Inflammation

Bowel disorders are common in dogs, and they are often related to intestinal inflammation.

Dog models have been used to bridge the gap in scientific studies because they share similar pathophysiology to humans. The spontaneous canine model shares remarkable homology to human IBD including known genetic basis, impact of gut bacteria, similar clinical presentation and disease activity, method of diagnosis (biopsy), and positive response to immunosuppressive therapy. While not used as the sole marker consistently elevated calprotectin may be associated with a diagnosis of IBD in dogs, as it is in humans.                                                                                                

CALPROTECTIN  

What is it:
Fecal (fCP) concentration is a sensitive but nonspecific marker of intestinal inflammation in adult dogs, and is useful for differentiating organic intestinal disorders from functional disorders.[1] Calprotectin has demonstrated a high sensitivity for organic intestinal disease. Calprotectin is expressed mostly by neutrophils, monocytes and activated macrophages, and also has bacteriostatic and fungistatic properties that protects intestinal epithelia.[2] GI conditions have been divided into organic (OBD) and functional (FBD) disorders. Organic diseases have measurable physiological changes, such as the intestinal inflammation found in Inflammatory bowel disease (IBD). Examples of functional GI disorders, include irritable bowel syndrome (IBS) or functional abdominal pain, they cause symptoms but are not associated with any physiological damage. Calprotectin has also been used for monitoring IBD activity and predicting relapse.[3]

Possible causes of elevated calprotectin:

  • IBD can cause elevations or relapses. Testing may aid in identifying and monitoring disease.
  • Calprotectin has been used as a surrogate marker of disease severity in dogs with chronic inflammatory enteropathies.[4] Elevated fecal calprotectin predicted severe clinical signs CCECAI scores ≥12 (canine chronic enteropathy clinical activity index), and correlated with histologic inflammatory lesions, particularly lamina propria lymphocytes in the ileum.[4, 5]
  • Obesity and type 2 diabetes are conditions characterized by chronic inflammation and increased intestinal permeability in humans and may have an impact in dogs.[6]
  • Calprotectin was increased in dogs eating a high-protein greaves-meal (HPGM) diet.[2]
  • Fecal calprotectin can be significantly influenced by age, with higher concentrations in younger puppies, but was not influenced by viral or parasitic infection.[7]

Treatments:
If a dog has a high level of calprotectin and any alarming symptoms it is recommended IBD, malignancy, or other cause of significant GI inflammation is rule-out. Lower levels may help differentiate which clients may not need further evaluation, or those that may benefits from other treatments first. A low level identifies that GI inflammation is unlikely. A moderate level may address the cause of inflammation and recheck in 4-8 weeks.

  • Evaluate diet. Anti-inflammatory diet or immune support supplement
    • Fecal calprotectin was higher on a high-protein greaves-meal diet [crude protein: 609 g/kg, starch: 54 g/kg].[2] Consider a better quality food.
  • Address possible causes of inflammation:
    • Suspected or history of IBD – A protective effect of probiotic VSL#3 (renamed as Visbiome) significantly decreased clinical and histological scores and decreased CD3+ T-cell infiltration in dogs with IBD.[8]
    • Chronic NSAID use can lead to increased levels.
    • Colorectal polyps or cancer.
  • Lower pretreatment concentrations of fecal calprotectin in dogs that have failed dietary and antibiotic treatment trials could indicate a higher likelihood of a response to anti‐inflammatory/immunosuppressive treatment.[4]
  • Minimizing anxiety and stress.
SECRETORY IGA:

What is it:
“Beneficial (i.e., mutualists) bacteria promote mucosal health by strengthening barrier integrity, increasing local defenses (mucin and IgA production) and inhibiting pro-inflammatory immune responses and apoptosis to promote mucosal homeostasis.”- Albert Jergens [9]

IgA is an important antibody isotype involved in protective responses on mucosal surfaces. It acts primarily by effectuating immune exclusion of foreign material. sIgA is a marker of intestinal maturation in young animals, and an indicator of intestinal inflammation and immunity in adult dogs. It is the dominant antibody type found in mucosal secretions, in the protective layer between the mucosa and microbe, and is thought to regulate the intestinal microbiota.[10] The difference among species in the number of genes coding for α chains; humans have 2, and dogs only 1. In humans there are 2 subclasses IgA1 found in serum and IgA2 in secretions, a dichotomy absent in dogs. 

