A new framework for chronic GI disease in dogs and cats

Chronic enteropathy (CE) is the term now used to describe long-term GI disease that lacks a specific diagnosis in canine and feline patients.

Gastrointestinal complaints are common in clinical practice, with acute patients typically resolving with symptomatic and supportive treatment. However, a small subset (1% to 3% of the total caseload) have relapsing or chronic signs in the absence of the usual suspects (such as repeated dietary indiscretion, foreign body ingestion with intermittent partial obstruction, parasites, or enteropathogens).1 Chronic enteropathy (CE) is an umbrella term now used to describe such gastrointestinal (GI) disease in dogs and cats that lasts longer than three weeks and lacks a more specific diagnosis.

The causes of canine and feline chronic enteropathies are multifactorial, and include breed predisposition, environmental factors (e.g. dietary antigens), and intestinal microbiota. While breed specific factors are important and may be useful, such as gluten-sensitive enteropathy in Irish setters7 and antibiotic-responsive enteropathy in German shepherds,4 the genetic makeup of the patient in the exam room is unalterable. A change of diet is a leading action generally associated with positive, sometimes long-term, outcomes. Chronic enteropathies can be defined by treatment response according to four general categories: food-responsive, antimicrobial-responsive, immunomodulation-responsive, and non-responsive.

Food-responsive enteropathy (FRE)

Similar to food protein-induced enteropathy in people (e.g. gluten sensitivity), about 50% of dogs and cats with CE respond to diet change alone. FRE is more common in younger cats and dogs, whose signs arise from an adverse food reaction, food allergy, and/or food intolerance. It is common for CE patients to have an allergic reaction to certain types of dietary protein. In contrast, food ingredients most likely to cause food intolerances are much more varied and do not require prior exposure. These include carbohydrates (e.g. disaccharides: milk lactose, sucrose and dextrins), pharmacologically active products (e.g. histamine/histidine in certain cheeses and fish), food additives (e.g. food color dyes), and food toxin contamination or overconsumption (e.g. phytohaemagglutinin aka PHA lectin in beans, among many other naturally-occurring plant toxins through to mycotoxins). Improvement can take up to 14 days after switching diets, and several diets may need to be tested. An elimination diet can be effective at identifying allergies or food sensitivities but can be challenging for clients to implement. Some studies report that a hydrolyzed protein diet8 or an easily digestible diet9 are successful at mitigating signs of CE in dogs. As is the case for elimination diets, these special diets can provide short term benefit; however, reducing the diversity of foods provided in the diet in the long run will lead to reduced bacterial diversity in the gut microbiome.

Bacterial dysbiosis is associated with CE and can often be modified by diet. Changes in macronutrient ratios and nutrient bioavailability contribute to shifts in bacterial composition in the digestive tract. Remission in patients with CE induced by a hydrolyzed protein diet was accompanied by decreased abundances of the pathobionts Escherichia coli and Clostridium perfringens, reduced bacterial dysbiosis, and increased levels of the secondary bile acids, lithocholic and deoxycholic acid.10 Improvements in clinical signs are also reported after switching from a high carbohydrate, low protein diet to a low carbohydrate, high protein diet, including raw diets. Likewise, the addition of prebiotic fibers can help firm up stool while also feeding beneficial bacterial populations.

Early life events can influence the likelihood of developing a CE. In a new study, exposure to a high fat, low carbohydrate, non-processed, meat-based diet during early life, and a normal body condition in puppyhood, were significantly associated with less IBD in adult dogs.11 The opposite trend was found with early life exposure to ultra-processed carbohydrate-based diets.

