An adverse food reaction is any symptom caused by eating a specific food or food component. These reactions can range from mild to severe and may manifest in a variety of ways, including^1-3:

• Digestive issues (eg, bloating, gas, diarrhea, constipation, abdominal pain)
• Skin rashes (eg, hives, eczema, psoriasis, acne)
• Headaches or migraines
• Fatigue or lethargy
• Joint pain or stiffness
• Brain fog or difficulty concentrating
• Mood changes (eg, anxiety, depression, irritability)
• Respiratory issues (eg, wheezing, coughing, nasal congestion)
• Insomnia or other sleep disturbances
• Muscle pain or weakness
• Anaphylaxis (a severe and potentially life-threatening systemic allergic reaction)

Many people may believe they have a food allergy when they experience discomfort or adverse symptoms after eating certain foods.^1,4 However, it is important to recognize that there are several types of food reactions, each defined by how the body reacts to a specific food or food component. While some reactions may be immediate and severe, others may be more subtle or delayed.

The scientific literature and popular media are riddled with inconsistent terminology related to potential reactions to foods or food components. To minimize confusion, we at Life Extension use the following definitions as consistently as possible throughout this Protocol:

• “Food allergy” – Food allergy is an adverse reaction to food that is mediated by the immune system and is reproducible. Food allergies can be life-threatening. The common conception of “food allergy” refers to a rapid reaction mediated by immunoglobulin-E (IgE), though other types of allergic reactions to foods can occur.
• “Food intolerance” – Food intolerance is a gastrointestinal adverse and reproducible reaction to food that does not involve an immune reaction. Food intolerances are generally thought to result from difficulty digesting certain food components. Examples of food intolerances include lactose intolerance, histamine intolerance, and gastrointestinal reactions to fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).
• “Food sensitivity” – We use “food sensitivity” to refer to food reactions that are not better described as immune-mediated “allergies” or non–immune-mediated “intolerances.” Some innovative medical practitioners believe that IgG antibodies may mediate adverse reactions to foods that are sometimes described as food sensitivities. Sometimes, “food sensitivity” is used as an umbrella term to refer to any non-allergy food reaction.
• “Celiac disease” – Celiac disease is an autoimmune reaction triggered by the protein gliadin in gluten, the molecule that gives bread its soft texture. While some people may be allergic to gluten, celiac disease is not classified as an allergy. In celiac disease, the body mistakenly attacks the intestinal lining when gluten is ingested. Readers interested in celiac disease should refer to Life Extension’s Celiac Disease & Non-Celiac Gluten Sensitivity Protocol for more information; celiac disease is not covered in detail in this Food Reactions Protocol.

Food Allergies

Food allergies can be categorized as follows⁵:

• IgE-mediated allergies, also called hypersensitivities, that result in significant release of inflammatory factors such as histamine, leukotrienes, and cytokines
• Non–IgE-mediated food allergies where T cells of the immune system release inflammatory chemicals in response to signals other than those mediated by IgE
• Mixed-type food allergies, which have features of both IgE- and non–IgE-mediated allergies

The primary differences between these types of allergies are the part of the immune system involved in reacting to an allergen and often the timing of the response.⁶ Estimates of the prevalence of food allergies among U.S. adults range from about 3.5% to 10%.^3,7

IgE-mediated food allergy. IgE-mediated food allergies are generally thought of as true or classical allergies. IgE-mediated food allergy symptoms occur when the immune system mistakenly identifies a food component (often a protein) as a harmful substance and produces IgE antibodies specific to the food allergen. This first exposure to an allergen is called “sensitization.” When the food is eaten again, the IgE antibodies recognize the allergen and signal immune cells called mast cells, eosinophils, and basophils. The mast cells and eosinophils release histamine and other compounds in a process called degranulation. The release of these immune-mediator compounds causes problematic and bothersome symptoms such as swelling, itching, congestion, and inflammation. These reactions may be mild but can also be life-threatening—such as in the case of anaphylactic shock, which requires immediate medical attention.^5-8 If one suspects an IgE-mediated food allergy they should seek testing and guidance from an allergist as soon as possible to avoid these life-threatening reactions.

Common foods that may trigger IgE-mediated allergies in susceptible individuals include⁸:

• Peanuts
• Tree nuts
• Milk (different from lactose intolerance)
• Eggs
• Soy
• Wheat (different from gluten intolerance or celiac disease)
• Fish
• Shellfish
• Sesame
• Red meat (caused by sensitization to a compound called alpha-gal via tick bites)

In fact, potentially serious allergies to some of the above-mentioned allergens are common enough that the U.S. Food and Drug Administration (FDA) mandates that products containing the following allergens disclose as much on product labeling: milk, eggs, fish, shellfish, tree nuts, peanuts, wheat, soybeans, and sesame.

There are many hypotheses as to why allergies develop. For instance, one possibility is that allergies are a misdirected immune response that is meant to protect the body against parasites and other harmful invaders. However, in the developed world, where parasites are less of a threat, this same immune response can cause harm by leading to the development of allergies.⁹

• Loss of oral tolerance. Loss of naturally occurring oral tolerance appears to be another contributing factor to food allergies.¹⁰ The natural response to antigens in food is immune tolerance, but some people gradually become less tolerant over time. This issue causes sensitization to certain food antigens that leads to an IgE-mediated food allergy.¹¹

  Oral immunotherapy may be recommended to circumvent the loss of oral tolerance. Oral immunotherapy involves administering food protein to an individual with a food allergy through oral ingestion to help increase the reaction threshold to a specific food allergen. The initial dosage is very low and is then increased carefully under the supervision of a qualified allergist to ensure safety. This process progressively restores oral tolerance for many individuals by promoting desensitization.¹⁰ A maintenance dosage helps sustain desensitization, but standardized maintenance dosages and schedules are still being established as of mid-2024. Studies are ongoing to determine the safety and efficacy of oral immunotherapy for the purpose of restoring oral tolerance. Oral immunotherapy should not be attempted without the supervision of a qualified healthcare provider.

  The gut microbiota plays a vital role in establishing and maintaining oral tolerance to food allergens through mechanisms involving immune regulation, short-chain fatty acid (SCFA) production, and maintaining mucosal barrier integrity. Dysbiosis (ie, gut microbiome imbalance) is linked to increased susceptibility to food allergies, while probiotics and prebiotics may offer therapeutic benefits. Ongoing research continues to unravel the intricate connections between the gut microbiome and immune responses to dietary antigens.^12-14

• Cross-reactivity of allergens. The IgE antibodies that the body develops against one antigen can sometimes also recognize other proteins through a process called “cross-reactivity.” For example, the proteins in cashews might be structurally similar to related nuts, such as pistachios, and cause an allergic reaction. In oral allergy syndrome, also known as pollen-food allergy syndrome (PFAS or PFS), IgE antibodies produced against plant pollens cross-react with proteins in raw fruits, vegetables, and nuts, which leads to itching and swelling of the mouth, lips, face, tongue, and throat soon after eating. However, the allergens in foods that IgE antibodies recognize are often heat sensitive (heat-labile) proteins, which means that cooked fruit or vegetables generally do not cause a reaction.⁸

Non–IgE-mediated food allergy. Non–IgE-mediated food allergies occur when the body’s immune system reacts to certain proteins in food as if they were harmful substances, thus triggering an inflammatory response. Unlike an IgE-mediated food allergy, which involves the production of IgE antibodies that bind to the allergen and trigger a reaction, non–IgE-mediated reactions involve a different type of immune cell called T cells.^15,16 These T cells are activated by the allergen and release different immune signaling molecules, which cause inflammation and various symptoms. Non–IgE-mediated reactions are not usually life-threatening but can still cause significant discomfort and health problems.¹⁷ Typical non–IgE-mediated food allergies often affect infants and young children; these include food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE), and food protein-induced allergic proctocolitis (FPIAP). Celiac disease is a immune-mediated (non-IgE) food reaction that affects adults and children.³

