The term adverse food reaction refers to the appearance of a variety of clinical pictures consequent to the ingestion of a specific food (or, more rarely, of an additive). Adverse food reactions can take place with or without the involvement of the immune system. Immune-mediated adverse food reactions are true food allergies and consist of an abnormal immune system response to the ingestion of foods that a subject should normally tolerate. Food allergies occur through mechanisms independent of the amount of allergen taken and may be IgE-mediated (type I hypersensitivity, with immediate response) or cell-mediated (with delayed response); forms in which both components are apparently involved also exist.
When the immune system is not involved in the food response a food intolerance is instead present, which includes metabolic and pharmacological food reactions, food intoxications and food idiosyncrasies. A classification of adverse food reactions is represented in Figure 1.
Fig. 1. Classification of adverse food reactions
FOOD ALLERGY
Not much is known about the incidence of food allergies in the dog, and virtually nothing in the cat. Since food allergies in the dog mostly affect the skin and/or the GI tract, several authors have tried to estimate the percentage of such conditions that recognise a nutritional cause.
In the case of dog dermatosis, the data in the literature are conflicting, with estimates of food-related skin conditions of 1% (Walton, 1967), 5% (Carlotti et al., 1990), 4% (Denis and Paradis, 1994), 7.6% (Chesney, 2002), 1.7% (Wilhelm and Favrot, 2005) and 12% (Proverbio et al., 2010). If the focus is narrowed down to dog dermatosis with unseasonal pruritus, the incidence of food-based cases rises to 17-35% (Chesney, 2002; Biourge et al., 2004; Loeffler et al., 2004). Finally, only 10-15% of cases of dog allergic dermatosis are of dietary nature (Carlotti et al., 1990; Scott et al., 2001), as such forms are more often caused by flea-bite sensitisation and by environmental allergens. It should however be emphasised that many of the studies cited are of poor scientific value, due to methodological aspects, such as the fact that the number of dogs examined was often very low and coming from circumscribed geographical areas. Furthermore, by the very nature of allergic dermatitis the results of such studies are often extremely subjective; this is true starting with the inclusion criteria used in the individual studies, continuing with the diagnosis of the disease and the possible identification of the allergen involved. Apart from these considerations, the data in the literature show that in the dog, food-borne allergic dermatosis does exist, but it is relatively infrequent.
With regards to the incidence of food-based enteropathies, the picture is still very confused. In dogs with chronic gastroenteropathy, symptom improvement following diet change (consisting, in general, in the transition to a so-called exclusion diet, be it commercial or homemade) is a common finding, reported in 56% (Allenspach et al., 2007) or even in 88% (Mandigers et al., 2010) of cases (but the latter study included only 28 dogs). However, the same authors observed that most of the dogs which improved following diet change had no relapse of the symptoms when they returned to the previous diet (provocation test), clearly pointing out that an allergic mechanism was not at the basis of the diet-responsive gastroenteropathy (Allenspach et al., 2007; Mandigers et al., 2010).
Finally, in extremely severe cases exposure to a food allergen can result in an anaphylactic reaction. Typically, in the dog, food anaphylaxis causes angioedema of the face, lips, eyelids, ears, conjunctiva and tongue, with or without the presence of pruritus (Scott, 2001). These manifestations typically appear suddenly, following contact with the allergen, and disappear within a few hours.
Food allergens
Food allergens typically consist of water-soluble glycoproteins, with a molecular weight between 10 and 70 kDa (Ho et al., 2012). In human medicine, based on epidemiological data, there is evidence of the fact that some proteins are more often responsible for food allergies compared to others; however, potentially, any protein may be the cause of allergy.
In terms of allergenicity, a distinction is made between allergens capable of inducing sensitisation (these may be of either animal or plant origin and are usually resistant to heat treatment) and those which, vice versa, do not induce sensitisation (these are mostly allergens of vegetable origin and are often heat-sensitive), although the latter may still be the cause of allergic manifestations via cross-reactions with the IgEs induced by another allergen (Burks, 2004).
As regards the effects of cooking on allergens, this may alter their conformation, and, consequently, their allergenic potential. In the case of heat-sensitive allergens, it is possible for a subject to tolerate the ingestion of a specific ingredient, which in raw form causes the allergic manifestation, if this is previously subjected to cooking. It is however also true that various allergens, although cooked, recover their conformation once they cool; in some cases, it is even possible that cooking may increase the allergenicity of a protein because of aggregation phenomena (Chirino et al., 2004) and glycation reactions (Chung et al., 2003).