Antimicrobial-responsive enteropathy (ARE)

Some forms of CE may be alleviated by using antimicrobial treatment to treat a known or suspected bacterial pathogen, to alter the bacterial composition of the gut microbiome, and/or to allow for lower doses of anti-inflammatory medication (immunomodulation). Why such cases respond to antibiotics is often unclear, and an imbalance of the gut microbiome is strongly implicated. Common antibiotics used to treat CE are Tylosin, Tetracycline, Doxycycline, Azithromycin, Enrofloxacin, Rifaximin, and Metronidazole. Menozzi et al12 reports that antibiotics can be effective, at least temporarily, at resolving CE signs. However, relapse rates are high. Tylosin has a relapse rate of 86% in 30 days13,14 and 88% within two months,14 and metronidazole has a relapse rate of 100% within six to 12 months.15

In addition to high relapse rates and contributing to antibiotic resistance, the use of antibiotics can produce unhealthy, long term changes in a pet’s gut microbiome. A recent study found that metronidazole had lasting effects on the fecal microbiomes of healthy dogs.16 In our research, we find that prior antibiotic exposure is significantly associated with elevated levels of Escherichia, diarrhea, and bacterial dysbiosis in both cats and dogs (presented at the 2020 ACVIM Forum). Targeted bacteriophage cocktails, such as those designed to target problematic strains of Escherichia coli, provide an alternative to the use of broad spectrum antibiotics.

Immunomodulation-responsive enteropathy (IRE)

Medications that suppress the immune response in order to reduce inflammation of the gastrointestinal tract lining are the defining treatment for IRE, which is more commonly found in older cats and dogs. Several types of anti-inflammatory drugs are available, some of which are used in combination with antibiotics in more severe cases. Prednisone, Prednisolone (preferred for cats over Prednisone), Chlorambucil (preferred for diabetic cats), Mycophenolate, and Budesonide have been reported as effective treatments for reducing inflammation within two weeks, with remission rates as high as 78%.17 Reported data is limited, but one study published a relapse rate of 22.7% following immunosuppressant treatment.18

While important and useful, these medications are associated with significant side effects, including negative behavioral shifts and gastrointestinal ulceration. Notari et al19 reported that dogs on corticosteroids were less playful, more nervous, fearful and/or aggressive in the presence of food, and more prone to barking or to startle, to reacting aggressively when disturbed, and to avoiding people or unusual situations. Healthy dogs administered Prednisone exhibited gastrointestinal bleeding and ulceration, even in the absence of clinical signs.20 Mycophenolate has recently been reported to produce gut dysbiosis21, 22 but was also reported to reduce gut dysbiosis in spontaneously hypertensive rats.23 Approximately a quarter of canine recipients of mycophenolate experience GI signs.24 While mycophenolic acid acyl glucuronide metabolites, produced by enterocytes and excreted into bile with hepatic metabolism, contribute to osmotic diarrhea by a local irritative effect25, the gut microbiota play a prominent role in GI toxicity.22 The exact players and mechanisms have yet to be determined.

Non-responsive enteropathy (NRE)

Because CE is a broad term with numerous causes, it’s not surprising that 15% to 40% of cases do not respond to treatment in the short term.26 If a patient is non-responsive to treatment, it is possible that another disease or condition could be contributing to signs. For example, pets can still have a cobalamin deficiency, despite an adequate diet, due to malabsorption as a result of an unbalanced gut microbiome and mucosal inflammation. That said, not all the causes of CE are understood, let alone known. Altering the gut microbiome is an emerging and promising treatment for clinical signs of a gastrointestinal condition, even when the cause is unknown.

Fecal transplantation to restore key beneficial microbes

Should an imbalance in the gut microbiome be suspected or detected in a chronic CE patient, it is possible to augment the intestinal community with probiotics. However, numerous studies report that supplementing with probiotics is unlikely to make a noticeable permanent difference to the gut microbiome. Instead, a fecal microbial transplantation29 (also known as Microbiome Restoration Therapy or MBRT) is the best known practice for restoring a balanced gut microbiota, and contains native gut microbes not found in today’s probiotics. FMT has proven to be effective in both animals30 and humans31 for a number of conditions, such as gut microbiome recovery after antibiotic treatment,32 and to resolve IBD and Clostridioides difficile infections.31 Fecal transplants may be administered a number of ways, including via upper and/or lower endoscopy, enema, or oral delivery.33 Of course, microbiome restoration is most effective when supported by a diet that also feeds these beneficial gut bacteria.

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1Dandrieux JRS, Mansfield CS. Chronic Enteropathy In Canines: Prevalence, Impact And Management Strategies. Vet Med (Auckl). 2019;10: 203–214.