Mixed-type food allergies. Mixed-type food allergies involve both IgE-mediated and T cell-mediated immune responses.¹⁸ Symptoms may include hives, swelling, itching, anaphylaxis, vomiting, diarrhea, abdominal pain, and eczema. When a food allergy involves both IgE-mediated and non–IgE-mediated immune responses, it can be more difficult to diagnose and manage because the timing of the reaction may be delayed.¹⁹ In addition, the specific symptoms often vary and may not always be immediately apparent. A few common triggers for mixed-type food allergies include milk, peanuts, eggs, shellfish, and wheat.¹⁸

• Eosinophilic gastrointestinal disorders. Eosinophilic gastrointestinal disorders (EGIDs) are a group of chronic digestive system disorders characterized by an abnormal accumulation of eosinophils, a type of white blood cell, in the gastrointestinal tract. These conditions can affect any part of the gastrointestinal tract, from the esophagus to the rectum. Examples of EGIDs include eosinophilic esophagitis (EoE), allergic eosinophilic gastroenteritis, eosinophilic colitis, and eosinophilic enteritis. Among EGIDs, EoE is by far the most common. Although EoE is often diagnosed in infancy, the rate of diagnosis in adults is increasing.^6,20,21

  Symptoms of EGIDs include vomiting, gastrointestinal pain, swallowing difficulties, diarrhea, loss of appetite, and acid reflux that does not respond to antacids.^8,22 Over time, the inflammation and damage that EGIDs cause can lead to the thickening of gastrointestinal tissues and difficulty moving food through the gastrointestinal system.²⁰

Food Intolerance

In contrast to immune-mediated food allergies, food intolerances occur when the digestive system struggles to process a specific food or food component in an amount that is normally tolerated by most people.²³ Food intolerances are not the result of an immune reaction; instead, they involve an abnormal digestive response. The amount of food ingested is directly linked to the severity of symptoms—as opposed to allergic reactions that can be triggered by even a very small amount of the allergen—and the specific food or food component causes the same type of symptoms with each exposure.^8,24 The occurrence of food intolerances may be due to a lack of certain digestive enzymes that promote the absorption and breakdown of food in the gut.²³ The classic example is lactose intolerance due to a deficiency of the lactase enzyme. Typical symptoms of food intolerance often manifest as bloating, gas, diarrhea, and abdominal pain.^6,25

Carbohydrate intolerance. When certain carbohydrates are not digested and absorbed properly, they have an osmotic effect, causing water to accumulate in the small bowel. This can lead to bloating and drives food and water into the colon where bacteria ferment the carbohydrates, leading to excessive production of gas (eg, carbon dioxide, hydrogen, methane) that can cause flatulence and intestinal pain. These kinds of easily fermented carbohydrates are referred to as FODMAPs, an acronym that stands for fermentable, oligo-, di-, monosaccharides, and polyols.^23,25

Gastrointestinal symptoms (eg, diarrhea) only develop under certain conditions, including the accumulation of malabsorbed carbohydrates at a rate that exceeds bacterial fermentation, thus causing an overload in the colon and digestive upset. Efficient bacterial fermentation is also disrupted by certain medications (eg, antibiotics) and the presence of inflammatory disease. In the absence of these circumstances, small amounts of malabsorbed carbohydrates may not cause symptoms of intolerance.

• Lactose intolerance. Lactose intolerance is a common adverse reaction to food that occurs when the body is unable to digest lactose, a type of sugar found in milk and other dairy products.^26-28 This happens when the body produces insufficient amounts of lactase, the enzyme that breaks down lactose in the small intestine. Symptoms are generally proportionate to dose (ie, the more dairy a person consumes, the worse the symptoms may be). The prevalence of lactose intolerance in the United States is about 36% of the population. However, the prevalence varies substantially around the world, with lower prevalence in much of Europe (generally 10–40%) and much higher prevalence in the Middle East (about 50–90%) and central Africa (roughly 80–100%).^29,30 The most common treatment for lactose intolerance is the avoidance of dairy foods and lactase enzyme supplementation.
• Fructose intolerance. Fructose intolerance is an adverse reaction to foods that contain fructose, a type of sugar found in many fruits, vegetables, and sweeteners such as honey or high-fructose corn syrup. The condition occurs when the body cannot efficiently absorb fructose in the small intestine, possibly due to a deficiency in fructose transporters. For this reason, fructose intolerance is usually referred to as fructose malabsorption, as the symptoms are caused by the inability to transport fructose rather than break it down.²⁵ A hereditary mutation of the enzyme aldolase B can also cause fructose sensitivity, although this is rare.³¹ Fructose intolerance is usually diagnosed via breath tests. Supplementation with enzymes such as xylose isomerase may be used for the treatment of fructose intolerance, but the condition is generally managed by avoiding foods that contain fructose to minimize symptoms.^31,32 Foods with high concentrations of fructose include honey; dried fruits; fruit juices; sweeteners like agave syrup and high-fructose corn syrup; sweet sauces such as barbeque sauce and some salad dressings; and some whole fruits such as pears, figs, and mangoes.³³
• Sucrose intolerance. Congenital sucrase-isomaltase deficiency causes sucrose intolerance. Sucrose is a natural sugar found in a wide variety of fruits, vegetables, and nuts; table sugar is sucrose as well. Individuals may also experience a mild negative reaction to isomaltose, a carbohydrate released during the digestion of starch.²⁵ Sucrose intolerance is diagnosed via duodenal biopsy.³⁴ Since many foods contain these carbohydrates, it is often necessary to take a sacrosidase (sucrase) enzyme supplement (Sucraid).^35,36 Estimates as to the prevalence of sucrose intolerance in adults vary geographically, ethnically, as well as among studies and with diagnostic method. One study reported an incidence of sucrose malabsorption of about 34% using hydrogen-methane breath tests and almost 27% using the 13C-sucrose breath test.³⁴ Another study indicated that the incidence of sucrase-isomaltase deficiency, which leads to sucrose intolerance, ranges from 0.2% in North America to 10.0% in Greenland Inuit populations. These variations highlight the complexity and potential underdiagnosis of sucrose intolerance in the adult population.³⁷

Pharmacological or chemical food intolerance. Pharmacological or chemical food intolerances occur when a person experiences an adverse reaction to certain foods due to the presence of additives or naturally occurring chemicals—as opposed to a protein as in most other types of reactions—in the foods that affect the body.^6,38 Some chemicals that may cause symptoms of a pharmacological food intolerance include caffeine, histamine, and other biogenic amines, which are a specific type of molecule that is usually made when amino acids (ie, the building blocks of protein) are broken down by enzymes.

• Caffeine. Caffeine is a common stimulant found in foods and drinks such as coffee, tea, energy drinks, and chocolate. However, some people may experience negative effects, including headaches, sleep disturbances, and jitters after consuming caffeine, particularly in large amounts. Caffeine intolerance can be caused by an inability to metabolize or process caffeine effectively, or intake of excessive amounts, leading to these adverse reactions. Caffeine is broken down in the liver by a group of enzymes known as cytochrome P450 enzymes, and genetic variations that affect the activity of these enzymes may cause slower or faster caffeine metabolism. The rate of caffeine metabolism affects the risk of caffeine-related side effects; slow metabolizers are more likely to experience caffeine intolerance.³⁹ Genetic tests, such as those offered by 23andMe, provide a report for caffeine metabolizer status, as a gene variant called CYP1A2 provides an indication of how fast the liver metabolizes caffeine.⁴⁰ Certain medications, such as statins, antidepressants, and antiepileptic drugs, may also induce or inhibit these enzymes, leading to significant drug interactions or unanticipated adverse reactions to caffeine.^41,42
• Histamine and biogenic amines. Histamine is a chemical messenger that acts as a signal for allergic and inflammatory reactions.⁴³ However, many foods contain histamine. Histamine intolerance occurs when the body is unable to break down histamine efficiently, either due to a deficiency of diamine oxidase (DAO; an enzyme in the gut that breaks down ingested histamine) or an overload of histamine in the diet.^44,45 Reduced DAO levels or activity can result from genetic variations, medication use, or certain medical conditions, such as inflammatory bowel disease or celiac disease.