Several authors have conducted studies involving dogs suffering from food allergies in order to determine which foods were more often responsible for the disorder. Unfortunately, these studies are rather old, mostly conducted during the eighties and nineties, in Anglo-Saxon countries, and involving extremely restricted populations of animals (White, 1986; Carlotti et al., 1990; Denis and Paradis, 1994; Jeffers et al., 1996). Based on these studies, beef, dairy products, fish and soybeans appear to be the raw materials most responsible for allergy in dogs, but in reality such data is not very reliable and is presumably influenced by the geographical context in which it was collected. In the medical field it is in fact widely recognised that foods that cause allergies vary geographically, depending on the eating habits encountered in the various countries (Ho et al., 2012). Finally, there is the issue of cross-reactivity; a subject allergic to a specific ingredient could also be allergic against others, if the proteins present are similar to the one against which sensitisation was developed (Sicherer, 2002). But there is more, there can even be cases of cross-reactivity between inhaled allergens and food allergens (Worm et al., 2014). All such cases of cross-reactivity have so far been studied only in the human medical field; no specific data exist for the dog and cat.
Aetiopathogenesis of food allergy
When an animal consumes a meal it inevitably ingests also proteins that, in the intestine, come into contact with the immune system (in this case with the GALT), which should be able to recognise these proteins as harmless (distinguishing them from what is instead potentially dangerous, such as viruses, bacteria, parasites, etc.) and learn to tolerate their presence at intestinal level.
Dietary proteins are digested in the stomach and in the small bowel by the proteolytic enzymes that the body produces, forming progressively smaller peptides with less and less allergenicity. Regardless of the proper functioning of the digestive processes, it is important for the contact between food proteins and the immune system to be as limited as possible: to this end, it is essential for the intestinal mucosa to be intact and that the other protective mechanisms (complete digestion of proteins, normal intestinal peristalsis, presence of mucus and IgAs on the surface of the intestinal mucosa) may properly exert their own specific function (Verlinden et al., 2006). There is however the possibility that a small amount of food proteins may come into contact with the immune system; it is at this time that sensitisation of the subject may take place (as well as the appearance of allergic manifestations following subsequent contact with the allergen). It is therefore essential for the immune system to recognise food proteins as harmless and to develop the so-called "oral tolerance" against such proteins (Verlinden et al., 2006).
Predisposing factors for the onset of food allergy have been recognised in both humans and in dogs; the most important ones include the young age of the subject and a possible genetic predisposition, as well as any alteration of the intestinal mucosa leading to its increased permeability (Verlinden et al., 2006). This notwithstanding, to date, the triggering causes of food allergy are still not fully clear.
In the medical field studies on the interaction between the immune system and the gut microbiota have been underway for years, in order to understand the impact of the latter on the body's immune response, also as regards the onset of food allergy, but overall knowledge is still limited (Feehley et al., 2012). Recently, two interesting theories to explain the increase in food allergies which appears to be affecting people living in industrialised Western countries have been proposed. The first of these is the so-called "hygiene theory", according to which the reduced contact of children, during the first months of life, with infectious and parasitic agents capable of stimulating the immune system increases the risk of developing allergies because of an abnormal modulation of the immune system itself (Lack, 2012). The second theory is instead the "dual-allergen exposure hypothesis", which considers the possibility that the risk of developing a food allergy increases when babies come into contact with a given food through a route which differs (for example the skin) from that of the digestive system, which would instead allow the development of oral tolerance to the antigen (Lack, 2008).
FOOD INTOLERANCE
As already mentioned, food intolerance consists of an adverse food reaction without the involvement of the immune system: the condition includes metabolic and pharmacological food reactions, food intoxication and, finally, food idiosyncrasies.
Metabolic food reactions
An example of metabolic food reaction is represented by the intestinal symptoms that accompany the ingestion of a specific nutrient in the absence of the enzyme responsible for its digestion.
Such a condition is observed in dogs and cats (particularly in adult ones) following the intake of more or less high amounts - depending on the sensitivity of the individual subject - of lactose: in adults, in fact, the production of lactase is extremely modest, or even absent, and the ingestion of milk may cause the production of malformed stools or even of real episodes of diarrhoea (osmotic diarrhoea). The same phenomenon may be observed following the ingestion of starch in dogs having an insufficient production of amylase (a phenomenon observed in some subjects of certain dog breeds, such as, for example, the Czechoslovakian Wolf). It is obvious that these phenomena are generally dependent on the dose of substance being taken, unlike what happens with food allergies, in which the reaction is not dose-dependent.
