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Protein hydrolysates: Do they really work ? Vincent C Biourge, DVM PhD Dipl ACVN & ECVCN Royal Canin, Centre de Recherche, Aimargues.

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Presentation on theme: "Protein hydrolysates: Do they really work ? Vincent C Biourge, DVM PhD Dipl ACVN & ECVCN Royal Canin, Centre de Recherche, Aimargues."— Presentation transcript:

1 Protein hydrolysates: Do they really work ? Vincent C Biourge, DVM PhD Dipl ACVN & ECVCN Royal Canin, Centre de Recherche, Aimargues

2 Adverse Reactions to Food Food intolerance Food Allergy Dermatologic: pruritus, alopecia,otitis,.. Gastrointestinal: vomiting, abd. discomfort Respiratory: asthma, rhinitis,... General: headache, arthritis,... Immune mediated (IgE, cell mediated) Non immune mediated (Lactose, chocolate, bioamines, additives, …) Probably the main cause (Olivry T, J Vet derm 2010)

3 Adverse Reactions to Food Diagnosis Clinical signs Novel ingredients Improvement of the clinical signs 4 to 12 Weeks Elimination diet Challenge Clin. signs Double blinded Dr Thierry Ximenes (France) + Serum IgE + Skin test

4 Definition Diets composed of ingredients to which the dog has not been exposed. Dietary history Home made Starch sources: Rice, Potato, Tapioca Protein sources: Lamb, Horse, Fish, Turkey, Venison,.. Essential fatty acids, Minerals and Vitamins Commercial Lamb & Rice, Fish & Potatoes, Venison & Potatoes Over the counter Not hypoallergenic ! Intact protein sources ! Sustainability Fish, Rabbit, Duck, Venison, … Elimination diets Gold standard Raditic et al, JAPAN 2010

5 Protein hydrolysates 2001 A new strategy to treat adverse reaction to food Enzymatic Hydrolysis protein polypeptides

6 Easier to digest Short half-life in the lumen Smaller peptides Molecular weight < 16 Kd Benefits of hydrolysate Cave, 2006

7 Do they really work ? What is the background ? Should molecular weight be as low as possible ? Are they trully hypoallergenic ? Can they be qualified as allergen free ? Are their efficacies substantiated by clinical studies ? Protein hydrolysates

8 Background Elisa immunoreactivity of soy protein depending of its source 1.Soy flour 2.Soy concentrate 3.Soy hydrolyzate Lallès, 1995 Adverse reaction to soy in milk replacer Poor appetite and growth Malabsorption/maldigestion – Diarrhea Soy antibodies Villus atrophy

9 Background Protein hydrolysate based milk replacer. Babies at risk for allergy Risk of cow milk allergy Baby allergy to cows milk Vomiting diarrhea Atopic dermatitis/ Urticaria Asthma/Rhinitis /

10 Dalton Arbitrary unit of atomic mass Sir John Dalton, Founder of the atomic theory 1 Dalton (d) = Weight of 1/12 nuclide of 12 C gramme Glycin = 75 d - Tryptophan = 204 d Casein = d or Kd Measurement: electrophoresis - chromatography Molecular weight Human serum albumin = 69 Kd

11 Molecular weight Mean Max Ingredients Vs diets Cave N, 2006 Mean MW

12 Most common food allergens Glycoproteins Protein with glucide moiete ? Lipids (Bacterial glycolipids) ? Carbohydrates Water - soluble Heat and acid resistants Molecular weight 10 to 40 Kd Small enough to pass the intestinal wall Large enough to induce immune reaction Antigens in selected food in man Sampson HA, 1993 Molecular weight Cave N, 2006 Looringh van Beeck FA, 2009

13 kDa 3 – 10 kDa 1– 3 kDa < 1 kDa > 40 kDa Highly reduced allergy No allergy Reduced allergy Most common Less common allergy Molecular weight Molecular weight Guilford GW,1996 Serra et al, 2006 Olivry T, 2010 Cave N, 2006

14 Molecular weight Antigenicity Epitope Few Many Close in 3D Hidden Gastroscopic score diameter Olson ME et al 2000

15 Molecular weight Antigenicity AJVR 2006;67:

16 Molecular weight Digestibility Soy source and aa ileal digestibility in calfs Lallès, 1995 Soy source and in vitro N digestibility Royal Canin, 2004 Cave NJ, Marks SL. Evaluation of the immunogenicity of dietary proteins in cats and the influence of the canning process. AJVR 2004; 10,

