FOOD SENSITIVITIES AND INTOLERANCE: FROM TRIGGERS TO TREATMENT (PT. 1)

Medically Reviewed by Dr. Rosmy Barrios - September 29, 2024

Food sensitivities and intolerances are thought to affect up to 20% of the population at any given time^[1]. Despite being more common than food allergies, they are not nearly as well understood.

The below article forms part 1 of this discussion, delving into the mechanisms underlying food sensitivities and intolerances, how they are different from allergies, as well as reviewing common risk factors, causes, and triggers for various types.

The discussion is continued in part 2, along with potential treatment options.

What Are Food Sensitivities and Intolerances?

Food intolerances and sensitivities are characterized by a loss of oral tolerance to a specific food, followed by unfavorable reactions^[2]. Their symptoms are usually less acute than those pertaining to allergic reactions, yet they are still significant enough to interfere with health and well-being.

Intolerance and sensitivity are commonly used as interchangeable terms, despite stemming from different causes. Here are the differences between them:

• Food Intolerance usually involves non-immune mechanisms as the primary underlying cause^[3]. These often pertain to enzyme dysfunction or deficiency, leading to indigestion, gut irritation, and resultant symptoms.
• Food Sensitivity. Until recently, food sensitivities were deemed to have no known causes. It is now increasingly understood that they can arise from multiple complex immune-related mechanisms, yet their diagnosis still remains a challenge^[4].

Despite these definitions, there is still quite a large overlap between food intolerances and food sensitivities, often mediated through the crosstalk between the gut microbiome and the immune system. They will be discussed in tandem throughout the article, with the terms used interchangeably.

How is a Food Sensitivity Different from an Allergy?

Both food sensitivities and allergies pertain to adverse immune reactions to ingested foods. The type of immune response involved is usually unique, yet there have been cases of food sensitivity developing into full-blown allergy.

• Allergy. In the case of an allergy, the immune system deploys IgE antibodies in response to allergens. The associated immune response is often more acute and inflammatory than that associated with food sensitivities or intolerances. Despite this, an allergic response can be delayed, with onset ranging anywhere between instantaneously to 48 hours. Typical allergic responses usually occur up to an hour after food is ingested. It is generally understood that the more severe the allergy, the quicker the immune response. Anaphylaxis is an allergic reaction that can occur over a period of a few minutes to hours with potentially life-threatening consequences.^[5]
• Food Sensitivity. In many types of food sensitivities, IgG antibodies are deployed in response to antigens known to trigger sensitivity. Adverse reactions due to food sensitivity are often delayed compared to an allergic response and are not life-threatening, yet can be potentially debilitating if chronic and severe. It can take anywhere between 12-72 hours for symptoms of food sensitivity to manifest^[6], which makes diagnosis tricky and prone to error.

Possible Underlying Causes

Food sensitivities are thought to be the result of lowered immune tolerance towards dietary components. Potential mechanisms are discussed below.

Oral Tolerance is a term used to describe a lack of immune reactivity towards antigens encountered in the digestive tract, on the skin, or in the lungs. Antigens are foreign proteins. The immune system constantly surveys the digestive tract by paying attention to the signals of gut microbes, sampling digestive contents at random, and through their attachment to specific receptors on cell membranes. When a foreign antigen is detected by an antigen-presenting cell, it signals an immune response mediated by T lymphocytes^{[7] [8]}. Tolerance is usually established after exposure to a new antigen. However, the maintenance of tolerance is dependent on several factors, including the concentration of the antigen, its properties, and the state of the microbiome.^[9]

Intestinal Permeability. Loss of oral tolerance has been linked to increased intestinal permeability and heightened immune reactivity towards antigens. If the intestine is more permeable, it increases the exposure of the immune system to antigens in the digestive tract, which has been associated with both allergy and food sensitivity onset^[10]. It can also increase the uptake of incompletely digested proteins or of larger unchaperoned molecules, which are more difficult for immune cells to break down and typically lead to an inflammatory response. Increased permeability can be a result of gut dysbiosis, inflammation, stress, overconsumption of fats or other acidic substances, or micro-lesions in the lining of the gut wall.

Immunoreactivity. The reactivity of the immune system can facilitate a loss of oral tolerance to a specific antigen. The signals emitted by antigen-presenting cells influence how strongly the immune system reacts to a particular antigen. Certain nutrients, such as retinoic acid (a form of Vitamin A), and signals from various strains of probiotic bacteria have been shown to regulate these signals and help to maintain oral tolerance^[11]. The ratio of T cells in the lymphatic compartments of the gut also plays a role in upholding tolerance. Regulatory T lymphocytes are a subset of lymphocytes that are known to stabilize adaptive immune responses by providing growth or inhibition factors and reducing inflammation as required. Low levels of regulatory T cells, by comparison to other types, are associated with heightened immune reactivity and a loss of oral tolerance as well^[12].