The prevalence of histamine intolerance worldwide is estimated to be around 1–3% of the population, although a lack of data and diagnostic tools make it difficult to determine the real prevalence. Even those without histamine intolerance may experience histamine toxicity after consuming large amounts of histamine. Foods that contain large amounts of histamine (see list below), or those that inhibit DAO activity (eg, alcohol), can also worsen symptoms of histamine intolerance.⁴⁶ Scombroid fish poisoning, or histamine fish poisoning, is a syndrome similar to an allergic reaction that is caused by consuming fish in the Scombridae family (most frequently tuna or mackerel) that has not been properly refrigerated. Improper refrigeration allows bacteria to begin to break down the fish and form histamine, which can lead to histamine-related symptoms.⁴⁷

Some symptoms of histamine intolerance include^45,48:

• Flushing or reddening of the skin
• Skin rashes, burning, tingling, and swelling
• Low blood pressure
• Headache
• Diarrhea
• Vomiting
• Sweating
• Heart palpitations
• Nasal congestion
• Respiratory failure or asthmatic symptoms

Foods containing high histamine levels include⁴⁶:

• Aged cheeses, such as cheddar, Swiss, and blue cheese
• Fermented foods, such as sauerkraut, kimchi, and pickles
• Cured meats, such as pepperoni, salami, and bacon
• Certain types of fish, such as tuna, mackerel, and anchovies
• Soy products, such as tofu and soy sauce
• Certain fruits, such as bananas, avocados, and raspberries
• Nuts and seeds, such as peanuts and pumpkin seeds

Food intolerances, allergies, and sensitivities can be difficult to diagnose, and may also cause a range of symptoms, from mild discomfort to severe allergic reactions. In addition to performing a physical examination and considering an individual’s medical history, a doctor may also use the results of diagnostic tests to identify the underlying cause(s) of adverse food reactions. Understanding the tests that are currently available can help individuals and healthcare providers make informed decisions about diagnosis and treatment, ultimately leading to improved quality of life for those affected by these conditions.⁷³

It is vital to understand that there is no perfect allergy, intolerance, or sensitivity test that can identify all the ways a food may be causing reactions. The different tests available all provide different information and look at different ways an individual may be adversly reacting to food. For example, one person may show positive for IgE reactions to milk but not show elevated IgG/IgA reactions for milk and not have intolerances (eg, lactose intolerance). Another person who also knows they react to milk may show negative for IgE allergy reactions but postive for IgG/IgA sensitivities and also be lactose intolerant. Yet another person may show negative for IgE, IgG, and IgA reactions, but is lactose intolerant and will have signficant gastrointestinal symtoms. Bottom line is no one test will provide all the answers; each test has its pros and cons and each test provides different information as to potential reasons for food reactions.

Common Tests

Skin prick and atopy patch tests. Skin prick and atopy patch tests are common diagnostic tests for food allergies (and environmental allergies) that are administered under the care of a board certified allergist.⁷³ The skin prick test involves placing a small amount of food allergen on the skin by pricking the skin with a needle containing the allergen. If the person is allergic to the food, a raised bump or hive will appear at the site. This test can help identify trigger foods in those with IgE-mediated food allergies, and the severity of the reaction to the prick test typically matches the severity of the food allergy.^6,38

However, it is important to note that there are some limitations to the skin prick test. For instance, the test may not detect non–IgE-mediated food allergies. Furthermore, a positive skin prick test result does not always predict that an adverse reaction will occur upon eating a certain food, or vice versa. Additionally, the methods and testing supplies used for skin prick tests are not standardized across testing kits, which can lead to inconsistent results upon re-testing. Skin prick tests may not be suitable for individuals with severe eczema or those who have recently taken antihistamines, as these factors can affect the accuracy of the test. In people with extensive inflammatory conditions affecting the skin, such as eczema, allergy tests administered via routes other than the skin may be recommended.^79-82

The atopy patch test involves holding potential food allergens on the skin for 48–72 hours, typically by applying a patch or bandage containing the allergens. Then, the test is “read” by looking for a reaction on the skin where the patch was placed. This test is useful for the identification of food reactions that take longer to develop, such as non–IgE-mediated and mixed-type allergies.⁶ The patch testing method may also be used in some cases where a skin prick test is negative, but the clinician retains suspicion of allergy.⁸³

While both the skin prick and atopy patch tests are useful in identifying potential triggers of food allergies, they cannot always predict whether a person will react to a certain food when ingested and should not be used alone when designing elimination diets.²⁰

Oral food challenge test. Food challenge tests are an important diagnostic tool for identifying food intolerances, sensitivities, and allergies, but are not often used due to time constraints. This test involves slowly consuming increasing amounts of the suspected food under medical supervision and monitoring for any adverse reaction(s).⁸⁴ The food challenge test may be used when skin and blood tests are inconclusive, such as to confirm the diagnosis of non–IgE-mediated food allergies, which can be challenging to diagnose using other tests. It is also used to determine if an individual has outgrown a food allergy or to identify the threshold at which a reaction occurs.⁸⁵

Elimination and reintroduction. Elimination diets are one of the best ways to identify foods that are responsible for causing adverse reactions, in particular those food reactions that are not thought to be IgE mediated. However, they are challenging to complete given most people’s busy lifestyles and the significant preparation needed. When used as a test for food reactions, foods that are suspected to cause adverse reactions are eliminated from an individual’s diet for 2–4 weeks. There are three general levels of food elimination⁸⁶:

• Level 1: Simple elimination diet (eg, gluten-free and dairy-free)
• Level 2: Moderate intensity elimination diet (eg, low-FODMAP)
• Level 3: The few-foods diet (strict diet for a limited duration)

The elimination diet level varies depending on how many suspected foods are being eliminated. After the elimination phase, individual foods are added back into the diet one at a time. If a reaction occurs, the food that caused an adverse reaction is removed and the diet is returned to the elimination phase to allow the body time to recover from the reaction. Once the symptoms of the last reaction subside, the next potential trigger food is reintroduced. Elimination diets continue through these elimination, reintroduction, and recovery phases until all suspected foods are tested.⁶

While these diets are easy in theory, consultation with a clinician experienced in the management of food reactions is recommended during this process as the elimination of certain foods may result in nutritional deficiencies, and they are meant to be more of a short-term tool rather than a long-term solution. There is also a potential for inaccurate self-diagnosis of food reactions if an elimination diet is not performed with the guidance of an experienced clinician.⁶

One potential elimination diet, designed primarily to address gastrointestinal symptoms, is the low-FODMAP diet. This diet eliminates high-FODMAP foods, such as dairy, grains, and certain fruits and vegetables, with the goal of finding which specific FODMAP foods trigger adverse reactions. This allows doctors and registered dietitians to design a customized diet for individuals with food sensitivities or reactions without sacrificing nutrition.^6,87

Serum immunoglobulin E (IgE) tests. The total immunoglobulin E (IgE) blood test looks at the total levels of IgE antibodies in the blood. This test can help determine whether an individual’s immune system is more primed for allergic responses. However, the total IgE test cannot identify which specific food may be responsible for the presence of high IgE levels in the blood or the allergic reaction.⁶

The radioallergosorbent test (RAST) is an allergen-specific IgE test that looks for IgE antibodies in the blood that recognize an allergen-specific IgE, such as the protein found in cod, egg whites, or soybeans. While this test is useful for determining if there is potential for a food to cause a reaction, it is not as useful in diagnosing or predicting future reactions to food. However, the RAST is helpful, standardized, and can help guide other tests such as picking foods to test for an elimination and reintroduction test or a food challenge test.^38,88

While some allergists are using the RAST in their practice, more have switched to using newer IgE testing such as ImmunoCap specific IgE tests (which utilize fluorescence enzyme immunoassay [FEIA] technology) and other types of enzyme-linked immunosorbent assays (ELISAs). ImmunoCAP assays represent the “next-generation” of allergen-specific testing. These newer testing methods, like ImmunoCAP, may better reflect the potency of IgE-mediated allergic reactions than older methods.⁸⁹

A more specific version of the allergen-specific IgE test is the component resolved diagnosis (CRD) test. This test can identify IgE antibodies that are specific for individual allergenic molecules.⁶ For example, if milk shows positive, the testing continues to examine individual components of milk (eg, lactalbumin, lactoglobulin, and casein) that may be trigging the allergy. However, CRD testing is not often used clinically in the routine diagnosis and management of food allergies.⁹⁰

Although there are a number of ways that IgE levels can be measured, IgE tests may not always detect an allergen-specific IgE. While IgE testing can be helpful, other tests may need to be performed to determine the cause of food reactions.

