Decoding chronic enteropathy in canine patients

Photo: Christian Müller/Adobe Stock

Chronic enteropathy (CE) describes a myriad of prolonged (greater than 3 weeks) gastrointestinal (GI) signs in animals who are suspected to have nondescript GI inflammation and in which treatment success has yet to be defined.¹ All dogs with CE will have some degree of GI inflammation and share similar changes in microbiota richness, diversity, or composition compared to healthy dogs.² However, their clinical and pathological response is different based on the treatments instituted and are categorized as food-responsive enteropathy (FRE), antibiotic-responsive enteropathy (ARE), immunosuppressant-responsive enteropathy (IRE), or nonresponsive enteropathy (NRE).

These treatment classifications have different etiologies but, dogs can display similar clinical signs and may require treatment through a multimodal approach involving 1 or more of these treatment categories. Further classification of CE includes those animals with loss of protein across the gut, termed protein-losing enteropathy (PLE). A diagnosis of PLE is based on the exclusion of neoplastic, parasitic, or infectious disease within the gut, and the presence of PLE with CE suggests a more guarded treatment response rate and prognosis.³ 

Food-responsive enteropathy

FRE is the most common form of CE in dogs, accounting for 50% to 65% of cases. These include dietary-associated GI signs caused by immunologic, nonimmunologic mechanisms, or both. Nonimmunologic causes include patients with a history of intoxication (bacterial, fungal, other toxins), pharmacological reaction, or an idiosyncratic reaction (metabolic, food intolerance or food indiscretion). It may be clinically difficult to distinguish between immunologic vs. nonimmunological causes in a patient with primarily GI signs; however, it is believed that most cases with acute food reactions are because of food intolerances.⁴ A highly digestible or fiber-enriched diet is generally chosen first in dogs with relatively mild GI disease and without cutaneous signs suggestive of an underlying food allergy. Fiber-enriched diets (greater than 40 g TDF/Mcal) or additive psyllium husk (2-3 tsp/kg/day) are particularly suitable for patients with large bowel disease.⁵ Low-fat diets (less than 0 g fat/Mcal ME) or home-prepared ultra-low-fat diets (less than 15 g fat/Mcal ME) are generally considered for dogs with lymphangiectasia or idiopathic PLE, although hydrolyzed or novel protein diets may be required in some patients who fail initial dietary macronutrient manipulation.^6,7

Immunologic causes, such as food allergy, describe an atypical immune response to certain food ingredients, which triggers an IgE, non-IgE-mediated immune disorder, or, in rare cases, a delayed-type hypersensitivity response.⁸ Although the pathogenesis is not completely understood, intolerance to food antigens likely arises from genetic predisposition, alterations in GI permeability, local immune surveillance, and dysbiosis of the gut microbiome. Dogs younger than 12 months of age are more likely to develop food allergies, and the most common allergens that provoke a canine response include beef, dairy, chicken, and wheat.⁹ Irish setters with gluten-sensitive enteropathy and border terriers with paroxysmal gluten-sensitive dyskinesia are also included in FRE.^10,11

Dogs with a suspected food allergy typically respond best to a diet with a novel protein, hydrolyzed protein, limited ingredient protein, or home-made ingredients.¹² Selection of an appropriate diet relies on a comprehensive analysis of the animal’s dietary history; however, it is increasingly difficult to source a novel protein that a pet has not previously consumed and without the potential for cross-contamination with other animal proteins not listed on the label.¹³ Hydrolyzed diets eliminate the requirement of finding a novel protein source, and theoretically should not evoke an immune response with proteins at a molecular weight greater than 5 kDa. However, complete removal of the protein antigenicity is not always possible, and a hydrolyzed protein or a nonanimal protein source should be chosen in a dog that is thought to be protein sensitized.¹⁴

Most dogs with food-responsive GI disease show improvement within 14 days of dietary change with a good to excellent prognosis,¹⁵ although the response is individualized and dependent on the nutrient (ie, fat intolerant, fiber responsive) or ingredient (like a chicken or beef allergy) manipulated. Multiple dietary trials are required before determining if a pet is nonfood responsive. Should the animal respond positively to an elimination diet without relapsing when transitioned back to their original diet (or components thereof), then a food allergy or intolerance is considered less likely.¹²