Possible causes of elevated and lower mucosal sIgA:

  • Age and diet interaction were observed for fecal IgA. Puppies had lower fecal IgA concentrations than mature dogs, while seniors had intermediary results.[11]Reduced fecal IgA concentration in puppies is consistent with the reduced serum and salivary IgA concentrations reported previously, suggesting a reduced mucosal immunity in this age group. Fecal IgA concentration may be influenced by enteropathogen shedding with a lower fecal IgA concentration in puppies shedding enteropathogen compared to puppies without. Fecal calprotectin and IgA may help to help to better understand the maturation of digestive tract.[7]
  • Low levels may indicate inadequate immune response. Selective IgA deficiency (SIgAD) is the most common immunodeficiency disease in dogs and humans and has consequences for mucosal immunity. In humans and dogs, symptomatic patients with SIgAD suffer most prominently from recurrent respiratory and gastrointestinal infection, as well as various forms of autoimmunity, allergy and canine atopic dermatitis. SIgAD has been defined as an undetectable fecal IgA concentration (i.e., below the lower detection limit) on four fecal samples [10, 12]
  • Low levels of IgA concentrations have been associated with canine atopic dermatitis.[10]

Treatments:

  • Consider changing protein source. Adult dogs fed soybean meal diet had increased IgA, older dogs also had higher levels with a soy diet and a diet supplemented with fermentable fibers. [7]
  • Probiotics (Lactobacillus) significantly increased average daily feed intake of elderly dogs and average daily weight gain of all dogs, with enhanced the level of fecal SIgA, and concurrently reduced the TNF-α (P< 0.05).[13] Though the same results were not noted with Lactobacillus kefiri (Lk).[14]
    • Dogs were fed a mixed prebiotic blend (beet pulp, fructooligosaccharide (FOS), mannanoligosaccharide (MOS), inulin, and kelp) had increased (P < 0.05) fecal IgA. It also elicited significant changes on microbiota and fermentative end-products.[15]
  • Infection or parasites – evaluate with additional laboratory tests as needed.
  • Consider evaluated for exocrine pancreatic insufficiency (EPI). Fecal sIgA was significantly lower in dogs with EPI. [12]

Figure 1: Vet Med Sci. 2021 Nov; 7(6): 2144–2155.

As noted in Figure 1, significantly lower fecal sIgA concentrations and a low serum canine trypsin‐like immunoreactivity (cTLI) concentration was consistent with a diagnosis of EPI.[12] 

  • Minimizing anxiety and stress.

References:

  1. Otoni, C.C., et al., Serologic and fecal markers to predict response to induction therapy in dogs with idiopathic inflammatory bowel disease. J Vet Intern Med, 2018. 32(3): p. 999-1008.
  2. Hang, I., et al., Impact of diets with a high content of greaves-meal protein or carbohydrates on faecal characteristics, volatile fatty acids and faecal calprotectin concentrations in healthy dogs. BMC Vet Res, 2013. 9: p. 201.
  3. Sutherland, A.D., R.B. Gearry, and F.A. Frizelle, Review of fecal biomarkers in inflammatory bowel disease. Dis Colon Rectum, 2008. 51(8): p. 1283-91.
  4. Heilmann, R.M., et al., Association of fecal calprotectin concentrations with disease severity, response to treatment, and other biomarkers in dogs with chronic inflammatory enteropathies. J Vet Intern Med, 2018. 32(2): p. 679-692.
  5. Collins, M.T. Canine Inflammatory Bowel Disease: Current and Prospective Biomarkers for Diagnosis and Management. Compendium: Continuing Education for Veterinarians 2013 [cited 2020 9.1.2020]; Available from: http://assets.prod.vetlearn.com.s3.amazonaws.com/43/5fa310872f11e2935e005056ad4734/file/PV0313_Collins.pdf.
  6. Ohlsson, B., et al., Calprotectin in serum and zonulin in serum and feces are elevated after introduction of a diet with lower carbohydrate content and higher fiber, fat and protein contents. Biomed Rep, 2017. 6(4): p. 411-422.
  7. Grellet, A., et al., Influence of Breed Size, Age, Fecal Quality, and Enteropathogen Shedding on Fecal Calprotectin and Immunoglobulin A Concentrations in Puppies During the Weaning Period. J Vet Intern Med, 2016. 30(4): p. 1056-64.
  8. Grzeskowiak, L., et al., Microbiota and probiotics in canine and feline welfare. Anaerobe, 2015. 34: p. 14-23.
  9. Jergens, A.E., et al., Rules of Engagement: Epithelial-Microbe Interactions and Inflammatory Bowel Disease. Front Med (Lausanne), 2021. 8: p. 669913.
  10. Ellis, J.A., Canine IgA and IgA deficiency: Implications for immunization against respiratory pathogens. Can Vet J, 2019. 60(12): p. 1305-1311.
  11. Zaine, L., et al., Faecal IgA concentration is influenced by age in dogs. Br J Nutr, 2011. 106 Suppl 1: p. S183-6.
  12. Grutzner, N., et al., Genomic association and further characterisation of faecal immunoglobulin A deficiency in German Shepherd dogs. Vet Med Sci, 2021. 7(6): p. 2144-2155.
  13. Xu, H., et al., Oral Administration of Compound Probiotics Improved Canine Feed Intake, Weight Gain, Immunity and Intestinal Microbiota. Front Immunol, 2019. 10: p. 666.
  14. Gaspardo, A., et al., Influence of Lactobacillus kefiri on Intestinal Microbiota and Fecal IgA Content of Healthy Dogs. Front Vet Sci, 2020. 7: p. 146.
  15. Panasevich, M.R., et al., Altered fecal microbiota, IgA, and fermentative end-products in adult dogs fed prebiotics and a nonviable Lactobacillus acidophilus. J Anim Sci, 2021. 99(12).

Published:  March 15, 2022
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