Alpha-gal syndrome: why the source of gelatin and collagen matters

A food allergy triggered by a tick bite sounds unusual. Yet alpha-gal syndrome is now recognised internationally as an important form of allergy to mammalian meat and other mammalian-derived products.

For the gelatin and collagen industries, alpha-gal syndrome is particularly relevant because some people with the condition may react not only to mammalian meat, but also to ingredients and products derived from mammalian tissues, including gelatin.

Understanding the distinction between the source of an ingredient, the presence of alpha-gal and an individual’s clinical sensitivity is therefore important.

What is alpha-gal syndrome?

Alpha-gal syndrome (AGS) is an IgE-mediated allergy to galactose-α-1,3-galactose, usually shortened to alpha-gal.

Unlike most major food allergens, alpha-gal is not a protein. It is a carbohydrate structure naturally present in most non-primate mammals, including cattle, pigs, sheep and other mammals. Humans do not produce alpha-gal.

Sensitisation to alpha-gal has been strongly associated with bites from certain species of ticks. Following sensitisation, some people develop allergic reactions after consuming mammalian meat or being exposed to other products containing alpha-gal.

Alpha-gal syndrome is also unusual because food reactions are frequently delayed. Rather than occurring immediately after eating, symptoms commonly develop several hours after consumption of mammalian meat. Reactions can include hives, swelling, gastrointestinal symptoms, breathing difficulties and, in some cases, anaphylaxis.

Australia played an important role in identifying the tick connection

The association between tick bites and mammalian meat allergy has an important Australian history.

In 2009, Australian researchers led by allergy specialist Dr Sheryl van Nunen reported a group of 25 patients living in a tick-endemic region of Sydney who had developed red-meat allergy following significant reactions to tick bites.

That publication in the Medical Journal of Australia was one of the earliest descriptions linking tick exposure and the subsequent development of mammalian meat allergy. The association has since been documented in countries around the world.

The Australasian Society of Clinical Immunology and Allergy (ASCIA) now specifically recognises the relationship between tick bites, mammalian meat allergy and reactions to mammalian-derived products including gelatin.

Where does gelatin fit into alpha-gal syndrome?

Gelatin is manufactured from collagen contained in animal tissues, most commonly from porcine and bovine sources, although gelatin can also be produced from other sources.

Research has demonstrated that alpha-gal can be present in mammalian gelatin.

A 2012 study published in the Journal of Allergy and Clinical Immunology investigated the relationship between red-meat allergy, gelatin sensitisation and alpha-gal. Researchers detected alpha-gal in bovine gelatin preparations and found a significant relationship between sensitisation to alpha-gal and gelatin.

Not everyone with alpha-gal syndrome reacts to gelatin. Sensitivity varies between individuals, which is why medical guidance is important.

Importantly, however, sensitisation does not necessarily mean that every person will experience a clinical reaction. In that study, many patients with red-meat allergy showed evidence of sensitisation to gelatin, while only a subset were clinically allergic to gelatin itself.

This variability remains an important feature of alpha-gal syndrome.

Clinical experience reported from a large cohort of patients with AGS also indicates that reactions vary considerably according to the individual and the type and quantity of exposure. Gelatin can be relevant for some patients, while many tolerate smaller exposures without symptoms.

Nevertheless, major clinical organisations recognise mammalian gelatin as a potential source of alpha-gal exposure.

ASCIA advises people diagnosed with mammalian meat allergy to avoid mammalian meat, mammalian meat products and mammalian gelatin. The US Centers for Disease Control and Prevention (CDC) similarly identifies gelatin made from beef or pork among products to which some people with alpha-gal syndrome may be sensitive.

Gelatin may be found in more than food

For people living with alpha-gal syndrome, identifying potential sources of exposure can be complicated because gelatin has applications extending well beyond familiar gelatin desserts and confectionery.

Gelatin in cosmetics and personal-care products

Gelatin can also be used in some cosmetics and personal-care products, which may prompt people with alpha-gal syndrome to look more closely at ingredient sources beyond food.

However, the clinical significance of topical exposure is less well established than ingestion, and the presence of gelatin in a cosmetic or personal-care product does not necessarily mean it will trigger a reaction.

People with diagnosed alpha-gal syndrome who are concerned about particular products should check ingredient information and seek advice from an appropriately qualified healthcare professional.

Depending on the product and market, gelatin may be used in:

• confectionery and desserts
• capsules and pharmaceutical products
• some vaccines and medical product
• nutritional supplements
• specialised medical applications
• cosmetics and personal-care products

Cases of reactions involving mammalian gelatin have been reported in medical settings, including reactions to gelatin-based plasma expanders and some gelatin containing vaccines.

This does not mean that every gelatin containing product presents the same level of risk, nor that every person with alpha-gal syndrome will react to gelatin. Route of exposure, quantity, formulation, processing and individual sensitivity can all influence clinical outcomes.

For this reason, decisions about foods, medicines or medical products should be made by people with diagnosed or suspected alpha-gal syndrome in consultation with an appropriately qualified healthcare professional.

What about collagen and collagen peptides?

The relationship between alpha-gal syndrome and collagen requires more nuanced interpretation.

Gelatin and collagen peptides both originate from collagen, but they are different ingredients produced through different processing steps. Gelatin results from the partial hydrolysis of collagen, while collagen peptides undergo further hydrolysis to produce much smaller peptide chains.

Research has demonstrated that alpha-gal structures can occur in association with mammalian collagen. For example, research examining beef allergens has identified alpha-gal associated with a bovine collagen protein, demonstrating that collagen-containing mammalian tissues can carry the alpha-gal epitope.

Clinical reviews of alpha-gal syndrome consequently identify some mammalian collagen products among potential sources of exposure.

However, there is currently much more direct clinical evidence concerning mammalian meat and gelatin than there is specifically concerning hydrolysed collagen peptides used as food ingredients or supplements.

It would therefore be inappropriate to assume either that all mammalian collagen peptide products will cause reactions in people with alpha-gal syndrome or that processing automatically makes them safe.

Where alpha-gal syndrome is a consideration, the biological source of the collagen and the characteristics of the finished ingredient are relevant, and individual consumers should obtain appropriate medical advice.

Why ingredient source matters

Alpha-gal syndrome provides a useful example of why the biological source of gelatin and collagen ingredients matters.

Gelatin and collagen can be produced from different raw-material sources. Alpha-gal is associated with non-primate mammals; it is not naturally produced by humans, birds or fish.

For manufacturers, formulators, health professionals and consumers, clear information about ingredient identity and origin can therefore be important.

It is also important not to interpret alpha-gal syndrome as evidence that gelatin or collagen are inherently allergenic ingredients for the general population. AGS is a specific acquired allergy involving IgE antibodies to alpha-gal in sensitised individuals.

For the overwhelming majority of consumers, this mechanism is not relevant.

An evolving area of allergy research

Scientific understanding of alpha-gal syndrome continues to develop.

Recent reviews have highlighted its unusual characteristics: the allergen is a carbohydrate rather than a conventional protein allergen; sensitisation is associated with tick exposure; reactions to food are often delayed; and potential sources of exposure extend beyond meat to certain mammalian-derived foods, pharmaceutical ingredients and medical products.

There are also still important areas of uncertainty, including why some people exposed to ticks develop clinically significant alpha-gal allergy while others do not, why sensitivity differs between patients and how different processing methods influence the amount and presentation of alpha-gal in mammalian-derived ingredients.

For the gelatin and collagen sectors, the appropriate response is therefore not alarm but ingredient awareness, accurate source information and evidence-based communication.