Other metabolic food reactions may be present, such as those linked to hereditary metabolic defects that disrupt the proper metabolism of specific nutrients, once these have been absorbed in the bowel: an example of this is the Dalmatian dog's tendency to form ammonium urate uroliths because of the defective conversion of uric acid (resulting from the catabolism of purines, particularly present in meat and body organs) into allantoin.
Pharmacological food reactions
A typical example of a pharmacological food reaction is the ingestion of food containing significant amounts of histamine, such as in the case of spoiled tuna and mackerel. The cardiotoxicity of theobromine contained in chocolate is well known in the dog. Ethyl alcohol may also be considered responsible for possible pharmacological food reactions.
Food intoxication
Food intoxication is a very common cause of gastrointestinal problems in the dog and cat; the aetiological factors involved are several, among which, in the first place, pathogenic microorganisms (especially bacteria and moulds) and the toxins they produce. Another example of food intoxication is represented by the anaemia in the dog and cat consequent to the ingestion of onions. Intoxication may also be the consequence of the excessive intake of essential nutrients, such as, for example, vitamins A and D and of some mineral trace elements (above all selenium, iodine and cobalt).
Food idiosyncrasy
Food idiosyncrasies are reactions observed in some individuals as a consequence of the ingestion of a certain substance, typically a food additive. To date, although little is known about the true incidence of this problem in the dog and cat, the cat’s idiosyncrasy against propylene glycol (with possible anaemia) is known, substance which is instead well tolerated in the dog and in humans.
Eating disorders
In human medicine, eating disorders include several particularly important alimentary behavioural dysfunctions, such as anorexia nervosa (which includes restrictive anorexia and bulimia). In veterinary medicine in addition to anorexia, which is well known especially in the cat (often of ‘nervous’ nature), other eating behavioural disorders are also present, including the ingestion of garbage and pica.
Hereditary gluten intolerance
In the dog, two forms of chronic gluten enteropathy (i.e. the protein that is found in some cereals, including wheat, rye, barley and oats) affect the Irish Setter and the Soft Coated Wheaten Terrier, respectively (in this second breed the involvement of gluten as an aetiological factor in a syndrome characterised by protein-losing enteropathy and/or nephropathy is currently only suspected; Vaden et al., 2000). In both cases the intolerance recognises an hereditary basis, similarly to what happens in the celiac disease of humans, the pathogenesis of which has however not yet been fully elucidated. Finally, gluten seems to be responsible for a particular intolerance found in some Border Terriers, with epileptic-type manifestations (Epileptoid Cramping Syndrome of the Border Terrier, Lowrie et al, 2015). It is however clear that in veterinary medicine hereditary gluten intolerance is a relatively limited problem, involving only a few family lines of very few breeds.
THE DIAGNOSIS OF FOOD ALLERGY
It is an accepted opinion that the only really reliable diagnostic tool for the diagnosis of food allergy consists in the use of an exclusion diet, followed by a provocation test (represented by the administration to the animal of the diet used when the symptomatology was present) whenever the exclusion diet resulted in a reduction or complete remission of the symptoms (Verlinden et al., 2006). Should symptoms reappear following the challenge test, the exclusion diet is then re-introduced in order to definitively confirm the diagnosis once the symptoms disappear. At this point, as a last step, new ingredients should be reintroduced, always one at a time, in order to identify which of these induces a relapse of symptoms (and is thus responsible for the intolerance) and which are instead safe and therefore consumable by the animal. This diagnostic approach (Figure 2) is particularly applicable for dermatological reactions, as the allergic nature of many forms of dermatitis caused by adverse food reaction appears to have been ascertained; the same approach, however, is not equally suitable in gastroenterology, as the aetiological factors at the basis of the so-called diet-responsive diarrhoeas have not yet been fully explained.
Fig. 2. Exclusion diet and food provocation test in the diagnosis of allergic dermatitis of food origin.
Notes:
1Should the symptoms not regress, consider the possibility that the animal may have also ingested non prescribed foods or that it may be allergic against a component of the exclusion diet
2Should the symptoms not reappear, consider the possibility that a food allergy may still be present but the offending food is not present in the challenge diet
In animals, other tests sometimes proposed for the diagnosis of food allergy/intolerance – including IgE determination and intradermal skin tests – are in fact unreliable, as they generate a high number of false positive results (Gaschen and Merchant, 2011; Bethlehem et al., 2012; Hardy et al., 2014).