17 « The number of IgE binding sites on the allergen, their location, and the tertiary shape of the protein are probably more important than the molecular weight » S.F. Hefle, 1996 Source of protein (Casein Vs Soy) Process - type of hydrolysis -exposure of epitopes Problem measuring MW on finished product Cut-off Molecular weight

18 In vitro testing - ELISA Immunogenicity Hannah, 1997

19 Western blot Immunogenicity native hydrolysed AJVR 2006; 67:

20 Skin test Immunogenicity Puigdemont et al, 2006 % of reduction of the wheal areas for soy hydrolysed versus native soy protein Soy protein concentration Dog 1 g/ml 10 g/ml 100 g/ml 1T2 53,8 45,7 42,0 1T3 53,5 54, T2 95,6 18,4 44,6 2T6 81, ,4 3T2 59,7 58,4 37,4 3T ,157,6 Mean SD 65,3 19,1 53,0 20,4 53,4 17,7 Control showed no wheal on both challenges

21 Clinical reactions Immunogenicity Puigdemont et al,2006 Control and 3 other sensitised dogs showed no adverse reactions Dogs Native soy protein Hydroly sed soy protein Soy specific IgE 8204 Vomits Diarrhoea (1) Pruritus NR Diarrhoea (2)NR Diarrhoea (2)NR++

22 Clinical reactions Immunogenicity Jackson et al, maltese x Beagle dogs with known clinical hypersensitivity to soy and corn No corn and starch diet Corn starchCornSoySoy hydrolysate diet 200 mg/kg bw Cutaneous Clinical Score (Max 35*3*3)

23 Immunogenicity Stomach reactivity Gastroscopic score diameter Olson ME et al 2000

24 Conclusion Hydrolyzed proteins are less antigenic than intact proteins. Hydrolyzed proteins are not anallergenic except if hydrolyzed to single or few amino acids. High digestibility is an important factor in reducing antigenicity. Immunogenicity

25 Clinical trials Shown efficacy Managing adverse reaction to food. Diagnosis of adverse reaction to food. Inflammatory bowel disease. Exocrine pancreatic insufficiency.

26 Clinical reactions Adverse reaction to food Jackson et al, maltese x Beagle dogs with known clinical hypersensitivity to soy and corn 3/14 dogs increased scores on hydrolyzed diet. No corn and starch diet Corn starchCornSoySoy hydrolysate diet 200 mg/kg bw Cutaneous Clinical Score

27 Evaluation on dogs with demonstrated adverse reactions to food 12 dogs ( breeds, sex, food allergy ) Controlled allergy (no clinical signs) Clinical 0 and 2 months (CADESI) Owners requested to report: –Pruritus, abnormal behavior of the dog –Digestive tolerance –Palatibility None of the 12 dogs relapsed Perfect tolerance J. Fontaine, CNVSPA 2001 Adverse reaction to food

28 Diagnosis of ARF Clinical signs 8 Weeks Soy hydrolysate diet Challenge Clin. signs 1.Recovery challenge + Adverse Reaction to Food (ARF) 2. Marked improvement challenge + ARF + atopy 3.Little or no improvement other elimination diet Recovery 4. Little or no improvement other elimination diet no improvement ? atopy No corticotherapy 2 dermatology specialty pratices J Fontaine (Brussels, B), M Vroom (Oisterwijk, NL) Inclusion in the study: Suspicion of skin hypersensitivity VC Biourge, J Fontaine, MW Vroom, 2004 J Nutr2002;134:2062S-2064S

29 Diagnosis of ARF 60 dogs included 31 M-3 MC - 13 F - 13FS Age 4.5±0.4 yrs (3 mo – 11 yrs ) 26 breeds German Sheperd (10), Bouledogue Français (2), Bouvier des Flandres (2), Boxer(5), English Cocker Spaniel (2), Golden Retriever (4), Jack Russel (2), Labrador (4), Shar Pei (3), Shi Tsu (2), WHWT (5), … Duration of the clinical signs 2.6±0.4 yrs (3 weeks – 10 yrs) Adverse Reaction to Food Atopy cases excluded

30 Diagnosis of ARF Adverse reaction to food *** 20 dogs 9 M-1 MC - 6 F – 4 FS Age 3.8±0.6 yrs (6 mo – 9yrs) No more pruritus No or very mild clinical signs left. Challenge + 18/20 responded to soy hydrolysate diet Rabbit and Rice Homemade soy diet

31 Golden Retriever Male, 4.5 yrs, 29.6 kg Generalized intense prurit with lichenification, hyperpigmentation BeforeAfter Diagnosis of ARF

32 Adverse reaction to food & Atopy *** 16 dogs 8 M-1 MC - 2 F – 5 FS Age 5.7±0.7 yrs (3 mo – 11yrs) Pruritus marketly improved Mild to moderate clinical signs left. Challenge + All dogs responded to the soy hydrolysate diet.

