Adverse Reactions to Food: Chronic Adverse Immunological Responses to Dietary Antigens
Introduction
The inflammatory bowel diseases (IBD) are the most common causes of chronic vomiting and diarrhea in dogs and cats, and refer to a group of idiopathic, chronic gastrointestinal tract disorders, characterized by infiltration of the lamina propria by lymphocytes, plasma cells, eosinophils, macrophages, neutrophils, or combinations of these cells.1 The diagnosis of IBD requires the comprehensive exclusion of potential causes of gastrointestinal inflammation, including intestinal parasites, small intestinal bacterial overgrowth, bacterial enterocolitis, dietary intolerances, and neoplasia.1 Failure to eliminate known causes of gastrointestinal inflammation which can mimic IBD can result in a poor response to dietary or pharmacologic therapy. The etiology of canine and feline IBD is poorly understood, but the main hypothesis for the etiopathogenesis of human IBD is that there is dysregulation of mucosal immune responses to intestinal microflora and/or dietary antigens.2-5 There is evidence from clinical observations and animal models to incriminate normal luminal bacteria or bacterial products in the initiation and perpetuation of the disease.6 In addition, antibiotics are often empirically administered in cases of IBD as adjunctive or primary therapy, and there is widespread acceptance of their efficacy.7,8
Regardless of the underlying etiology for any given patient, abnormal immune responses to dietary antigens are often suspected, and the clinical response to novel protein diets supports that hypothesis.9,10 Exaggerated humoral and cellular responses, and clinical food intolerance have been recorded in human IBD patients.11-13 Serum IgG concentrations specific to dietary antigens are consistently greater in dogs with chronic gastrointestinal disease than normal dogs, and fecal IgE specific to dietary antigens is consistently found in Soft Coated Wheaten terriers with IBD.14,15 However, the frequency with which these might occur and the significance that immune responses play in the pathogenesis of canine and feline IBD are unknown. Also unknown in any given patient is whether any abnormal immune response to the diet is the cause or result of a mucosal infiltrate. If the cause, it is expected that removal of the inciting antigen would lead to improvement. If the effect, it still may be that removing the largest single source of antigen during an elimination-diet trial is sufficient to reduce the inflammatory stimulus, allowing restoration of normal intestinal immunity. Because of the consistent partial or complete response, restriction or manipulation of individual dietary components is perhaps the single most important factor in the treatment of IBD, and may be sufficient in mild cases. Despite this fact, there is a paucity of information pertaining to the nutritional requirements of dogs and cats with IBD.
Potential Role of Dietary Antigens in the Pathophysiology of IBD
As stated, exaggerated responses to dietary antigens are often suspected in canine and feline IBD. Elimination diets have proved to be effective in dogs and cats with small and large intestinal lymphocytic-plasmacytic, eosinophilic, and mixed cellular infiltrates.9,10,16,17 In a study of 16 feline cases of elimination-challenge proven dietary hypersensitivity with chronic gastrointestinal signs, all 16 cats had mild to severe inflammatory infiltrates in at least one region of the bowel.16 The infiltrates were lymphocytic, lymphocytic-plasmacytic (most cases), or eosinophilic (2 cases). All cases responded completely to the elimination diet alone and offending foods were identified in all cases. In a report of 13 dogs with lymphocytic-plasmacytic colitis, clinical signs resolved in all 13 with the introduction of an elimination diet, and of 11 dogs re-challenged with their original diet, 9 relapsed.10 In a further report of 6 cats with lymphocytic-plasmacytic colitis, all 6 responded completely to an elimination diet.9 A complete clinical response to an elimination diet has been reported in a cat with duodenal and ileal lymphocytic infiltrates so severe that a histological diagnosis of intestinal lymphosarcoma was made.18
The application of food extracts to the intestinal mucosa can result in immediate hypersensitivity responses that can be visualized endoscopically. Extracts can be either dribbled onto the gastric mucosa over an endoscopic biopsy site, or injected directly into the mucosa. Colonic mucosal injections have proven to be efficient in detecting dogs with a type-I IgE mediated food hypersensitivity that was associated with gastrointestinal signs.19 It is unknown what percentage of dogs or cats with IBD might have similar immediate responses, and if the identification of immediate responses could be useful clinically in such cases. In the author's practice, gastroscopic food testing has been used in canine IBD using conventional allergen extracts with little success. However, the use of crude dietary protein extracts may prove to be more useful in the future.