Gut Dysbiosis refers to a chronic imbalance in the microbial ecology of the gut, which has been linked to the perpetuation of food sensitivities, intolerances, and allergies^[13]. Gut dysbiosis is often indicative of reduced microbial diversity of the gut, as well as incomplete digestion and increased intestinal permeability, also known as ‘leaky gut syndrome.’ Reduced diversity in the gut promotes fewer signals that serve to keep the immune system balanced, leading to increased reactivity towards foreign stimuli^[14]. Furthermore, the gut microbiome provides essential energy substrates to the cells lining the intestinal wall that diet alone cannot provide. These include short-chain fatty acids. The intestinal cells of the gut secrete mucin in return, which feeds and houses beneficial microbiome residents. When gut microbe diversity is reduced, the lining of the gut becomes weaker due to less energy substrate provision and lower mucin production, leaving the intestinal wall more permeable and vulnerable to damage. Often, increased intestinal permeability causes the immune system to react to LPS (lipopolysaccharide), which is a main component of the membranes of probiotic bacteria. This can lead to an inflammatory cycle where the immune system reacts to beneficial bacteria, increases intestinal permeability, and promotes chronic dysbiosis. ^[15]

Antigen Cross-Reactivity. It is common for those with chronic food sensitivities to be sensitive to multiple types of food that share a common molecular overlap. Once sensitized to an antigen, foods comprising similar proteins or other allergenic compounds can trigger a similar immune response. This is known as cross-reactivity. Some food antigens are chemically similar to self-antigens, which are protein identifiers found on cell membranes that the immune system uses to distinguish itself from foreign matter. In this scenario, food sensitivities can promote autoimmune responses and serve as a risk factor for autoimmune disease.^[16]

Antibody Production. Food sensitivities and intolerances are generally associated with elevations in IgG antibodies, which is often how they are also tested for. Some food sensitivities are also linked to IgE antibodies at lower quantities than that of allergy and IgM to a lesser extent. Alongside increases in these antibodies, those with chronic food sensitivities often show low levels of IgA. Secretory IgA antibodies are an added component of mucin, saliva and mucous. They naturally line the gastrointestinal tract and serve to neutralize foreign antigens, simultaneously reducing inflammation and the risk of their entering circulation. Low secretory IgA is often a sign of increased intestinal permeability, weaker mucosal defenses, and a higher degree of antigen exposure^[17] accompanied by potential immune reactivity (as seen in chronic allergy and food sensitivity). Retinoic acid increases the production of IgA, is linked with lower immune reactivity, and is stored in the gut and liver by immune cells and microbiota.

Risk Factors

A few factors that can increase the risk of developing food sensitivities include:

• Genetics. Specific genetic alleles can predispose individuals to allergies and sensitivities by promoting increased gut permeability and reduced IgA production^[18]. Both of these factors are linked to gut dysbiosis.^[19]
• Chronic Childhood Antibiotics and Dysbiosis. While antibiotics are designed to target specific pathogens, they are also able to demolish beneficial gut microbes and reduce diversity in the gut. Chronic antibiotic use is associated with gut dysbiosis^[20] and stands as a substantial risk for inflammatory and allergic diseases, including chronic food sensitivities. The gut microbiome goes through developmental stages through infancy and childhood. Disruptions to its development through antibiotic administration are associated with an increased risk of developing allergies, intolerances, and sensitivities later on in life.^[21]
• Indigestion, Reflux, and Gastrointestinal Problems. The inability to properly digest one’s food can easily increase the risk of developing food sensitivities. This is most often due to promoting gut irritation, inflammation, and increased permeability. In this scenario, proteins that have not been completely digested are of specific concern. Gastrointestinal conditions symptomatic of lowered stomach acid production and other digestive secretions have been associated with food intolerance and sensitivity.^{[22] [23]} Esophageal reflux bears strong associations with both indigestion and food intolerance to multiple foods.^{[24] [25]}
• Autoimmune and Other Diseases. As immune reactivity is often a component of adverse reactions to food, those with autoimmune diseases are typically at a higher risk for developing them compared to others.^[26] Many antigens in foods also cross-react with tissue antigens, as mentioned above, increasing the likelihood of food sensitivities in these individuals.^[27] Cross-reactivity is beginning to be recognized as a component of other disease states as well, including Parkinson’s disease^[28] and Guillain-Barre syndrome^[29].
• Heightened Exposure to Pollutants and Chemicals. Exposure to toxins, pollutants, or chemicals is known to incite a direct loss of oral tolerance and promote sensitivity towards chemicals, inhaled substances, and cross-reactive food antigens.^[30] In this way, inhaled substances such as pollen or exposure to plastic compounds or latex can also serve as triggers for hypersensitivity towards food antigens. ^[31]
• Excessive Stress. Despite the fact that low-grade stress inhibits digestive processes and absorption, acute stress is known to increase intestinal permeability in an attempt to promote the availability of water, sodium, and other nutrients to sustain energy demands.^[32] Preliminary evidence has shown that stress-induced gut permeability is associated with increased circulation of bacterial by-products, low-grade inflammation, gut dysbiosis, and immune reactivity.
• Malnutrition. Nutritional deficiencies have been linked to an increased prevalence of allergies and food sensitivities. Various nutrients are known to regulate gut permeability, immune tolerance, and the microbiome, including vitamin A^[33] and zinc^[34]. A diet low in fiber from whole grains, fruits, and vegetables may also be a contributing risk factor due to promoting reduced microbial diversity.

