Food Allergy vs. Intolerance + Reasons for Sensitivity

Around the world, many people suffer from unexplained migraines, nausea, brain fog, joint pain, and more. According to some researchers, the cause may be dietary: some foods may trigger our immune systems to attack our own bodies. Read on to discover the mystery of food sensitivity.

What is Food Sensitivity?

Food sensitivity or intolerance is a complicated topic with a lot of room for confusion; let’s go back to the beginning and explore what food sensitivity is and how to find it.

In this post, we’ll cover:

• How food sensitivity is different from allergies
• How some foods cause inflammation, and
• Why not everyone is sensitive to the same foods.

Food Allergy vs. Intolerance

Foods can cause inflammation in a variety of ways. The first and best-known is as part of a food allergy such as a peanut allergy. The second is as part of a food intolerance or sensitivity.

Food Allergy

Food allergies cause quick, serious, sometimes life-threatening inflammation when allergens activate the immune system.

At some point, usually during early childhood, a person encounters the allergen (say, peanuts), for the first time. The immune system responds to the peanuts as though they are a dangerous foreign agent, like a virus or bacterium [1].

The body produces immunoglobulin E (IgE), a type of antibody, specifically to bind the peanut allergens. After repeated exposure, the body builds up a store of IgE against peanut allergens, and the person develops a peanut allergy [1].

When this person next encounters peanut allergens, IgE binds to the allergen mast cells and basophils. Within a few minutes, these cells release inflammatory signals and trigger the allergic reaction [1].

People can outgrow childhood food allergies and become tolerant to the allergen if they carefully avoid contact. Regulatory T cells, also called Tregs, subdue the allergic response and promote tolerance to foods. Treg cells prevent the immune system from reacting to harmless proteins; allergic diseases can develop when Treg cells fail to do this job [1, 2, 3, 4].

Food Intolerance or Sensitivity

Food intolerance, also called food sensitivity, is not the result of an allergic reaction.

Rather, it is believed to result when one or more aspects of the immune system increases too much in response to foods being consumed.

The immune system is complex and it can help ward off infections, clear toxins, and heal injuries. However, an elevated immune system also causes damage when its activity is increased too much or for too long.

In people predisposed to autoimmunity, increased immune system activity can raise antibodies within certain regions of the body. For example, if an individual has Hashimoto’s, their thyroid antibodies will increase when they consume foods, such as gluten, that cause their immune system to spike too much [5, 6].

You may have heard of “leaky gut,” a poorly understood condition of increased intestinal permeability. The gut may be said to be “leaky” when the natural barriers between the intestine and the rest of the body break down, allowing potentially harmful compounds to pass through [7].

When you have leaky gut, more components from food can cross your gut barrier and cause inflammation to spike.

Immunoglobulins and Intolerance

Immunoglobulins, or antibodies, are a family of proteins that bind to specific foreign antigens and trigger a response from the immune system. Most of the time, those foreign antigens belong to dangerous pathogens like bacteria, viruses, or parasites. Sometimes, they belong to the food that we eat [8, 9].

As mentioned above, regulatory T cells, or Tregs, tell the immune system to tolerate certain antigens. They suppress an exaggerated immune response, maintain Th1/Th2 balance, and prevent reactions to harmless substances like food proteins [3, 4].

When Tregs are low and immunoglobulins (mainly IgA, IgM, and IgG) are high, the immune system responds. Depending on the person and the trigger, this response can be simple inflammation or more complex autoimmunity [8, 3, 10].

Each antibody binds a specific antigen, but it may also react (or cross-react) with other antigens, provided that they are structurally similar enough. Sometimes, a foreign food antigen can be similar to certain proteins in the human body. If an antibody can bind to both a food antigen and to one of our own proteins, it could potentially signal the body to attack itself [11, 12].

If regulatory T cells (Tregs) fail to suppress this reaction, antibodies may bind to similar antigens in nervous, joint, and other tissues, triggering an autoimmune response. This type of autoimmunity is the cause of celiac disease and a suspected cause of rheumatoid arthritis and some cases of autism [10, 13, 14, 11, 12, 15].

Common Food Antigens

We tend to have IgA and IgG against some foods more than others. The most common antigens include milk and wheat proteins; some researchers argue that our bodies are more likely to produce antibodies against processed foods than raw foods [16, 13, 17, 15].

An important note: the idea of antibody-mediated food sensitivity is controversial among scientists. One study found no relationship at all between food-specific immunoglobulins and perceived food sensitivity [18].

Where Allergy & Intolerance Overlap

Clearly, allergies and intolerance can be quite similar. They can both be triggered by food antigens, they can both be a result of immunoglobulins, and they are both suppressed by Tregs.

Allergies tend to be more immediately dangerous than sensitivities, with notable autoimmune exceptions like celiac disease [17].

Beyond the Immune System

Unlike allergies, intolerance can develop without involving the immune system. Other causes of food intolerance may include:

• Disorders of digestion and absorption [17]
• Enzyme disorders (enzymopathies). For example, people with lactose intolerance do not have functional lactase, the enzyme that breaks down milk sugars [19, 17].
• Toxic or pharmacological reactions. For example, some people who are intolerant to chocolate may be more sensitive to the psychological effects of heobromine. Some medications with sulfonamides or metronidazole have also been observed to trigger food intolerance [17, 19, 20].