The theoretical basis for the use of protein hydrolysate diets in IBD is that a reduction in immunogenic epitopes being presented to the mucosal immune system whilst dysregulation is present, will increase the potential for resolution. Thus the argument for the use of a hydrolysate diet is independent of whether a dietary specific immunological response is suspected to be present or not. Experience with protein hydrolysate diets is increasing, and anecdotally they appear to be very effective adjuncts to pharmacological therapy, even as sole therapy. Clinical resolution with histological improvement has been reported in 4 of 6 dogs with refractory IBD when treated with a hydrolyzed soy-protein diet alone.20 A similar study of dogs with IBD documented equally beneficial results utilizing a different hydrolyzed soy protein diet (Biourge V, personal communication).
Although small and uncontrolled, these results are encouraging, since 5 cases in the first study had previously failed elimination diet trials. However, it is possible that nutritional factors other than protein hydrolysis are responsible. These could include dietary digestibility, correction of vitamin or mineral deficiencies, and a lowered n-6:n-3 fatty acid ratio, and the potential for an immunomodulatory effect of soy isoflavones within the diet. One could argue that IBD should not be "diagnosed" if there is a complete response to dietary therapy alone and that a diagnosis of dietary intolerance should be made. However, this is probably more semantic than helpful, since it is equally possible that eliminating the quantitatively most significant antigen source is sufficient to eliminate clinical signs, reduce inflammation, and allow restoration of normal mucosal immunity, even if dietary hypersensitivity is not the primary pathogenic process.
Non-Immunological Adverse Reactions to Food
Cases of gastrointestinal disease that respond completely to appropriate dietary management and that have no histological evidence of enteritis or morphological changes, have been referred to as cases of food responsive vomiting or diarrhoea.21 In practice, cats and dogs that present with chronic vomiting and/or diarrhoea will usually be subjected to an elimination dietary trial prior to the collection of intestinal biopsies. Therefore, when vomiting or diarrhoea resolves on an elimination trial and no intestinal biopsies have been taken, the disease could be dietary hypersensitivity, dietary intolerance, or mild IBD. In those cases, the terms "food responsive diarrhoea", or "adverse food reaction" are appropriate. However, there are some circumstances that lead to procurement of intestinal biopsies prior to a dietary trial, which in some cases can produce unremarkable histological findings. In those cases, an adverse reaction to food cannot and should not be excluded.
The ideal diagnostic and long-term diets for patients with adverse food reactions are based mostly on protein novelty, or protein hydrolysis. However, other mechanisms than the immunological responses to dietary antigens are probably more important when no inflammatory mucosal infiltrate is present. In a study of 55 cats with chronic vomiting and/or diarrhoea, 16 cats were diagnosed as having food sensitivity based on elimination-challenge trials.16 However, a further 11 cats responded completely to an elimination diet, but did not recrudesce during a challenge trial. Similar to the food sensitive cats, the non-food sensitive cats had a range of histopathological changes from none to moderate lymphocytic-plasmacytic enteritis.
It is clear then that a large number of dogs and cats with chronic idiopathic gastrointestinal disease will respond completely to dietary manipulation. In the absence of a specific protein hypersensitivity, the mechanisms remain obscure. Possible mechanisms are listed in the table below. However, ignorance of underlying mechanisms further increases the desire to manage such cases with highly digestible diets that contain as few ingredients as possible. The same general approach to the dietary choices for acute gastroenteritis is probably suitable for such cases.
Potential mechanisms for non-immunological adverse food reactions.