Antibiotic-responsive enteropathy

Antibiotic-responsive enteropathy(ARE), formerly known as antibiotic-responsive diarrhea or small intestinal bacterial overgrowth, is a clinical manifestation of chronic enteropathy in dogs that is completely responsive to the administration of antimicrobial agents. Dogs with ARE account for 15% to 35% of dogs with CE.¹ The pathogenesis of ARE is multifactorial and likely involves defects in the mucosal barrier, aberrant mucosal immune responses, qualitative changes in the enteric bacterial flora (dysbiosis), or a combination of these mechanisms.¹⁶ Several tests have failed to reliably diagnose ARE (ie, cobalamin, folate, unconjugated bile acids, quantitative intestinal bacterial culture).¹⁷

Therefore, a diagnosis of idiopathic ARE in dogs is generally met with the following criteria:

• A positive response to the antibiotic treatment trial based on a resolution of relevant clinical signs,
• Immediate or delayed relapse of clinical signs on withdrawal of treatment,
• Remission occurring on the reintroduction of antibiotics after relapse, and
• Elimination of other etiologic agents based on a thorough diagnostic evaluation and histopathologic assessment.¹⁶

ARE is most commonly recognized in young large-breed dogs. German Shepherd dogs are overrepresented, likely through abnormal microbial-mucosal interactions and defective IgA secretion at the small intestinal mucosal surface.¹⁸ The most effective antibiotics for ARE include oxytetracycline (10-20 mg/kg given orally every 8 hours), metronidazole (10 mg/kg given orally every 8-12 hours), and tylosin (20 mg/kg given orally every 8-12 hours), all of which have immune-modulating properties. Antibiotic trials should be continued for 4-6 weeks, although a change of antibiotic therapy is recommended if no clinical response is seen by 2 weeks of initial therapy.16 Dogs with ARE appear to relapse more frequently, especially after discontinuation of antibiotic therapy.¹⁹

Dogs with CE experience both dysbiosis and significantly decreased fecal bacterial diversity compared to healthy dogs.²⁰ Despite clinical improvements with antibiotic therapy, metronidazole and tylosin cause dramatic alterations of the microbiota for a prolonged period after administration.^21,22 As such, novel therapies, such as prebiotics, probiotics, symbiotics, postbiotics, and fecal microbiota transplantation (FMT), have been recently investigated and used favorably to manipulate the microbiome in dogs with CE.²³ A recently proposed replacement of AREs is a category that encompasses all methods of modulation of the intestinal microbiota, termed “microbiota-related modulation-responsive enteropathy – MrMRE.”²⁴

Prebiotics in the form of beet pulp, potato fiber, soybean husk, and inulin-type fructans increase short-chain fatty acids, which nourish and feed beneficial intestinal bacteria. Albeit short-term, probiotics supply an exogenous source of live bacteria to the host that produces metabolites and antimicrobial peptides as it traverses the GI tract.²³ FMTs involve administering fecal matter (fresh, frozen, lyophilized) from a healthy donor to the patient through the endoscopic, capsule, or enema route. Treatment trials with FMT have favorable efficacy for both acute and chronic infections and enteropathies in dogs.^25,26 However, safety concerns and lack of practical guidelines and proper regulations remain the main limitation of FMT in a clinical setting.

Immunosuppressant-responsive enteropathy

Immunosuppressant-responsive enteropathy (IRE) also known as idiopathic inflammatory bowel disease (IBD), is defined as a multifactorial intestinal inflammatory disease in which diet, antibiotic, and microbial manipulation have failed.¹ This category accounts for 10% to 25% of dogs with CE.¹⁹ Intestinal histology shows varying degrees of mucosal inflammation, and treatment requires immune-suppressive drugs. Glucocorticoids are the mainstay induction treatment in most cases with IRE. Several studies show that administration of prednisone alone is as efficacious in dogs as treatment with budesonide alone or prednisone combined with metronidazole.^15,27-28 However, additional immune-suppressive therapy, such as cyclosporine, chlorambucil, azathioprine, and mycophenolate, can be implemented to reduce the adverse effects of corticosteroids and minimize clinical relapse. Dogs with CE who have failed immune-suppressant treatment are categorized as having nonresponsive CE, and these account for 9% to 45% of dogs with CE.¹⁹