Bypassing Natural Defenses

In the intestinal wall, each cell of the gut lining (epithelial cell) is connected to its neighbors with “tight junctions” made of special tight junction proteins (TJ proteins). TJ proteins regulate the flow of small molecules through the intestinal wall and into the blood [7].

The integrity of these junctions may be the most important physical barrier against infection. Many infectious bacteria and viruses target the tight junctions to invade the body: these pathogens disrupt TJ proteins and increase permeability. E. coli and Salmonella are just two common food-borne bacteria that cause disease this way [7].

Some researchers consider leaky gut to be a “danger signal” for autoimmunity. When intestinal permeability increases — that is, when tight junctions and other defenses break down — damaging compounds can get through, trigger inflammation, and wreak all kinds of havoc on the rest of the body [21].

Zonulin

Zonulin is a curious case. Scientists first detected a toxin in the bacterium that causes cholera and life-threatening diarrhea. They speculated that humans suffering from intestinal disorders might make a similar toxin. Sure enough, they soon discovered that human gut tissue can make a related protein they named zonulin [22, 23].

Zonulin regulates gut permeability by lowering the resistance of tight junctions. When zonulin increases, the gut becomes “leaky” and toxins can make their way through the tight junctions and into the bloodstream, where they can trigger inflammation. Zonulin has been called the “doorway to leaky gut” [22, 23, 24].

Bacterial infection and gluten exposure both increase zonulin expression. Dysfunctional zonulin may also play a role in autoimmune diseases such as type 1 diabetes. It has even recently been linked to cancer [23, 24].

Plant Toxins

Some plant compounds, such as saponins, may directly “poke holes” in cell membranes and damage the gut barrier that way [25].

When saponins are partially digested in the gut, they transform into smaller molecules that can insert into the cell membrane. In the cell membrane, they react with cholesterol and form pores. This allows other potentially toxic compounds, such as LPS, to pass through [25, 26].

Note that these effects have only been observed in animals; clinical studies to observe plant toxins’ effects in humans are challenging to design ethically.

Why Isn’t Everyone Sensitive to the Same Foods?

If so many food compounds are so destructive, how come everyone doesn’t have symptoms of food sensitivity all the time? How come different people have different sensitivities? Why is one person sensitive to wheat and another person sensitive to dairy?

Most of it has to do with how someone’s immune system is built. Certain people’s immune systems may be better at defending against infections, but also more likely to get stimulated by the diet.

Your innate tendencies are not fixed. Lifestyle also plays a large role. Stress, exercise and sun exposure can all change how the immune system responds to potential food triggers.

Numerous factors impact the resilience of the gut barrier. Genetics and stress are believed to play prominent roles in strengthening or weakening the barrier, affecting whether toxins will cross over and cause inflammation [27, 28].

Genetics

By the luck of the draw, some people may always be more susceptible than others to developing food sensitivities. Certain genes, such as the cannabinoid receptor gene (CNR1), play a surprising role in protecting the gut barrier. Some versions of this gene have been associated with a weaker gut barrier that allows more inflammatory compounds to pass through [29, 30, 31].

Celiac disease is an inherited food intolerance. Human leukocyte antigen (HLA) is a group of genes that accounts for 30-50% of the genetic component of celiac disease. The most important protein for food sensitivity is called MHC-DQ (encoded in HLA-DQB1 and HLA-DQA1 genes); the HLA-DQ2 and HLA-DQ8 forms of this protein appear to be the most problematic: nine out of ten Europeans with celiac disease have the HLA-DQ2 haplotype [32].

Through genome-wide association studies (GWAS), HLA and dozens of other genes and gene families have been linked to autoimmune diseases like celiac disease, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, and more [33, 34].

All of these autoimmune diseases have also been linked to food triggers and may be controlled through special diets [35, 36, 37, 11, 38].

Genetic enzyme disorders can also cause food intolerance. For example, lactose and histamine intolerances are both inherited [19].

Unfortunately, the genetics of food sensitivity have not been well researched. We have only just begun to understand the complex links between our DNA and an ideal diet.

Stress

When we are stressed, our brains produce a signal called corticotropin-releasing hormone, or CRH. When this signal reaches the gut, it causes increased mucus production. Over time, however, the mucus “runs out,” and the protective barrier that it forms is reduced. Thus, chronic stress eventually depletes the mucus layer of the intestine [28, 39].

CRH also increases gut permeability independent of the mucus barrier. The increased permeability allows LPS to cross tight junctions and trigger inflammation [39].

The gut and the brain are closely linked; some researchers have suggested that when the gut barrier fails, so does the blood-brain barrier. “Leaky brain” is linked to neurological problems, from dementia to depression. This conversation, therefore, goes both ways: poor mental health can lead to “leaky gut,” and “leaky gut” can worsen mental health [40].

