Alpha-Gal Syndrome: An Emerging Food Allergy Related to Tick Bites

Alpha-Gal Syndrome: An Emerging Food Allergy Related to Tick Bites 

A strange new food allergy called “alpha-gal syndrome,” also referred to as alpha-gal allergy, is on the rise, particularly in areas of the United States with endemic Lyme disease. Read on to learn why you should be aware of alpha-gal syndrome if you've experienced a tick bite and why identifying and treating this food allergy plays a crucial role in recovery from chronic tickborne illnesses. 

What is Alpha-Gal Syndrome?

Alpha-gal syndrome (AGS) is a type of allergy to mammalian meat. Mammalian meat includes beef, bison, pork, lamb, wild game, rabbit, and unusual meats from other mammals, such as kangaroos. AGS is unique because, unlike most food allergies, which involve the immune system mistakenly identifying specific proteins in foods as harmful, AGS is an allergy to a sugar molecule or carbohydrate found in mammalian meat called galactose-alpha-1-3-galactose.¹ The immune response to this molecule, as opposed to a protein, makes AGS unique amongst food allergies.

What Causes Alpha-Gal Syndrome?

People are not born with AGS, it most often develops in adulthood, though children can acquire the allergy, as well. The primary identified cause of AGS is a tick bite; more specifically, bites from the Lone Star tick or black-legged tick.² This finding explains why AGS is most common in regions where the Lone Star and black-legged ticks prefer to live, including the southeastern US, Texas, the Midwest, and New York.³

Ticks appear to synthesize alpha-gal carbohydrate inside their bodies with the help of enzymes called galactosyltransferases; it may be this endogenously-derived alpha-gal that triggers an immune response in the individual bitten by a tick. Interestingly, bites from ticks that carry the bacterium Anaplasma phagocytophilum, the cause of disease Anaplasmosis, may be more likely to cause AGS because Anaplasma increases the tick’s level of alpha-Gal.⁴

When an individual is bitten by a Lone Star or black-legged tick, or presumably any vector-containing alpha-gal carbohydrate in its saliva, the individual's immune system can start to react to alpha-gal, creating antibodies designed to attack the alpha-gal molecule. These antibodies are called “anti-α-Gal IgE antibodies.” Anti-α-Gal IgE antibodies break oral tolerance or the active regulatory immune response that allows our bodies to tolerate ingested foods.⁵ This breakdown of oral tolerance causes the body to react to food allergens, namely the alpha-gal carbohydrate in mammalian meat.⁵ The tick bite also skews the immune response more towards a T helper 2 (Th-2) response, the type of immune response more correlated with allergies. AGS differs from other IgE-mediated food hypersensitivities in that the response to mammalian meat occurs 3-6 hours after consumption, rather than immediately post-consumption.⁶

Once the reaction starts, the individual's immune system may also begin to cross-react to alpha-gal present in dietary mammalian meat, releasing more alpha-gal antibodies. The release of these antibodies causes an inflammatory response, leading to the symptoms of AGS.  

Interestingly, having anti-alpha gal antibodies inside your body offers a protective response against infection with pathogens that contain the alpha-gal carbohydrate because quick recognition of the carbohydrate molecule by the immune system would theoretically allow the immune system to recognize that a tick bite has occurred and thus target pathogens transmitted via the bite. The tradeoff is that, for this protection, the body must contend with a new food allergy.⁷ In my clinical experience, I've found that AGS can be attenuated in individuals over time, provided they are treating chronic infections and engaging in treatments, diet, and lifestyle practices that regulate the immune system. 

Common risk factors for alpha-gal syndrome include:

• A known bite from a Lone Star or black-legged tick⁸
• History of chigger or mite bites⁹
• Hiking, hunting, birding, or engaging in other hobbies that involve spending lots of time outdoors
• Jobs that involve spending time outdoors, such as field biologist, farmer, or park ranger 

Interestingly, alpha-gal syndrome can occur both in atopic individuals (people with a tendency to allergies) and non-atopic individuals, or those with no prior history of asthma or food or environmental allergies.^{10, 11}

Research suggests that factors that increase intestinal permeability (“leaky gut”), such as alcohol consumption and exercise, potentiate the severity of an AGS reaction by enhancing the translocation of alpha-Gal from the intestine into the bloodstream.¹² Based on this line of research, it follows that other factors that promote leaky gut, such as gluten consumption and emotional stress, may also intensify AGS reactions.

What are the Symptoms of AGS?