Common Food Intolerances: Symptoms, Potential Causes, and Food Triggers

Some of the top food sensitivities and intolerances are discussed below.

1. Wheat/Gluten

Wheat and gluten have been noted to trigger adverse reactions in people who do not have celiac disease and who are not allergic. Individuals sensitive to wheat or gluten are often said to suffer from non-celiac gluten sensitivity.

Symptoms:

• Bloating
• Abdominal pain and cramps
• Constipation or diarrhea
• Brain fog
• Headaches
• Fatigue
• Anxiety

Causes. Gluten is a complex collection of hundreds of proteins and is known to be the main trigger of sensitivity towards wheat and related grains. The proteins in gluten are similar to several known tissue proteins and are associated with promoting autoimmunity. However, this is not usually true of those with gluten intolerance without celiac disease. Instead, protein components of gluten appear able to activate receptors in the intestinal wall that promote epithelial cell damage and dysfunction, increase permeability and allow for more antigens to enter circulation before their proper digestion can take place. Wheat also contains alpha-amylase/trypsin inhibitors and agglutinin, which are both known to contribute towards reduced digestion of wheat components and exacerbate symptoms.^[35] As wheat and other gluten-containing grains also tend to have a high level of FODMAPs in them, they may trigger reactivity in a similar way to that of FODMAPs upon reaching the colon (see below).^[36] Wheat and gluten can also absorb water in the intestines, which may contribute to distention and gastrointestinal symptoms.

Food Triggers. Wheat contains some of the highest levels of gluten among all foods. However, gluten can be found in rye, barley, oats, spelt, and other grains as well. Those sensitive to gluten or wheat may also be triggered by FODMAPs, binders, fillers, emulsifiers, or dietary glutamates, including MSG.

2. FODMAPs

FODMAPs (Fermentable Oligo- Di- Mono-saccharides And Polyols) refer to a group of highly fermentable carbohydrates that are commonly known to trigger adverse reactions in those with Irritable Bowel Syndrome and related gastrointestinal conditions.

Symptoms:

• Bloating
• Abdominal pain
• Flatulence
• Constipation or diarrhea

Causes. Most high FODMAP foods contain a large degree of fermentable fibers as well as fruit and vegetable sugars. While it is not conclusive yet, these foods are thought to contribute to symptoms through several mechanisms. FODMAPs are known to be high in fermentable fibers, sugars, and water, capable of increasing water uptake and bacterial fermentation in the gut, which can promote gas production, intestinal distention, and pain. An overabundance of gut bacteria is associated with intestinal permeability and bacterial translocation. The membranes of bacteria and the sugars found in FODMAPs can both activate immune receptors and trigger an immune response, which lends itself to a cycle of increased permeability, inflammation, and dysbiosis.^{[37] [38]}

Food Triggers. FODMAPs usually consist of foods high in fructose, lactose, sorbitol, mannitol, fructans, galacto-oligosaccharides, and other fermentable compounds. Fruit, dairy, onion family, and other high-fiber vegetables, mushrooms, artichokes, cauliflower, legumes, certain nuts and seeds, as well as some grain varieties (especially rye and wheat), are known to have a high FODMAP content. Usually, only the least absorbed FODMAPs will trigger symptoms in patients, with fructans and galacto-oligosaccharides being especially pertinent triggers as these are never absorbed by the gut.

Foods and beverages high in refined sugar, artificial or natural sweeteners, and starch^[39] can also count as potential triggers for FODMAP-sensitive individuals, as can gluten, caffeine, food, and chemical additives^[40].

Since the bulk of whole foods contains FODMAPs, it is advisable to opt for a nutritionally balanced, low FODMAP diet rather than complete avoidance of FODMAP foods.

To be continued in part 2.

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