Hydrogen breath testing. Hydrogen breath tests are a diagnostic tool sometimes used to identify food intolerances, particularly those related to lactose and fructose. These tests involve drinking a solution containing lactose or fructose, followed by the measurement of hydrogen levels in the breath. If the body is unable to digest lactose or fructose, the undigested sugars will inappropriately ferment, producing excess hydrogen gas, which is then expelled through the breath. Elevated levels of hydrogen in the breath indicate that the individual may be intolerant to the specific sugar tested.^25,27,28

It is important to note that hydrogen breath tests are not always reliable and can produce false-positive or false-negative results. Additionally, they may not be suitable for individuals with certain conditions (eg, irritable bowel syndrome [IBS]) or inflammatory bowel disease) as these conditions can affect the accuracy of the test. However, careful reading of results can often provide helpful and actionable information. In many cases, a healthcare provider may recommend a combination of different diagnostic tests to accurately diagnose food intolerances.²⁵

Endoscopy and biopsy. For some diseases, endoscopy and biopsy of the affected gastrointestinal tissue is needed for a diagnosis. Endoscopy is a medical procedure that involves the use of an endoscope (ie, a long, thin, flexible tube with a camera and light at the end) to examine the inside of the body. During an endoscopy, the doctor uses the camera to look for abnormalities or signs of disease, such as inflammation, bleeding, or tumors. A doctor can also obtain tissue samples (biopsies) or perform procedures such as removing polyps. Diseases that may require an endoscopy, and in some cases a biopsy, include EoE, food protein-induced syndromes, and celiac disease.^27,88 In extreme cases, some food intolerances can be diagnosed through a biopsy in which enzyme levels in the tissue are measured.^27,45 In most cases of food sensitivity, endoscopy and a biopsy are not necessary or indicated for diagnosis. In some cases of food reactions, such as EoE, an esophageal biopsy is necessary for diagnosis, but this is not a standard diagnostic procedure for food sensitivity.⁹¹

Additional Testing Options

Immunoglobulin G (IgG) tests. Blood tests to measure immunoglobulin G (IgG) antibodies directed at a panel of food antigens have been suggested by some innovative medicine practitioners as a method of identifying potential triggers of food sensitivities.

IgG antibodies are critical components of the immune system produced by B cells. They participate in protection against microbial pathogens, vaccination-induced immunity, and ensuring tolerance of nonpathogenic antigens. At the same time, they can also contribute to the pathogenesis of some autoimmune and inflammatory diseases. Their function is complex and context-dependent.⁹²

The body normally produces IgG antibodies to food antigens upon typical dietary exposure. At the center of the research around IgG food sensitivity testing is the kind of immune response these food-directed IgG antibodies trigger: tolerance (non-reactive/non-inflammatory) or intolerance (reactive or inflammatory). The research on this topic is complex and incomplete, but it is clear that the type of response orchestrated by IgG antibodies varies depending on several factors (eg, interindividual genetic variability; route, dose, and duration of antigen exposure; and underlying inflammatory conditions).

There are four subclasses or isotypes of IgG: IgG1, IgG2, IgG3, and IgG4. The different IgG isotypes exert variable influences over the immune response to or tolerance of antigens. For example, there is robust evidence that IgG4 antibodies mitigate IgE-mediated allergic responses. This effect arises in part due to IgG4 blocking of IgE receptor binding and to an anti-inflammatory effect mediated through IgG4 signaling via Fc-gamma receptor II-beta (FcγRIIβ).^93-95 IgG isotypes 1 and 3 have often been described as pro-inflammatory given their greater ability to activate the complement immune response (IgG2 only weakly activates complement and IgG4 does not activate complement). However, more recent evidence has clarified that IgG1–3 (and IgG1 in particular) can also counteract the inflammatory allergic response to antigens, in part through FcγRIIβ signaling in some cell types. IgG isotypes 1, 3, and 4 have been reported to have higher binding affinities for FcγRIIβ than IgG2.^92,94 Interestingly, oral immunotherapy for food allergies triggers an increase in IgG1–4 levels, suggesting that increasing IgG production (of all isotypes) is characteristic of a shift from reactive to tolerant immunity to a particular food antigen.^93,94 Research is ongoing to better characterize the roles of IgG1–3 in immune tolerance to food antigens typically encountered in the diet.

Advocates of IgG blood testing historically recommended testing all four IgG subclasses or only IgG4. However, as the protective role of IgG4 in the context of food allergies became clearly established in the literature, advocates of IgG food sensitivity testing began suggesting assessment of IgG isotypes 1–3 only. Both types of tests remain available on the market as of mid-2024.

Proponents of IgG testing point to several published reports of benefits of IgG-guided elimination diets in conditions such as irritable bowel syndrome and migraine headache,^88,96-104 and some alternative medicine clinicians perceive value in IgG testing for food sensitivities (the food reactions not related to intolerances or allergies), particularly to guide elimination diets. These clinicians also sometimes suggest that elevated blood IgG levels may provide insight into a patient’s gut health. An example of when these clinicians may feel IgG testing is justified is when a patient reports ongoing perceived adverse food reactions despite having ruled out specific allergies or intolerances. In these cases, identifying the foods the patient frequently eats via IgG testing may aid the clinician in constructing a therapeutic trial elimination diet. Conversely, clinicians who do not advocate the use of IgG testing may prefer to pursue dietary changes guided by other means, such as a food diary or simply the elimination of one or a few foods often perceived to be problematic in association with the patient’s specific concern. Other clinicians may prefer to help the patient improve adherence to a generally healthy dietary pattern, such as the Mediterranean diet. The preferred approach will depend on the clinician’s experience.^105-110 Some researchers and clinicians have suggested that IgG antibodies may cause or contribute to non–IgE-mediated food sensitivities in some cases. In particular, some evidence for potential IgG involvement in the context of EoE has emerged in recent years. Several studies have found that blood IgG testing helped guide the design of elimination diets as well. Elimination diets based on IgG testing have been shown to improve symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D) and migraine in small studies. One study that enrolled and placed people with migraines on an elimination diet based upon IgG testing found that the IgG-guided elimination diet reduced the number of migraine-like headaches at four weeks, but not 12 weeks.

Basophil and mast cell activation tests. Basophil activation tests involve the blood collection of basophils, one of the immune cells responsible for allergic responses. After collection, the basophils are exposed to specific allergens and the degree of basophil reaction is measured.¹¹¹

Mast cell activation tests are similar to basophil activation tests, except the serum (clear part of the blood) of an individual is added to mast cells in a laboratory. Mast cells—a type of immune cell that plays a role in immediate allergic reactions—also help regulate how the immune system responds to certain parasites and bacteria. This test is positive if the mast cells that were treated with serum activate when they are exposed to allergens.¹¹¹

Both the basophil and mast cell activation tests may help predict whether an individual will react to a certain food. However, more research is needed to standardize these tests and make them more widely available.^90,111

Genetic screening. Genetic screening is a relatively new approach to diagnosing food intolerances and allergies. This test analyzes an individual's DNA to identify any genetic variations that are associated with an increased risk of developing a food intolerance or allergy. For instance, genetic testing can help determine whether an individual is at risk for developing celiac disease.^51,112 Genetic testing may also identify individuals with histamine, fructose, or lactose intolerance, although this is not often done in clinical practice.^23,45 However, more direct-to-consumer genetic testing has become available in recent years.

