicates properly with the gut.
Stress and loss of oral tolerance
Chronic stress is one of the most common causes of hormone imbalances. Increased production of the adrenal hormones cortisol and catecholamines suppresses SIgA cells and intestinal immunity, thus creating an environment for bacterial overgrowth and loss of oral tolerance.
When gut immunity is weak, yeast and bacteria flourish and gastric ulcers can develop. In addition to addressing the root causes of your stress, whether it’s unstable blood sugar or a toxic relationship, adrenal adaptogens and phosphatidylserine can help support you through stress.
Blood sugar imbalances and oral tolerance
Every time blood sugar goes too low or high, this causes a stress response that suppresses SIgA cells and promotes inflammation and leaky gut. For most Americans, this response happens throughout each day. Blood sugar instability is also a major cause of hormonal imbalances and myriad metabolic disorders.
If you ignore your blood sugar it will be difficult to restore oral tolerance. Blood sugar is a deal breaker.
Thyroid hormones and oral tolerance
If you suffer from thyroid hormone deficiency, many health problems may arise, including loss of intestinal integrity, immune function, and oral tolerance.
Thyroid hormone consists of two primary components, T3 and T4. T3 the active portion of thyroid hormone and is vital for intestinal integrity and repair, and thus oral tolerance.
Unfortunately, many patients take medication that is T4 only because that is the health insurance model. It is believed the body converts enough T4 to T3.
However, chronic inflammation hinders conversion of T4 to T3. As a result, many thyroid patients end up deficient in T3 and suffer from continued inflammation, leaky gut, and loss of oral tolerance.
This explains why many people feel better on thyroid hormone replacement that includes T3.
A variety of nutritional compounds have been shown to help in the conversion of T4 to T3.
It can also be helpful to rub topical liposomal glutathione over the thyroid gland to reduce inflammation.
For more information about how to support your thyroid health, please refer to my book Why Do I Still Have Thyroid Symptoms?
Female hormones and oral tolerance
Hormones affect inflammation and oral tolerance because immune cells have receptors for hormones. This is why hormone fluctuations in women (PMS, perimenopause) can cause inflammation.
Also women need sufficient estrogen to regenerate the gut lining, keep inflammation in check, and help the brain communicate with the gut.
It’s common to see women who struggle with hormone fluctuations also struggle with an inability to manage their immune function, tame inflammation, or improve oral tolerance.
Estradiol, the most active form of estrogen, is vital to brain function in women, which is in turn necessary for good oral tolerance. Estradiol is also necessary for the lining of the small intestine to stay healthy and be able to regenerate and to keep inflammation in check.
The ability to break down and clear estrogens from the body is also important to oral tolerance. Estrogen not properly metabolized by the liver can turn into a more more toxic and inflammatory form. You can read more about metabolizing estrogen here.
In fact, most women we see clinically do not have an estrogen deficiency but rather an excess of estrogen. Symptoms of excess estrogen include bloating, swelling, depression, weight gain, and mood changes.
At the same time, phytoestrogens can impact the uptake of estrogen at estrogen receptor sites. Phytoestrogens are compounds that enhance or modulate estrogen receptors. A variety of botanical compounds can help sensitive receptor sites to estrogen, including black cohosh, dong quai, indole d-carbinol, genistein, and daidzein.
(Note: Synthetic estrogens, such as in birth control pills, do not show up on lab tests. However, synthetic estrogens can bind to estrogen receptor sites so that a woman has symptoms of estrogen deficiency but a lab does not reflect true estrogen levels.)
Excess testosterone in women
The most common hormone imbalance in women is high testosterone. In fact, it is the number one reason for female hair loss.
Excess testosterone is a result of insulin surges caused by eating too much sugar, too many carbohydrates, or overeating. These insulin surges up regulate an enzyme in the ovaries called 17’20 lyase, which triggers testosterone production. The excess testosterone then promotes insulin resistance in a vicious cycle.