Which diet to use in the diagnosis of adverse food reactions?
As already mentioned, the diagnosis of adverse food reaction is based on the use of an exclusion diet, meaning, ideally, a diet based on ingredients that the animal has never taken and that excludes foods previously taken. In clinical practice it is however very difficult to know exactly what ingredients the animal is taking, especially if it is fed with a commercial diet (for companion animals, today's legislation does not provide for the obligation to indicate on the label the list of the individual ingredients; the producer may thus decide to list only the categories of ingredients used) and/or with table scraps.
This is why in order to reduce the risk that an exclusion diet may contain a protein against which the animal is allergic the diet should contain a limited number of ingredients, chosen among the so-called "unconventional" ingredients, meaning those rarely used by the pet food industry (this is true not only for foods used as a protein source but also for those used as a source of starch and lipids).
If in compliance with the above indications, exclusion diets can be either homemade or commercial; it is however undisputed that homemade diets provide the best guarantee concerning what the animal is indeed receiving. Special commercial diets are also present, of great interest for the diagnosis (and management) of food allergy and intolerance, consisting of products containing hydrolysed proteins. These diets contain proteins previously subjected to a chemical-enzymatic hydrolysis process, which significantly reduces their molecular weight and, consequently, their allergenic potential.
There is however evidence of the fact that the commercial diets proposed for animals with suspected or confirmed diagnosis of adverse food reaction often contain proteins not specified on the label (Ricci et al., 2012), presumably due to carry-over phenomena (the residues of an earlier production contaminate the food in question) or to the presence of proteinaceous contaminants (the so-called hidden allergens) in the raw materials used. Similarly, should a homemade exclusion diet be used, it is good to remember that the use of particular ingredients (i.e. commercial nutritional supplements, but not only) could represent a source of occult allergens and that the different steps of meal preparation must be carefully monitored in order to minimise the risk of contamination with unwanted proteins. Finally, it should be remembered that a homemade exclusion diet, typically constituted by a pair of ingredients only, cannot clearly represent a complete and balanced diet and should therefore not be given to the animal for long periods of time, especially when dealing with growing subjects.
PREVENTION OF FOOD ALLERGIES
Although the problem of food allergy has been the object of numerous studies in the human field, little is known about strategies to prevent its occurrence; this is even more true with regards to the dog and cat. To date, in human medicine, studies designed to test the effectiveness of specific nutritional strategies (supplementing the diet with nutrients such as vitamin D, omega-3 essential fatty acids, antioxidant molecules, probiotic bacteria and prebiotic molecules) have produced results which are inconclusive, to say the least (de Silva et al., 2014). Similarly, no evidence exists of the fact that the exclusion of an ingredient considered at risk from the mother's diet (during pregnancy and lactation) and from the offspring (in the first years of life) is an effective allergy prevention strategy against that same ingredient (Lack, 2012). Conversely, should future studies confirm the "dual-allergen exposure" theory, the dietary restriction often recommended by paediatricians could even have a detrimental effect, resulting in an increased risk of developing food allergies.
In view of the absence of any certainty, it is today impossible to propose a scientifically sound food strategy, aimed at the prevention of food allergies in puppies and kittens. An advice that can certainly be given is to avoid the administration of many different protein sources to subjects that may have an altered intestinal permeability (e.g., bowel infection and parasites, surgery, trauma, intake of foods containing high levels of biogenic amines), as they may trigger allergic sensitisation. In the presence of such conditions it might be necessary to recommend the use of commercial hydrolysed protein diets, the only truly hypoallergenic diets available.
CONCLUSIONS
Although their incidence is relatively low, adverse food reactions are a problem that Veterinarians must consider in the differential diagnosis of various disease states, particularly in those involving the skin and the GI tract of dogs and cats. Exclusion diets are still today the only truly reliable diagnostic tool available, be them homemade or specifically formulated commercial diets. Unfortunately, existing knowledge on how to prevent food allergies is still extremely limited, in both veterinary and human medicine.
References
ll1. Allenspach K. et al. 2007. Chronic enteropathies in dogs: evaluation of risk factors for negative outcome. J. Vet. Intern. Med. 21:700-708.
2. Bethlehem S. et al. 2012. Patch testing and allergen-specific serum IgE and IgG antibodies in the diagnosis of canine adverse food reactions. Vet. Immunol. Immunopathol. 145:582-589.