Although genetic testing can provide useful information about an individual's genetic risk for food intolerances and allergies, it does not definitively predict whether a person will develop an intolerance or allergy. This means that having a genetic variation that is associated with a certain intolerance or allergy does not necessarily indicate that the individual will develop the condition; however, it does reveal an increased probability for developing the condition.¹¹² Furthermore, many of the genes that may contribute to the development of adverse food reactions are still unknown.¹¹³ For these reasons, genetic testing may be used along with other diagnostic approaches to provide a more comprehensive understanding of an individual's risk.^111,114

Gut barrier testing. There is no standardized test to measure how permeable, or “leaky,” a person’s gut is. There are tests in development that are designed to determine if different compounds and molecules can “leak” out of the gut and into the bloodstream. These include blood tests that look for bacterial components in the blood and urine tests that look for different types of sugars that have escaped the gut. In particular, gut barrier panel tests detect specific markers that contribute to the regulation of gut barrier function or indicate its permeability, such as zonulin, occludin, Candida albicans, and LPSs. The results of these panels provide a means of assessing the presence of leaky gut and monitoring gut barrier function. Biopsies and endoscopies can also help determine whether the gut barrier is damaged.¹¹⁵ Some of these tests are still in experimental stages and others are available commercially. A qualified healthcare practitioner can help decide whether gut barrier testing is appropriate in any given case.

While there are many tests available to diagnose the causes of adverse food reactions, some causes are difficult or impossible to diagnose definitively with one test. There is no one test that can test for all food allergies/sensitivities/reactions/intolerances because all the different tests are assessing different ways the body can react to foods. Each test provides different information on how the immune system and body react. For some conditions, such as histamine intolerance, there are no tests currently available to diagnose them. Only after the elimination of other causes is histamine intolerance considered as a diagnosis.^23,45 A licensed health professional can also help determine the type and combination of diagnostic procedures that can lead to an accurate diagnosis.

Food sensitivities, intolerances, and allergies can cause a range of unpleasant symptoms and can be challenging to diagnose and treat. However, making certain dietary and lifestyle changes can help alleviate symptoms and improve overall health. Here are some useful tips:

The first line of treatment for food reactions is to eliminate trigger foods from the diet. In many cases, this addresses the entirety of the problem, and no further treatment (medical or otherwise) is necessary. However, avoidance may be difficult for those with sensitivities to common foods or ingredients. Peanuts, for example, can contaminate foods that are processed in the same facility. This could even eliminate foods that do not contain peanuts from the diet of people with peanut allergies.⁵ In addition, the exclusion of certain foods can lead to vitamin and nutrient deficiencies, especially in children. For example, an individual with lactose intolerance may need to supplement their diet with calcium and potassium, as well as vitamins B12 and D, as dairy products are a major source of these nutrients.^6,28,116

When deciding to eliminate or limit foods in the diet, the severity of the reaction that typically occurs should be considered. Individuals with non–immune-mediated intolerances might be able to handle small amounts of trigger foods, as the severity of the reaction often depends upon how much of the trigger food is ingested. For example, many lactose intolerant people can tolerate up to 12 grams of lactose (equivalent to about 200–250 mL, or about 8 fluid ounces of milk) at a time without experiencing symptoms when taken with other foods.²⁵ Some studies suggest fermented dairy products, like yogurt, may be more easily digested than other kinds of dairy foods due to their bacterial content. The bacteria may contain lactase enzymes that support lactose digestion, but individuals may react differently, and additional research is required.^25,117-119

For immune-mediated sensitivities such as food allergies or celiac disease, it is often necessary to completely remove trigger foods from the diet. Consuming gluten with celiac disease can cause irreparable damage to the gut which means all gluten-containing foods must be avoided. Food allergies may also result in anaphylaxis and potentially death. Furthermore, some foods that are related to known trigger foods should be avoided because they may cause a reaction due to cross-reactive IgE antibodies.³⁸

As it is often difficult to avoid and replace common foods associated with adverse reactions, we have prepared a table of common triggers and some potential alternatives:

Caution: The nutrients described here will not eliminate a true food allergy. Individuals with diagnosed food allergies should work closely with their allergist or immunologist and never assume that any supplement will allow them to consume foods to which they are allergic.

Supporting the Gut Microbiome

Probiotics. Changes in the gut microbiota of modern humans have probably contributed to the increasing prevalence of food allergies.¹²⁴ Observational studies have identified quantitative and qualitative differences in the gut microbiota between people with food allergies and those without. As a result, supporting the health and diversity of the gut microbiome is rational for those with food allergies and sensitivities.¹²⁵ However, because there are numerous strategies through which the microbiome can be targeted, evidence is generally preliminary for any given intervention, such as probiotic supplementation. Nevertheless, taking steps to support the gut microbiome is probably wise for individuals with food sensitivities. One such step is probiotic supplementation. However, as of late 2023, most research on probiotics in the context of food allergies has involved children, primarily those with cow’s milk or peanut allergies. In this context, research is promising though preliminary.^126,127

Various probiotic species, including Lactobacillus casei, Bifidobacterium lactis, L. rhamnosus, and/or B. bifidum, have been reported to potentially induce immune tolerance in children with a cow milk allergy.^128,129 A trial enrolled 61 children aged 1–18 years who had a cow’s milk allergy and allocated one group to oral immunotherapy plus probiotic supplementation and the other group to oral immunotherapy plus placebo. Supplementation with Lactiplantibacillus plantarum YIT 0132 led to slightly improved tolerance to cow’s milk after 24 weeks.¹³⁰ In a multicenter, randomized, controlled trial, 151 children with a cow’s milk allergy and atopic dermatitis who were being treated with an elimination diet received daily supplementation with a placebo or 1 billion bacteria from the strains L. rhamnosus ŁOCK 0900, L. rhamnosus ŁOCK 0908, and L. casei ŁOCK 0918. The participants taking the probiotics were found to have significantly improved atopic dermatitis symptoms at three months compared with participants receiving placebo.¹³¹ A cohort study that evaluated 330 children with a cow’s milk allergy found that L. rhamnosus GG supplementation along with extensively hydrolyzed casein protein was associated with reduced functional gastrointestinal disorder prevalence compared with casein alone.¹³² Other evidence also suggests L. rhamnosus GG supplementation may benefit children with an allergy to cow’s milk.^133,134

Of note, no one probiotic works for everyone due to individual genetic/biochemical differences. While one person may feel improved with one strain of probiotic another may feel worsened. Trial and error is sometimes needed to find the best probiotic blend for each individual.

Digestive Support

Enzymes. Enzymes in the digestive tract promote nutrient absorption and digestive function. For certain food intolerances and sensitivities, enzymes available in supplement form may help minimize symptoms by improving digestion of the trigger compound. These include amylase, proteases, cellulase, xylose isomerase, sucrase, maltase, lactase, and glutenase, which may help support the digestion of various ingested compounds like complex carbohydrates, plant-based proteins, sugar, lactose, and gluten.¹³⁵ Lactase is useful for people with lactose intolerance, while gluten-degrading enzymes have been explored for those with gluten sensitivities and celiac disease.^136,137 It is important to note that as of late 2023, the only well-accepted treatment for celiac disease is a gluten-free diet. However, these digestive enzymes may help minimize symptoms linked to food sensitivities that are associated with gastrointestinal diseases (eg, IBS).¹³⁵

One specific enzyme, AN-PEP (ie, a prolyl endoprotease derived from Aspergillus niger), has been studied in vitro and shown to degrade gluten. AN-PEP was shown to effectively degrade gluten in the pH range of the stomach, compared with other commercially available protease supplements. In this in vitro study, AN-PEP effectively degraded nine immunogenic gluten peptides, whereas five commercially available digestive enzyme supplements did not.¹³⁸ In 18 subjects with self-reported gluten sensitivity, taking AN-PEP along with a gluten-containing porridge significantly reduced gluten levels in the stomach and duodenum compared with placebo. This study used two doses of AN-PEP: a low-dose and a high-dose, which provided double the enzymatic activity of the low dose. The dosages were based on enzymatic activity. Both dosage regimens were effective, and the effects did not differ significantly between the two dosages.¹³⁹ Other evidence from a small clinical study also supports the potential of AN-PEP to degrade gluten in the stomach.¹⁴⁰ However, another small clinical study found that people with celiac disease who took AN-PEP and introduced gluten under controlled conditions did not exhibit significantly different celiac disease quality scores or gut lining health upon close examination (histology) compared with those who took a placebo.¹⁴¹ More research is needed to clarify the effectiveness of AN-PEP supplementation in the context of gluten sensitivity.