Gut Bacteria

The bacteria that live in our intestines communicate with the immune system. A healthy gut flora helps maintain the balance between Th1 and Th2 immunity. It also promotes Treg cells, which suppress the immune response and prevent intestinal inflammation, autoimmunity, and allergic reactions [41, 42, 43].

Unbalanced gut flora can even trigger autoimmunity in the eyes, a condition called uveitis. The eyes, like the brain, are normally protected by a special barrier that shields them from most compounds and immune cells in the blood. In uveitis, the gut flora causes T cells to cross this barrier and attack the eyes [44].

Lipopolysaccharides

In some circumstances, our own gut flora can cause inflammation by producing lipopolysaccharides (LPS), sometimes called endotoxins. These inflammatory compounds disrupt tight junctions and cross the weakened gut barrier [45].

Once they have crossed the gut barrier, LPS bind to toll-like receptor 4 (TLR4), which in turn activates NF-κB. NF-κB is one of the most important inflammatory signals: it increases the production of inflammatory cytokines, directly triggering inflammation throughout the body [45, 46].

Certain species of gut bacteria produce large quantities of LPS, while others don’t. Some of the species that produce the most LPS include Akkermansia muciniphila and Bacteroides fragilis [45, 47].

LPS from B. fragilis may accelerate Alzheimer’s disease. A. muciniphila is a more complex case: in multiple studies, increased A. muciniphila in the gut is associated with decreased inflammation [45, 47, 48].

Akkermansia muciniphila

One of the most common bacteria in the human gut, A. muciniphila produces chemical signals that communicate with our bodies. These signals activate AMPK, an energy-sensing enzyme that speeds up metabolism. In the intestine, AMPK strengthens the tight junctions and decreases intestinal permeability. Thus, A. muciniphila is believed to protect the gut barrier and prevent “leaky gut” [49, 50, 51].

One study found that people with constipation-predominant irritable bowel syndrome (C-IBS) have significantly more A. muciniphila than the healthy average. This result suggests that the presence of A. muciniphila doesn’t universally prevent food sensitivity or disease; however, the same study notes that this bacterium is anti-inflammatory, even in C-IBS patients [52].

Overall, Akkermansia muciniphila is considered a beneficial and protective species.

Bacteroides fragilis

One of the more important species for Th1/Th2 balance is Bacteroides fragilis. In mouse studies, B. fragilis produced a polysaccharide that corrected imbalances between the different types of T cells [42, 53].

SIBO

Small intestinal bacterial overgrowth, or SIBO, is a condition in which the gut bacteria grow out of control. It often includes both an imbalance in the species of bacteria and an increase in the total number of bacteria in the gut [54].

SIBO can cause bloating, diarrhea, poor absorption of nutrients, malnutrition, and unhealthy weight loss. SIBO and IBS have overlapping symptoms, and the interaction between them is not well understood. Up to a quarter of the people with Crohn’s and up to half of the people with celiac disease also have SIBO, suggesting a relationship between SIBO and food reactions [54].

Infection

Bacterial infection can send destructive signals to the immune system and trigger food sensitivities and autoimmunity. Some bacteria in the gut may increase zonulin, which lowers resistance in the tight junctions and increases intestinal permeability. Thus, bacterial infection may contribute to “leaky gut” [23, 55, 56].

Chemical Exposure

Chronic exposure to toxic chemicals in the environment may set the stage for sensitivity to completely unrelated triggers. For example, the buildup of mercury or lead in the tissues may predict “sensitivity-related illness” associated with food or animal dander [57].

These secondary sensitivities can have symptoms ranging from migraines to wheezing to unexplained panic attacks [57].

In multiple case studies, removing the triggers (certain foods, cats, etc.) and treating the accumulated toxic metals resolved all symptoms. In these cases, after treatment, people were able to reintroduce the triggers without symptoms [57].

Age & Sex

Women appear to be more likely to develop food sensitivities than men. Female sex steroids, like estrogen, are pro-inflammatory and may be linked to allergies as well [58, 59, 60, 61].

Importantly, there does not appear to be a difference in the rates of food intolerance among boys and girls before puberty. The greater danger appears and develops in adulthood, which further supports the role of estrogens [62, 59].

Children, adults, and the elderly may also have different degrees of susceptibility to food intolerance. Younger people may be more susceptible to ovalbumin (eggs) and gliadin (wheat) sensitivities. According to one study, people under the age of 40 were significantly more likely to have sensitivities to gliadin, egg white, and barley than people over 40 [58].

Some food sensitivities look different in children and adults as well. Children with celiac disease are much more likely to have typical gastrointestinal symptoms; adults are more likely to have atypical symptoms like anemia and hypertransaminasemia (high levels of some liver enzymes) [63].

These poorly understood differences across age and sex can make it very difficult to diagnose food intolerance.

Now What?

This article is the first of a three-part series. In the second part, we’ll go over:

• Our bodies’ natural defenses against these foods,
• Some of the compounds most likely to cause inflammation, and
• Symptoms to watch out for.

Finally, our third post will explain:

• How “food sensitivity tests” are supposed to work,
• Why they don’t work, and
• How to actually find and address food sensitivity.