AGS exists on a spectrum; as such, the symptoms of AGS vary. While some individuals with AGS may manifest an anaphylactic reaction upon consuming beef, another individual may manifest gut discomfort and fatigue. The spectrum of responses in AGS can make it difficult to assess. However, according to a recent article published in The Journal of Allergy and Clinical Immunology, “the a-Gal syndrome should be considered as an explanation for allergic symptoms, including abdominal pain, related to red meat at any age, regardless of atopic history, ABO blood group, symptom severity, and timing of symptom onset.”¹³

The most common symptoms of AGS include:

• Gastrointestinal symptoms, including abdominal pain, cramping, diarrhea, and emesis
• Pruritus (itchy skin)
• Hives
• Angioedema (swelling of the skin or body parts)
• Anaphylaxis (severe allergic reaction) 
• Nasal congestion
• Improvement of symptoms when adhering to a mammalian meat-free diet

AGS reactions are often delayed, beginning 3-8 hours after eating mammalian meat or meat-derived products. AGS may also “unmask” mast cell issues, causing people to demonstrate symptoms consistent with mast cell activation syndrome (MCAS). 

Diagnosis of Alpha-Gal Allergy

The diagnosis of alpha-gal allergy is based on a clinical history of delayed reactivity to mammalian meat and a blood test that assesses reactivity to galactose-alpha-1-3-galactose. A positive blood test (>0.1 IU/mL) for IgE to alpha-gal establishes the diagnosis.¹⁴ Notably, skin prick tests for allergies to beef or pork are not reliable for diagnosing AGS. 

Both Quest and LabCorp offer testing for the alpha-gal syndrome. It is essential to ensure that you're using the proper test. You do NOT want to test for alpha-galactosidase, which sounds similar but is an entirely different marker. The Quest Alpha-gal Panel Test Code is 95241 or 91380, and the LabCorp Alpha-gal Panel Test Number is 650003. 

Importantly, only 1-8% of individuals sensitized to alpha-gal have clinical alpha-gal syndrome, meaning they neatly fit the clinical diagnostic criteria for AGS.¹⁴ This means that many people who test positive for alpha-gal IgE do not exhibit apparent symptoms after eating red meat. However, because the symptoms of AGS exist on a spectrum, a portion of these people may react to some medications or medical products containing alpha-gal, such as bioidentical porcine-derived thyroid hormone medication and adrenal glandular supplements or experience symptoms after eating mammalian organs, which have more alpha-gal than mammalian muscle meats.¹⁵

Treatment of Alpha-Gal Allergy

The first step in treating alpha-gal allergy is to remove mammalian meat products from the affected individual's diet for some time. The length of this elimination period is at the discretion of the healthcare provider. It will depend on whether the underlying factors contributing to AGS – chronic tickborne infections, immune dysregulation, compromised gut health – are simultaneously being addressed alongside the mammalian meat elimination.

If you test positive for alpha-gal syndrome, you will need to avoid the following mammalian meat-derived foods:

• Beef
• Bison
• Elk
• Pork
• Lamb
• Venison
• Goat 
• Beef or bison bone broth
• Gelatin 
• Collagen 
• Organ meats from mammals; interestingly, kidney and other mammalian organ meats may result in more severe and rapid AGS reactions due to their higher concentrations of alpha-gal antigen¹⁵
• Tallow and lard (These are fats derived from beef and pork, respectively. Research indicates that mammalian lipids can incorporate alpha-gal.)
• Some people with AGS may also need to avoid cow, sheep, and goat milk dairy products

People with alpha-gal may also need to temporarily avoid the following supplements, which contain ingredients derived from mammalian meat:

• Porcine-derived thyroid hormone medication 
• Ox bile
• Betaine HCl from a bovine or porcine source
• Pancreatic enzymes from a bovine or porcine source
• Organ meat supplements
• Vitamin D3 made from lanolin (vegan vitamin D3 is fine) 

Finally, carrageenan is a source of alpha-gal, though it comes from seaweed, not mammalian meat. Carrageenan is present in many processed foods, so you’ll want to watch out for this item on ingredient lists. 

People with AGS can generally eat the following foods:

• Poultry
• Seafood
• Vegetables
• Fruits
• Grains and legumes (Ideally, properly-prepared gluten-free grains and legumes. By properly-prepared, I’m referring to grains and legumes that have been soaked, pressure-cooked, fermented, or sprouted to reduce their antinutrient content, since antinutrients can further compromise intestinal barrier function and allergies)

In clinical practice, I’ve found that a Paleo template diet works best for most individuals with tickborne infections and allergies, so it is an ideal dietary template for those with AGS. A knowledgeable nutritionist and health care team can help you determine the appropriate personalized diet for your unique needs. 