As discussed elsewhere in this Protocol, histamine and other biogenic amines may contribute to food intolerance symptoms. The concept of “histamine intolerance” has been put forth by some researchers as a potential contributor to symptoms that may be described as food sensitivities, such as gastrointestinal discomfort, headache, skin flushing, sneezing or runny nose, and asthma. Diamine oxidase (DAO) is the main enzyme that breaks down histamine in the gut (ie, food histamine), and histamine intolerance is thought to be characterized by a relative lack of DAO enzyme activity.⁴⁶

Studies have investigated the effects of supplemental DAO derived from pig kidney and have suggested some potential benefits (eg, improved gastrointestinal symptoms, urticaria [hives] symptoms, and migraines) for people thought to be histamine intolerant.^142-144 However, more recently, a form of DAO derived from white pea (Lathyrus sativus) was shown to have higher specific activity than animal-derived DAO and prevented histamine-related tissue damage.^145,146

Omega-3 Fatty Acids

Omega-3 polyunsaturated fatty acids (PUFAs) have been shown to influence immune system responses and inflammatory pathways. Preclinical research suggests omega-3 supplementation can suppress allergic responses and improve symptoms.¹⁷³ Additionally, PUFA-derived pro-resolving mediators, such as resolvins, lipoxins, maresins, and protectins, are anti-inflammatory agents that may have beneficial, protective effects on inflammatory states, including potentially allergies and asthma.¹⁷⁴

It has been suggested that maintaining a healthy omega-6:omega-3 ratio (closer to 4:1, instead of the more common 20:1 in typical Western diets) may be an effective strategy for reducing inflammation, allergies, and autoimmune reactions.¹⁷⁵ In a small clinical study, individuals with a peanut allergy were shown to have higher levels of arachidonic acid (omega-6) and lower levels of the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with healthy controls. Screening also demonstrated an inverse correlation between specific IgE levels and total PUFA concentration.¹⁷⁶ These findings provide evidence of the role that PUFA consumption plays in the occurrence, progression, and possible treatment of chronic allergic disorders and food reactions; hopefully, future studies will elucidate the role of omega-3 PUFAs in food reactions and related conditions.

Polyphenols

Polyphenols, antioxidants found in fruits and vegetables, as well as plant-based foods and beverages like tea and wine, are known for their anti-inflammatory properties and have been studied in the context of a variety of health concerns. Their antioxidant activity helps reduce inflammation and may potentially support the treatment of some food reactions.^177-179 Polyphenols may also potentially help improve symptoms of inflammatory bowel disease.^180,181 Furthermore, polyphenols have recently been described as important prebiotics that can positively affect the microbiome. When ingested, prebiotic polyphenols promote the growth of beneficial bacteria and the production of important metabolites.¹⁸²

It has been suggested that polyphenols could “mask” allergens and food triggers by binding to proteins in the gut and preventing immune cells from detecting them.^183,184 For example, the polyphenol epigallocatechin gallate (EGCG) from green tea has been shown to bind to gluten and block its recognition by gut immune cells in vitro.^183,185 Numerous other polyphenols have been shown to interact with potentially immunogenic food proteins, but the clinical effects of polyphenols on food reactions needs to be further studied.¹⁸³

In relation to food allergies, there is some preliminary research suggesting certain polyphenols may have anti-inflammatory properties and may help reduce allergic reactions.¹⁸⁶

Green tea polyphenols. A 2013 pilot study found that treatment with 400–800 mg EGCG daily improved symptoms of ulcerative colitis with few side effects. This was a small study that involved 20 people, thus future research with a larger group of participants is needed to provide further evidence regarding whether green tea polyphenols can be used in the treatment of other food reactions and related conditions.¹⁸⁷

Resveratrol. Resveratrol is a polyphenol found in grapes, berries, and red wine. A small study performed in 2015 found that treatment of ulcerative colitis patients with 500 mg resveratrol daily for six weeks improved disease severity and patient quality of life. However, the study size was small, with 50 participants.¹⁸⁸

Quercetin. Quercetin is one of the most common flavonoids found in a wide variety of foods, including bell peppers, red onions, cranberries, lettuce, and coriander. Quercetin has been shown in vitro to stabilize the cell membrane of mast cells and basophils, thus preventing them from releasing excess pro-inflammatory mediators.¹⁸⁹ Animal studies suggest quercetin may help improve allergic rhinitis, atopic dermatitis, and other allergic-related conditions¹⁹⁰; however, more studies are needed to determine whether quercetin is beneficial in food reactions and other related conditions.

Zinc

Zinc is an important mineral that plays a central role in immune function in the intestinal lining and throughout the body. Proper zinc signaling helps control mast cell, T-cell, B-cell, eosinophil, and basophil activity, limiting inflammatory and allergic immune activity.^191,192 Zinc deficiency has been implicated as a contributor to allergic and inflammatory diseases.^191-193 In fact, patients with eczema and asthma—conditions closely associated with food reactions—have consistently been found to have lower zinc status than healthy individuals.^194,195 This may be due in part to zinc’s effects on T-cell populations: laboratory research has indicated zinc signaling promotes regulatory T cells and T-helper 1 (Th1) cells while zinc deficiency skews the immune response by increasing T-helper 2 (Th2) cell activity.^191,193 Excessive Th2 activity is seen in allergic conditions, including IgE-mediated food allergies.^7,196 Zinc supplementation may help restore Th1/Th2 balance.¹⁹¹

Various zinc transporters work with zinc-binding molecules called metallothioneins to regulate zinc absorption, its movement into and out of cells, and its distribution within cells, controlling zinc homeostasis and preserving balanced immune activity.^192,197 Inflammation and infection have been shown to disrupt zinc homeostasis by altering expression of zinc transporters. Because zinc deficiency can cause poor inflammation control and increased allergic reactivity, this suggests there may be a vicious cycle involving zinc depletion and allergy/inflammation.¹⁹¹

Zinc supplementation may restore balanced immune function in the intestinal wall, and clinical research has indicated it reduces gut inflammation and improves health in patients with inflammatory bowel disease.¹⁹⁸ Some preclinical and clinical evidence suggests zinc supplementation may improve gut barrier function by supporting tight junctions between cells in the intestinal lining.^199-201 By reducing gut leakiness,²⁰¹ zinc supplementation has the potential to limit immune reactions to foods. In animal research, zinc deficiency suppressed immune tolerance in the gut,²⁰² demonstrating another possible mechanism by which low zinc status may increase the likelihood of food reactions.

A vegan diet is often deficient in zinc.²⁰¹ Zinc absorption is enhanced by citrate and dietary protein, especially animal protein. On the other hand, calcium and phytates (found in plant fiber) interfere with its uptake.^193,197 Fermentation and sprouting can increase dietary zinc availability by reducing phytate.¹⁹⁷ Zinc oxide has been found to be less effective for raising zinc levels than zinc salts, such as zinc gluconate, zinc citrate, and zinc acetate, while zinc salts appear not to vary substantially in their bioavailability.^197,203 Importantly, PPIs interfere with normal zinc absorption, and certain diuretics and antihypertensive medications can deplete zinc.^197,201

It is important to note that supplementing with 50 mg zinc per day or more over a long period of time can lead to zinc toxicity and related immune dysfunction due to disruption of copper and iron metabolism. Symptoms may include nausea, vomiting, diarrhea, and muscle cramping.¹⁹⁷

Propionyl-L-carnitine

Research suggests that propionyl-L-carnitine (PLC), a derivative of L-carnitine, can help restore intestinal microvasculature and reduce mucosal inflammation in the context of ulcerative colitis.²⁰⁴ In a multicenter phase 2 trial, individuals with mild-to-moderate ulcerative colitis were given 1 gram per day PLC, 2 grams per day PLC, or a placebo to evaluate the impact of PLC on symptom severity. Each study participant was also taking stable oral medication. The results showed that 72% (57 of 79) of the individuals who took either 1 or 2 grams PLC daily had a marked, clinical response compared with those who took the placebo, with the highest response being observed for the participants who took 1 gram per day.²⁰⁵ Furthermore, 55% (22 of 40) of the participants in the 1 gram group experienced remission. These results indicate PLC is a beneficial adjuvant treatment for mild-to-moderate ulcerative colitis. PLC’s role in ameliorating food reactions and related conditions has yet to be studied, but this appears to be an area of research that should be explored.