33 Diagnosis of ARF Atopy 22 dogs 13 M-1 MC - 5 F – 4 FS Age 4.5±0.6 yrs (1.2 – 11yrs) No or little improvement of pruritus, clinical signs. No response to other elimination diets and + to skin test

34 Diagnosis of ARF ARF: response to the hydrolysate 94.4 % of ARF dogs responded to the soy hydrolysate based diet

35 Diagnosis of ARF Other study Loeffler et al., Vet Derm 2006;17: Chicken hydrolysate diet Vs homade diets 181 dogs 17 dogs excluded 35 allergic skin disease ARFAtopy ARFAtopy 15 Poultry hydrolyzate (109) Homade (72) Excluded: 27Excluded: 13 No significant difference

36 Veterinary Dermatology,2010,21: dogs selected and divided In 2 groups 1 dog showed severe signs when fed hydrolyzed chicken

37 Before After Diagnosis of ARF Cats Dr Aranda

38 Diagnosis of ARF ARF: response to the hydrolysate 87.5 % of ARF cats responded to the soy hydrolysate based diet MW Vroom, C. Swinnen, A clinical study of a soy protein isolate hydrolysate diet, in dogs and cats with adverse reactions to food. Proc. of Voorjaarsdagen

39 Food responsive chronic diarrhea

40 Dogs: –26 dogs over a 2 yr-period. –24/26 dogs with IBD –4 IF, 10 SF, 8 IM, 4 CM. –Age: 4.3 ± 3.3 yrs ( yrs) –Weight 23 ± 12 kg ( kg) –Duration of the clinical signs: 1 to 36 months before presentation. Treatments before inclusion: –Antibiotics (7), Metaclopramide (6), cimitidine (6), Prednisolone (4), sulfazalazine (3). Diets before inclusion: –Low residue intestinal diets (7), novel protein diets including homemade (12), other diets (7). Food responsive chronic diarrhea Mandigers et al., 2010 Objectives To compare the response of dogs with chronic diarrhea on soy hydrolysate Vs intestinal diet.

41 Clinical signs after 2 months No more clinical signs 23/26 dogs 3 last dogs improved but vomiting and diarrhea persisted 11% 12.5% Food responsive chronic diarrhea * Weight gain

42 Follow-up after median 6 months, range 3-15 mo. 15/16 test dogs – 6/7 control dogs 87 % of dogs on hydrolyzate diet remained free of clinical signs on follow-up ! The signs were minor in the remaining 2 dogs. 13% 67% Food responsive chronic diarrhea

43 Similar findings by other authors. Marks SL, Laflamme D, McCandlish A. Dietary trial using a commercial hypoallergenic diet containing hydrolyzed protein for dogs with IBD. Vet Ther 2002; 3: Similar finding in cats 8 cats Chronic diarrhea (4-36 Mo) 1 Colitis, 2 gastritis 6 IBD Soy hydrolyzate based diet Resolution of clinical signs within 4-8 d Median weigh gain 0.75 kg within 2 Mo 11Mo follow-up 6/8 cats free of clinical signs

44 German Shepherds EPI and skin disease GI signs controlled within 7 d Weight gain with 2 months Skin within 3 months Exocrine pancreatic Insufficiency J Nutr2002;134:2166S-2068S

45 Conclusion Hydrolyzed proteins are less antigenic than intact proteins. Molecular weight (except if extremly low (<1Kd) is a poor predictor of protein immunogenicity. Hydrolyzed protein based diet are not anallergenic. Hydrolyzed proteins are sustainable. Clinical studies to support benefits in: Diagnosis and management of ARF Idiopathic chronic diarrhea - IBD Exocrine pancreatic insufficiency ? Perianal fistula. Protein hydrolysates

46 If you want to know more … Obrigado …

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