3. Biourge V. et al. 2004. Diagnosis of adverse reactions to food in dogs: efficacy of a soy-isolate hydrolyzate-based diet. J. Nutr. 134:2062S-2064S.
4. Burks W. 2004. Food allergens. J. Allergy Clin. Immunol. 18:319-337.
5. Carlotti D.N. et al. 1990. Food allergy in dogs and cats. A review and report of 43 cases. Vet. Dermatol. 1:55-62.
6. Chesney C.J. 2002. Food sensitivity in the dog: A quantitative study. J. Small Anim. Pract. 43:203-207.
7. Chirino A.J. et al. 2004. Minimizing the immunogenicity of protein therapeutics. Drug Discov. Today 9:82-90.
8. Chung S.Y. et al. 2003. Linking peanut allergenicity to the processes of maturation, curing, and roasting. J. Agric. Food Chem. 51:4273-4277.
9. De Silva D. et al. 2014. Primary prevention of food allergy in children and adults: systematic review. Allergy 69:581-589.
10. Denis S. e Paradis M. 1994. L’allergie alimentaire chez le chien et le chat. Etude retrospective. Med. Vet. Que. 1:15-20.
11. Feehley T. et al. 2012. Microbial regulation of allergic responses to food. Semin. Immunopathol. 34:671-688.
12. Gaschen F.P. e Merchant S.R. 2011. Adverse food reactions in dogs and cats. Vet. Clin. Small Anim. 41:361-379.
13. Hardy J.I. et al. 2014. Food-specific serum IgE and IgG reactivity in dogs with and without skin disease: lack of correlation between laboratories. Vet. Dermatol. 25:447-456.
14. Ho M.H-K. et al. 2014. Clinical spectrum of food allergies: a comprehensive review. Clin. Rev. Allerg. Immu. 46:225-240.
15. Jeffers J.G. et al. 1996. Responses of dogs with food allergies to single-ingredient dietary provocation. J. Am. Vet. Med. Assoc. 209:608-611.
16. Lack G. 2008. Epidemiologic risks for food allergy. J. Allergy Clin. Immunol. 121:1331-1336.
17. Lack G. 2012. Update on risk factors for food allergy. J. Allergy Clin. Immunol. 129:1187-1197.
18. Loeffler A. et al. 2004. Dietary trials with a commercial chicken hydrolysate diet in 63 pruritic dogs. Vet. Rec. 154:519-521.
19. Lowrie M. et al. 2015. The clinical and serological effect of a gluten‐free diet in Border Terriers with epileptoid cramping syndrome. J. Vet. Intern. Med. 29:1564-1568.
20. Mandigers P.J.J. et al. 2010. A randomized, open‐label, positively‐controlled field trial of a hydrolyzed protein diet in dogs with chronic small bowel enteropathy. J. Vet. Intern. Med. 24:1350-1357.
21. Proverbio D. et al. 2010. Prevalence of adverse food reactions in 130 dogs in Italy with dermatological signs: a retrospective study. J. Small Anim. Pract. 51:370-374.
22. Ricci R. et al. 2012. Identification of undeclared sources of animal origin in canine dry foods used in dietary elimination trials. J. Anim. Physiol. An. N. 97:32-38.
23. Scott D.W. et al. 2001. Skin immune system and allergic skin diseases. In: Muller and Kirk’s Small Animal Dermatology:615-624.
24. Sicherer S.H. 2002. Food allergy. Lancet 360:701-710.
25. Vaden S. L. et al. 2000. Food hypersensitivity reactions in Soft Coated Wheaten Terriers with protein‐losing enteropathy or protein‐losing nephropathy or both: gastroscopic food sensitivity testing, dietary provocation, and fecal immunoglobulin E. J. Vet. Intern. Med. 14:60-67.
26. Verlinden A. et al. 2006. Food allergy in dogs and cats: a review. Crit. Rev. Food Sci. 46: 259-273.
27. Walton, G.S. 1967. Skin responses in the dog and cat to ingested allergens. Vet. Rec. 81:709-713.
28. White S.D. 1986. Food hypersensitivity in 30 dogs. J. Am. Vet. Med. Assoc. 188:695-698.
29. Wilhelm S. and Favrot C. 2005. [Food hypersensitivity dermatitis in the dog: diagnostic possibilities. Schweiz. Arch. Tierheilkd. 147:165-171.
30. Worm M. et al. 2014. Food allergies resulting from immunological cross-reactivity with inhalant allergens. Allergo J. 23:1-16.