Vitamin D

Vitamin D plays an important role in immune function and anti-inflammatory pathway modulation, with research showing that elevated levels of vitamin D in the blood are associated with stronger immune responses and decreased production of inflammatory cytokines.^206,207 Furthermore, vitamin D produced from sun exposure activates antimicrobial proteins; helps protect the gut microbiome; enhances gut barrier function; and balances mast cell, dendritic cell, and T-cell activity.²⁰⁸

Insufficient levels of vitamin D are associated with immune-mediated inflammatory processes in inflammatory bowel disease, as individuals with these conditions typically have lower than normal levels.²⁰⁷ Although vitamin D supplementation may support improved health for people with intestinal diseases (eg, inflammatory bowel disease), the effect of supplementation in people with food allergies or sensitivities has not yet been elucidated; but research in this area is warranted.^207,208

Food allergy can cause serious and potentially life-threatening complications.^23,209 If you believe you are experiencing an allergic reaction to food, seek medical attention immediately.

There are several types of medications that may be used to treat food reactions.²³ However, the use of off-label drugs for the management of food sensitivities, allergies, or intolerances should only be undertaken with the guidance of a qualified health professional.²¹⁰ In addition, it is important to address the root cause of the sensitivity or allergy rather than rely on medication to manage symptoms.

Note: individuals with celiac disease should refer to Life Extension’s Protocol on Celiac Disease and Non-Celiac Gluten Sensitivity.

Treatment of Food Allergies

While avoidance of trigger foods is the primary strategy for the treatment of food allergies, there are several approved and off-label treatments that may help reduce food allergy symptoms if the trigger food is ingested.³⁸ People with true food allergies should always consult with a qualified allergist regarding the best treatment approach for them.

Epinephrine. EpiPen auto-injectors administer epinephrine (Adrenaline), a hormone and neurotransmitter, as an emergency treatment for anaphylaxis caused by food allergies.³⁸ Individuals who have experienced or are at risk for anaphylaxis should carry an EpiPen at all times to rapidly decrease the body’s allergic reaction to a food allergen.

Off-label anti-IgE antibodies. Two anti-IgE monoclonal antibodies sometimes used off-label to treat food allergies are omalizumab (Xolair) and dupilumab (Dupixent).^22,211,212

Oral immunotherapies. Peanut (Arachis hypogaea) allergen powder (Palforzia) is an oral immunotherapy drug recently approved by the FDA to prevent anaphylaxis in children aged 4 to 17 years with peanut allergies.^213,214 Importantly, those being treated must still strictly avoid peanuts in their diets; the drug is intended to prevent severe reactions in case of accidental exposure. Oral immunotherapy is described further in the “Emerging Therapies” section.

Antihistamines and corticosteroids. These well-known medications, including antihistamines like diphenhydramine (Benadryl) and cetirizine (Zyrtec) and corticosteroids like prednisone, may be used to treat inflammatory reactions caused by food allergies.^215,216 Antihistamines are generally used for milder allergic reactions, while corticosteroids are generally used short term and then tapered off to reduce inflammation following a severe allergic reaction.

Allergen immunotherapy. Allergen immunotherapy involves administering gradually increasing doses of an allergen to an allergic individual over a period of several months or years. The aim of allergen immunotherapy is to desensitize the individual's immune system to the allergen by gradually building up tolerance. While it may help reduce symptoms, allergen immunotherapy requires consistent exposure to allergens to maintain tolerance. These kinds of treatments are typically only offered in specialized clinics under close medical supervision due to the potential for severe allergic reactions during treatment.³⁸

• Oral immunotherapy. Oral immunotherapy typically involves the daily oral administration of an allergen extract under close medical supervision. Some research shows that oral immunotherapy is effective at desensitizing individuals to certain food allergens, such as peanuts, milk, and eggs, but there is a risk of severe allergic reactions during treatment and the therapy likely must be continued indefinitely to maintain desensitization.^217,218 One oral immunotherapy drug, Palforzia, has been FDA-approved to reduce the risk of severe allergic reactions to peanuts (see above).²¹⁹
• Epicutaneous immunotherapy. For epicutaneous immunotherapy (EPIT), an allergen extract is administered through a patch applied to the skin. This relatively new therapy is currently being evaluated for the treatment of peanut allergies.^218,220 EPIT appears to be effective at desensitizing individuals to peanuts, but the therapy must be continued long-term to maintain desensitization.^220,221
• Sublingual immunotherapy. Sublingual immunotherapy (SLIT) involves the administration of gradually increasing doses of the allergen extract in the form of allergy drops or tablets under the tongue. This therapy has been used for decades to treat respiratory allergies, such as hay fever, and has also been studied for use in treating food allergies. SLIT is effective at desensitizing individuals to certain food allergens. SLIT is typically administered at home and is considered safer and more convenient than other forms of immunotherapy.²¹⁸

Treatment of Food Intolerances

Avoiding the food or ingredient that causes an adverse reaction is the main form of treatment for food intolerances. However, as most intolerances are due to a deficiency of a particular enzyme, another common treatment is to add an enzyme supplement to the diet. The two most frequently recommended enzyme supplements are lactase and sacrosidase, which are used to treat lactose and sucrose intolerance, respectively.^27,36 Some people may also find relief from certain symptoms of food intolerance by using over-the-counter medications, as recommended by a health professional, for acid reflux or diarrhea medication for gastrointestinal symptoms.

Treatment for Eosinophilic Esophagitis (EoE)/Eosinophilic Disorders (EGID)

Recent clinical evidence shows that eliminating animal milk alone may be a beneficial starting point for people who have EoE. Individuals following a one-food elimination diet (1FED) of animal milk for about six weeks experienced marked improvement of EoE symptoms and a substantial reduction of eosinophil (immune cell) levels in the blood, with 34% experiencing complete symptom remission (histological remission).¹⁰⁷ Individuals who did not respond to the 1FED were able to proceed to a six-food elimination diet (6FED; eliminating animal milk, wheat, egg, soy, fish and shellfish, and peanut and tree nuts) to improve the possibility of experiencing EoE symptom improvement or histological remission; of those who proceeded to the 6FED, 43% experienced complete remission.

In addition to recommending dietary changes, medication may also be prescribed to manage symptoms, decrease inflammation, and reduce tissue damage. Common medications used to treat EoE include PPIs, which can help reduce acid reflux, and corticosteroids that target inflammation in the esophagus.

Dupilumab, which was FDA approved in 2022 for the treatment of EoE, is an antibody that targets interleukin (IL)-4 and IL-13, two immune proteins involved in eosinophilic-related inflammation.²²² Dupilumab also appears to be potentially useful for the treatment of other EGIDs, thus this particular medication may offer promise as an approach for non-EoE EGIDs.

In extreme cases, endoscopic dilation may be necessary to widen the narrowed areas of the esophagus or intestine.²²³

Treatment for Histamine Intolerance

There are no drugs specifically approved for the treatment of histamine intolerance, as it is not yet a recognized medical condition by many healthcare providers. However, some medications may be used off-label to help manage symptoms associated with histamine intolerance.

• Second generation antihistamines that have less sedating effects, such as loratadine (Claritin), fexofenadine (Allegra), and cetirizine, are commonly used to treat allergic reactions and may also help alleviate some symptoms of histamine intolerance, such as itching, hives, and runny nose. However, they may not be effective for all symptoms associated with histamine intolerance, such as digestive issues.²³
• Corticosteroids, which suppress overactive immune responses, may also be useful in treating symptoms of histamine intolerance. However, high-dose corticosteroid use can suppress the immune system over time and therefore these drugs are generally used short term for acute inflammation crises. Lower dosages (eg, 5mg a day of prednisone) are more appropriate for longer term use and generally do not cause significant side effects.^23,224
• Additionally, some people with histamine intolerance may benefit from medications that help stabilize mast cells, such as cromolyn sodium or ketotifen.⁸ These medications can help prevent the release of histamine and other inflammatory compounds from mast cells, which can reduce symptoms such as hives, itching, and gastrointestinal discomfort.