This can play a significant role in loss of oral tolerance.
To lower testosterone, you must support blood sugar stability by eating a diet that does not spike blood sugar and exercising regularly to make insulin receptors more sensitive.
Stress and hormonal imbalances in women
In menstruating women, the most common cause of hormonal imbalance is chronic stress.
Chronic stress in women leads to pregnenolone steal. Pregnenolone is a hormone used to make several hormones, including estrogen, progesterone, and the stress hormone cortisol.
The body can make only so much pregnenolone. If stress is chronically high, it “steals” pregnenolone from the sex hormones to make enough cortisol to meet the ongoing stress demands.
High cortisol degenerates the intestinal lining and suppresses immune SIgA cells, both of which contribute to the development of oral tolerance.
To balance hormones, address chronic mental and physiological stress (blood sugar and inflammation are the most common causes) and support stress handling through diet and lifestyle and with adrenal adaptogens and phosphatidylserine.
However, if balanced hormone function does not return in perimenopausal or menopausal women, you may want to consider bioidentical hormone therapy with a qualified and experienced practitioner.
Male hormones and oral tolerance
When it comes to male hormone imbalances, the biggest battle is inflammation.
Testosterone is made by Leydig cells in the testes. Leydig cells are extremely sensitive to and destroyed by inflammation. The testes cannot grow new Leydig cells in an environment of chronic inflammation. Thus testosterone production gradually declines.
If a man receives testosterone hormone therapy while in an inflamed state, Leydig cell population goes down even more — the body does not make new cells if it senses there is plenty of testosterone in circulation. A man may feel better for a few weeks initially after hormone therapy begins, but as Leydig cell numbers continually decrease symptoms return.
Inflammation also increases estrogen in men by upregulating the aromatase enzyme. This not only gives men female characteristics of estrogen (male breasts, crying, hips), but it also further drives down testosterone. Men who use testosterone therapy may see their estrogen levels go up on blood tests due to this mechanism.
Aromatase is in body fat so overweight men may struggle with excess estrogen. Weight loss can release stored estrogen into the bloodstream, worsening symptoms of excess estrogen for a while. Fortunately, the botanical chrysin, delivered in a liposomal cream, can help dampen aromatase activity in men.
An aggressive anti-inflammatory diet and lifestyle approach is necessary for men struggling with inflammation-induced hormonal imbalances. High doses (several thousand milligrams) of emulsified turmeric and emulsified resveratrol can help combat this inflammation. Dose according to inflammation, not body weight, raising the dose gradually until you notice improvement.
Stress and male hormones
As with women, chronic stress from blood sugar imbalances, inflammation, and lifestyle can impact hormone balance in men. Diet, lifestyle, and nutritional therapy protocols can help manage this mechanism.
However, sometimes when the stress response is removed and the pathways are supported, balanced hormone function does not return and bioidentical hormone therapy may be warranted in older men.
Oral tolerance conclusion
The beauty and the curse of functional medicine is that everything is intertwined with something else. The hard part is knowing where to begin. The good part is you can start feeling better across multiple fronts once you understand your underlying mechanisms.
The immune system is delicately balanced and impacted by everything the body encounters. Virtually all systems in our body play a major role in how well our gut, brain, and immune system function.
Maybe you are one of the lucky ones who is constitutionally strong and notices significant relief from chronic sensitivities with a few basic changes.
Or perhaps you are one of the many for whom loss of oral tolerance is a red flag asking you to begin making some major shifts.
Addressing the root causes of our health disorders is never easy. Luckily, plenty of other people are on the same journey and there is amazing support online these days.
Though it’s a journey that requires more work and discipline than taking a prescription drug (and I’m not knocking prescription drugs, there are times they are necessary), many people are exponentially rewarded for their efforts in the way of more energy, better mood, and less suffering.
To see Part II of this series, go to Part II: The overlooked power of short-chain fatty acids (SCFAs) for immune health, brain health, and food sensitivities.