The prognosis of IRE is generally good, with up to 90% clinical response within 1 month. However, clinical relapse can occur at a rate of 11% within 3 months of initiating immune-suppressive therapy, followed by 8% relapse at 6 months and 10% relapse at 12 months. A reduction of body condition (BCS less than 4/9), lower serum albumin concentration (albumin less than 2.1 g/dL), and higher presence of lacteal dilatation on intestinal histology at diagnosis were associated with a decreased response rate, higher mortality rate, and lower chance of achieving long-term remission.²⁹ In other studies, negative prognostic factors for dogs with CE include a high Canine Inflammatory Bowel Disease Activity Index(CIBDAI), marked endoscopic disease in the duodenum, hypocobalaminemia, hypoalbuminemia, and hypovitaminosis D.^30-33

Protein losing enteropathy

Protein losing enteropathy (PLE) is a syndrome that is classified based on the presence of low levels of albumin in the absence of other protein-losing diseases, like protein-losing nephropathy and protein-losing dermatopathy.²⁹ PLE in dogs can be caused by IBD in 66% of dogs, followed by lymphangiectasia in 50% of dogs. Less common causes include infections such as parvovirus, Clostridium, Campylobacter, Salmonellosis, Histoplasmosis,and Heterobilharzia americana, nonsteroidal enteropathy, hypoadrenocorticism, intestinal crypt disease, hookworms, Strongyloides stercoralis, idiopathic primary intestinal lymphangiectasia, lymphangitis (granulomatous/inflammatory), or secondary intestinal lymphangiectasia caused by neoplasia, lymphatic infections, or right-sided congestive heart failure.³¹

If a secondary cause of PLE is identified, partial to complete clinical response may be achieved. PLE associated with lymphangiectasia and IBD is managed with a combination of immune-suppressive agents (prednisone, secondary immune-suppressive agents), as well as a dietary change (ie, low fat or ultra-low-fat diet, hydrolyzed protein diet, or a combination thereof), microbial manipulation, +/- antibiotic therapy.³⁴ However, some patients with PLEs may respond to dietary therapy alone, particularly in Yorkshire terriers.⁶ Although any combination of glucocorticoids and secondary immune-suppressive therapy can be implemented, a combination of chlorambucil-prednisolone was shown to be more efficacious for the treatment of chronic enteropathy and concurrent PLE in dogs compared with azathioprine-prednisolone combination.³⁵ Additional treatment targeting secondary complications of PLE may be considered, including antithrombotic agents like clopidogrel, GI tract protectants, antacid therapy, antiemetics, probiotics, visceral pain medication, promotility agents, oncotic support, octreotide, and select vitamin supplementation.³⁴

Negative prognostic indicators in dogs with PLE include hypocobalaminemia and hypovitaminosis D, although its relationship with survival in these patients is not known.³⁶ Median survival times of dogs with PLE are variable in studies; however, long-term responders are typically Yorkshire terriers treated with combination therapy.³⁷ Complicated factors may include thromboembolic disease, hypocalcemia, and third spacing, and current treatment is associated with a 54% mortality rate in dogs with PLE compared to less than 20% in dogs with IRE.^31,38

Conclusion

Chronic enteropathy is a general term describing a collection of GI signs in animals that has yet to be pathologically defined. CE can be further subdivided into categories based on treatment response, and this response to treatment and several diagnostic results may predict overall prognosis in these patients. It is reasonable to consider multiple dietary trials, microbial manipulation, or antibiotic therapy prior to consideration of advanced diagnostics (endoscopic or surgical full-thickness GI biopsies) or immune-suppressive therapy. Overall treatment response rate is high; however, PLE in dogs suggests a worsening and guarded prognosis.

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