For people with histamine intolerance, medication should not be relied upon as the primary form of treatment. The most effective approach typically involves identifying and eliminating trigger foods from the diet. Working with a healthcare provider or registered dietitian to ensure proper nutrition and management of any related symptoms or conditions is another important approach.

Allergies

Emerging therapies for allergies focus on reducing the immune system’s overactive response to allergens. Currently the outcomes for emerging therapies are disparate, but each therapeutic route focuses on the basic principles of desensitization.²¹⁰

Anti-IgE strategies. Anti-IgE antibodies were originally approved for the treatment of asthma and chronic spontaneous urticaria, although they may also be used off-label in the treatment of food allergies.²²⁵ As these antibodies bind to all IgE molecules, they are not specific for one allergen or trigger. Anti-IgE antibodies can be used as a pretreatment before immunotherapy, such as oral immunotherapy, to encourage desensitization to an allergen.²²⁰ Omalizumab is one such anti-IgE antibody that has shown promise in the treatment of food allergies both as a monotherapy or in conjunction with oral immunotherapy.²²⁶ Ligelizumab is another anti-IgE antibody that, as of late 2023, is in phase 3 clinical trials for the treatment of peanut allergies.²²⁷

Another IgE-related strategy for food allergy treatment is to prevent the immune response that leads to IgE production. Dupilumab is an antibody that binds to a specialized structure called IL-4 receptor. When immune proteins bind to this receptor in response to an allergen, the production of IgE begins to increase. Dupilumab disrupts this interaction and prevents the production of IgE by blocking immune proteins from binding to the IL-4 receptor. Dupilumab is approved for the treatment of several conditions such as asthma and atopic dermatitis, and several clinical trials are ongoing to determine whether it is useful in the treatment of food allergies.^22,212

Eosinophilic Esophagitis (EoE) and Eosinophilic Disorders (EGID)

Complex allergic disorders such as EoE and EGID can be difficult to treat, but several emerging therapies are under investigation.

Antibody treatments. As of mid-2023, a number of antibodies are being developed for the treatment of eosinophilic disorders, particularly EoE, including:

• Lirentelimab. Lirentelimab (AK002) is an antibody that targets the sialic acid-binding immunoglobulin-like lectin (Siglec)-8 receptor, a protein expressed on the surface of eosinophils and mast cells, with low expression on basophils. Siglec-8 is an important immune protein that tells eosinophils, mast cells, and basophils that they are no longer needed to fight off an infection. The overactivity of immune cells (eg, eosinophils, mast cells, and basophils) is associated with allergic reactions and overactive immune responses. Lirentelimab showed promising results in reducing inflammation caused by eosinophils and improving symptoms of EoE in a phase 2 clinical trial.²²⁸ Lirentelimab has been granted orphan drug status for eosinophilic gastritis, eosinophilic duodenitis, and eosinophilic esophagitis.²²⁹
• RPC4046. RPC4046 is an IL-13 antibody that was evaluated in a phase 2 clinical trial. The result of this trial found that RPC4046 treatment lowered eosinophil counts and improved symptoms in individuals with steroid-resistant EoE.^230,231 An open-label extension of this trial found that continued treatment with RPC4046 for up to one year was well tolerated and led to continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE disease compared with baseline.²³²
• Reslizumab. Reslizumab (Cinqair) is an anti–IL-5 antibody that is approved for the treatment of eosinophilic asthma.²³³ Thus far, results in EoE have shown only moderate benefit.²³⁴
• Benralizumab. Benralizumab (Fasenra) is an antibody that is used for the treatment of asthma by blocking the IL-5Rα receptor and disrupting the IL-5 pathway,^234,235 which is involved in eosinophil activity and survival. Disrupting this pathway can help reduce the production of IgE. As of late 2023, benralizumab is undergoing phase 3 trials to investigate its efficacy in the treatment of EoE and eosinophilic gastritis and gastroenteritis.²³⁴
• Dupilumab. Dupilumab is an antibody that targets IL-4 and IL-13 and has already been approved for use in EoE, asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. It is currently being evaluated for other eosinophilic conditions.
• Cendakimab. Cendakimab (CC-93538) is an anti–IL-13 antibody that is undergoing clinical trials for the treatment of EoE.²³⁶ As of early 2024, an ongoing late-stage (phase 3) trial is investigating the efficacy of 48 weeks of treatment with CC-93538 in adults and adolescents with eosinophilic esophagitis. The estimated completion of the study is late 2024.²³⁷

Other Therapies in Development

• Etrasimod. Etrasimod (Velsipity) is a selective sphingosine-1-phosphate (S1P) receptor modulator that prevents white blood cells from leaving the lymph nodes to cause inflammation. It was first developed for the treatment of ulcerative colitis and, as of late 2023, is in phase 2 clinical trials to evaluate whether it is also useful for the treatment of EoE.^236,238
• IRL201104. IRL201104 is a peptide drug derived from an immune-regulating protein produced by the bacteria Mycobacterium tuberculosis. This peptide drug alters how the immune system recognizes antigens, and (as of mid-2024) it had undergone a phase 2 study for EoE, with some promising initial results.²³⁹ The FDA granted orphan drug designation to IRL201104 in January 2024.²⁴⁰

What are some tests for food reactions?

It can be hard for doctors to accurately diagnose food reactions. Several testing approaches may be used in any given case, and often more than one test may be needed to make the diagnosis since there is no one perfect test for food reactions. A qualified healthcare professional can help ensure the right tests are chosen for particular symptoms. Some approaches include:

• Skin prick and atopy patch tests by an allergist
• Oral food challenge test by an allergist, although less common
• Elimination and reintroduction
• Serum immunoglobulin E (IgE) tests, often done by allergist
• Serum immunoglobulins IgG and IgA may be recommended by innovative integrative doctors
• Hydrogen breath testing, usually done by a gastroenterologist
• Endoscopy and biopsy by gastroenterologists

What causes food reactions?

Food reactions can be an allergy, sensitivity, or an intolerance. Food allergies are mediated by the immune system mistakenly reacting against a food or food component, either from IgE antibodies or a T cell inflammatory cascade.^5,6 Food intolerances, on the other hand, are not related to an immune reaction but rather to abnormal or incomplete digestion.²⁴

Food sensitivities are sometimes associated with IgG and IgA antibodies or other factors such as sensitivities to chemicals like histamine and salicylates, or to “leaky gut” or similar conditions.

Which foods are commonly associated with food reactions?

Many foods may trigger food reactions, and trigger foods can be different from person to person. The best way to figure out which foods may be problematic for you is to undergo testing with the guidance of a qualified clinician. However, the following foods or food components are often associated with food reactions⁷³:

• dairy (lactose)
• eggs
• peanuts
• soy
• raw fruits or vegetables
• wheat
• caffeine
• fructose

Can food reactions develop over time?

Yes, food reactions may develop over time, such that foods you did not used to be sensitive to may become problematic. Food allergies usually first emerge during childhood, but sometimes the first occurrence of a reaction may be in adulthood or even old age.⁸

Unfortunately, the exact reasons for developing food reactions are difficult to determine and are complex. Preliminary research suggests that some environmental chemicals can act as haptens, which are small molecules that bind to proteins in the body. Once bound to proteins, haptens can alter their structure, potentially confusing the immune system and leading to abnormal autoimmune-like reactions or inflammatory responses. It is also postulated that increased oral exposure to some environmental compounds may interfere with the development of oral tolerance to food proteins, predisposing individuals to food protein allergies. Studies are needed to test these hypotheses.^241,242

If you begin to notice bothersome symptoms after eating a certain food or food component—even if it did not used to cause you any problems—it may be a good idea to discuss food sensitivity or intolerance testing with a qualified healthcare provider.

Do food reactions ever go away?

In some cases, food reactions may go away or become less troublesome over time. However, if you have a history of severe reactions to foods, make sure you do not try to re-introduce the food if you have avoided it for a long time without first talking with your doctor. Immune-mediated allergies are less likely to resolve over time than non–immune-mediated intolerances.

Can you reverse food reactions?

There are treatments available for both food allergies (immune-mediated) and food intolerances (not immune-mediated). Their effectiveness may vary from person to person. Food allergies likely are not reversible in most cases, but food intolerances may get better over time for some people.