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Factor
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Mechanism
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Digestibility
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Poorly digestible nutrients leading to bacterial fermentation, osmotic diarrhoea etc
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Lactase deficiency
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Undigested lactose leading to fermentation and osmotic diarrhoea
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Nutrient deficiency
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e.g., zinc, B12 leading to mucosal dysfunction
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Fiber
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Fiber responsive diarrhoea--promotion of water resorption, restored motility, pre-biosis, increased fecal bulk, passage of hairballs
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Food additives
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Idiosyncratic, pharmacological
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References
1. Guilford WG. Idiopathic inflammatory bowel diseases. In: Guilford WG, Center SA, Strombeck DR, Williams DA, Meyer DJ, eds. Strombeck's Small Animal Gastroenterology 3rd ed. Philadelphia: W.B. Saunders; 1996.
2. Guarner F, Casellas F, Borruel N, et al. Role of microecology in chronic inflammatory bowel diseases. Eur J Clin Nutr 2002;56 Supplement 4:S34-S38.
3. Magne ML. Pathophysiology of inflammatory bowel disease. Semin Vet Med Surg (Small Anim) 1992;7:112-116.
4. Giaffer MH, Cann P, Holdsworth CD. Long-term effects of elemental and exclusion diets for Crohn's disease. Aliment Pharmacol Ther 1991;5:115-125.
5. Belsheim MR, Darwish RZ, Watson WC, et al. Bacterial L-form isolation from inflammatory bowel disease patients. Gastroenterology 1983;85:364-369.
6. Rutgers HC, Batt RM, Elwood CM, et al. Small intestinal bacterial overgrowth in dogs with chronic intestinal disease. J Am Vet Med Assoc 1995;206:187-193.
7. Tams TR. Feline inflammatory bowel disease. Veterinary Clinics of North America--Small Animal Practice 1993;23:569-586.
8. Jergens AE. Rational use of antimicrobials for gastrointestinal disease in small animals. J Am Anim Hosp Assoc 1994;30:123-131.
9. Nelson RW, Dimperio ME, Long GG. Lymphocytic-plasmacytic colitis in the cat. J Am Vet Med Assoc 1984;184:1133-1135.
10. Nelson RW, Stookey LJ, Kazacos E. Nutritional management of idiopathic chronic colitis in the dog. J Vet Intern Med 1988;2:133-137.
11. Pearson M, Teahon K, Levi AJ, et al. Food intolerance and Crohn's disease. Gut 1993;34:783-787.
12. Van Den BJ, Cahill J, Emmanuel AV, et al. Gut mucosal response to food antigens in Crohn's disease. Aliment Pharmacol Ther 2002;16:1903-1915.
13. Van Den BJ, Kamm MA, Knight SC. Immune sensitization to food, yeast and bacteria in Crohn's disease. Aliment Pharmacol Ther 2001;15:1647-1653.
14. Foster AP, Knowles TG, Moore AH, et al. Serum IgE and IgG responses to food antigens in normal and atopic dogs, and dogs with gastrointestinal disease. Vet Immunol Immunopathol 2003;92:113-124.
15. Vaden SL, Hammerberg B, Davenport DJ, et al. 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 VetInternMed2000Jan-Feb;14(1):60-7 2000;14:60-67.
16. Guilford WG, Jones BR, Markwell PJ, et al. Food sensitivity in cats with chronic idiopathic gastrointestinal problems. J Vet Intern Med 2001;15:7-13.
17. Hirt R, Iben C. Possible food allergy in a colony of cats. J Nutr 1998;(Supplement) 128:2792S-2794S.
18. Wasmer ML, Willard MD, Helman RG, et al. Food intolerance mimicking alimentary lymphosarcoma. J Am Anim Hosp Assoc 1995;31:463-466.
19. Allenspach K, Vaden SL, Harris TS, et al. Evaluation of colonoscopic allergen provocation as a diagnostic tool in dogs with proven food hypersensitivity reactions. J Small Anim Pract 2006;47:21-26.
20. Marks SL, Laflamme DP, McCandlish AP. Dietary trial using a commercial hypoallergenic diet containing hydrolyzed protein for dogs with inflammatory bowel disease. Veterinary Therapeutics 2002;3 109-118.
21. German AJ, Hall EJ, Day MJ. Immune cell populations within the duodenal mucosa of dogs with enteropathies. J Vet Intern Med 2001;15:14-25.