Making dietary changes is beneficial for those with AGS because it allows the body to calm down the inflammatory response, making for smoother sailing during tickborne infection treatment. Many people find it helpful to work with a functional medicine practitioner who has experience in repairing and healing the gut in order to return to optimal health as quickly as possible. 

References:

1. Commins et al. (2014). Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose. The Journal of Allergy and Clinical Immunology, 134(1), 108-115. https://doi.org/10.1016/j.jaci.2014.01.024
2. Commins et al. (2011). The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. The Journal of Allergy and Clinical Immunology, 127(5), 1286-1293. https://doi.org/10.1016/j.jaci.2011.02.019
3. Iglesia, E. G. A., Stone, C. A., Flaherty, M. G., & Commins, S. P. (2020). Regional and temporal awareness of alpha-gal allergy: an infodemiological analysis using Google Trends. The Journal of Allergy and Clinical Immunology, 8(5), 1725-1727. https://doi.org/10.1016/j.jaip.2019.12.003
4. Cabezas-Cruz et al. (2019). Environmental and molecular drivers of the α-gal syndrome. Frontiers in Immunology, 10. https://doi.org/10.3389/fimmu.2019.01210
5. de la Fuente, J., Pacheco, I., Villar, M. & Cabezas-Cruz, A. (2019). The alpha-gal syndrome: new insights into the tick-host conflict and cooperation. Parasites & Vectors, 12 (154). https://doi.org/10.1186/s13071-019-3413-z
6. Wilson, J. M., Schuyler, A. J., Schroeder, N., & Platts-Mills, T. A.E. (2017). Galactose-α-1,3-galactose: atypical food allergen or model IgE hypersensitivity? Current Allergy and Asthma Reports, 17(1). https://doi.org/10.1007/s11882-017-0672-7
7. de la Fuente, J. & Cabezas-Cruz A. Alpha-Gal syndrome Trade-off between allergy and protection to infectious diseases. Research Outreach. Retrieved September 2021 from https://researchoutreach.org/articles/alpha-gal-syndrome-trade-off-between-allergy-protection-infectious-diseases/?cn-reloaded=1
8. Crispell et al. (2019). Discovery of alpha-gal-containing antigens in North American tick species believed to induce red meat allergy. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2019.01056
9. Stoltz, L. P., Cristiano, L. M., Dowling, A. P.G., Wilson, J. M., Platts-Mills, T. A.E., & Traister, R. S. (2019). Could chiggers be contributing to the prevalence of galactose-alpha-1, 3-galactose sensitization and mammalian meat allergy? The Journal of Allergy and Clinical Immunology, 7(2), 664-666. https://doi.org/10.1016/j.jaip.2018.07.014
10. Fischer et al. (2017). Prevalence of type I sensitization to alpha-gal in forest service employees and hunters. Allergy, 72(10), 1540-1547. https://doi.org/10.1111/all.13156
11. Commins et a. (2012). Galactose-α-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma. American Journal of Respiratory and Critical Care Medicine, 185 (7), 723-730. https://doi.org/10.1164/rccm.201111-2017OC
12. Versluis, A., van Os-Medendorp, H., Kruizinga, A. G., Blom, W. M., Houben, G. F., & Knulst, A. C. (2016). Cofactors in allergic reactions to food: physical exercise and alcohol are the most important. Immunity, Inflammation, and Disease, 4(4), 392-400. https://doi.org/10.1002/iid3.120
13. Wilson et al. (2019). Investigation into the α-gal syndrome: characteristics of 261 children and adults reporting red meat allergy. The Journal of Allergy and Clinical Immunology: In Practice, 7(7), 2348-2358. https://doi.org/10.1016/j.jaip.2019.03.031
14. Commins, S. P. (2020). Diagnosis & management of alpha-gal syndrome: lessons from 2,500 patients. Expert Review of Clinical Immunology, 16(7), 667-677. https://doi.org/10.1080/1744666X.2020.1782745 
15. Fischer, J., Yazdi, A. S., & Biedermann, T. (2016). Clinical spectrum of α-gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat. Allergo Jounral International, 25, 55-62. https://doi.org/10.1007/s40629-016-0099-z