2Makielski K, Cullen J, O’Connor A, Jergens AE. Narrative review of therapies for chronic enteropathies in dogs and cats. J Vet Intern Med. 2019;33: 11–22.

3O Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC. Prevalence of disorders recorded in dogs attending primary-care veterinary practices in England. PLoS One. 2014;9: e90501.

4Kathrani A, Werling D, Allenspach K. Canine breeds at high risk of developing inflammatory bowel disease in the south-eastern UK. Vet Rec. 2011;169: 635.

5O’Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC. Prevalence of disorders recorded in cats attending primary-care veterinary practices in England. The Veterinary Journal. 2014;202: 286–291.

6Guilford WG, Jones BR, Markwell PJ, Arthur DG, Collett MG, Harte JG. Food Sensitivity in Cats with Chronic Idiopathic Gastrointestinal Problems. J Vet Intern Med. 2001;15: 7–13.

7Simpson KW, Jergens AE. Pitfalls and progress in the diagnosis and management of canine inflammatory bowel disease. Veterinary Clinics: Small Animal Practice. 2011;41: 381-98.

8Marks SL, Laflamme DP, McAloose D. Dietary trial using a commercial hypoallergenic diet containing hydrolyzed protein for dogs with inflammatory bowel disease. Vet Ther. 2002;3: 109–118.

9Mandigers PJJ, Biourge V, van den Ingh TSGAM, Ankringa N, German AJ. A randomized, open-label, positively-controlled field trial of a hydrolyzed protein diet in dogs with chronic small bowel enteropathy. J Vet Intern Med. 2010;24: 1350–1357.

10Wang S, Martins R, Sullivan MC, Friedman ES, Misic AM, El-Fahmawi A, De Martinis EC, O’Brien K, Chen Y, Bradley C, Zhang G. Diet-induced remission in chronic enteropathy is associated with altered microbial community structure and synthesis of secondary bile acids. Microbiome. 2019 Dec;7(1):1-20.

11Hemida M, Vuori KA, Moore R, Anturaniemi J, Hielm-Björkman A. Early Life Modifiable Exposures and Their Association with Owner Reported Inflammatory Bowel Disease Symptoms in Adult Dogs. Frontiers in Veterinary Science. 2021;8.

12Menozzi A, Dall’Aglio M, Quintavalla F, Dallavalle L, Meucci V, Bertini S. Rifaximin is an effective alternative to metronidazole for the treatment of chronic enteropathy in dogs: a randomised trial. BMC Vet Res. 2016;12: 217.

13Westermarck E, Skrzypczak T, Harmoinen J, Steiner JM, Ruaux CG, Williams DA, et al. Tylosin-responsive chronic diarrhea in dogs. J Vet Intern Med. 2005;19: 177–186.

14Kilpinen S, Spillmann T, Syrjä P, Skrzypczak T, Louhelainen M, Westermarck E. Effect of tylosin on dogs with suspected tylosin-responsive diarrhea: a placebo-controlled, randomized, double-blinded, prospective clinical trial. Acta Veterinaria Scandinavica. 2011;53: 1-0.

15Allenspach K, Culverwell C, Chan D. Long-term outcome in dogs with chronic enteropathies: 203 cases. Vet Rec. 2016;178: 368.

16Pilla R, Gaschen FP, Barr JW, Olson E, Honneffer J, Guard BC, Blake AB, Villanueva D, Khattab MR, AlShawaqfeh MK, Lidbury JA. Effects of metronidazole on the fecal microbiome and metabolome in healthy dogs. Journal of Veterinary Internal Medicine. 2020;34: 1853-66.

17Dye TL, Diehl KJ, Wheeler SL, Westfall DS. Randomized, controlled trial of budesonide and prednisone for the treatment of idiopathic inflammatory bowel disease in dogs. J Vet Intern Med. 2013;27: 1385–1391.

18Marchesi MC, Timpano CC, Busechian S, Pieramati C, Rueca F. The role of diet in managing inflammatory bowel disease affected dogs: a retrospective cohort study on 76 cases. Vet Ital. 2017;53: 297–302.

19Notari L, Burman O, Mills D. Behavioural changes in dogs treated with corticosteroids. Physiology & Behavior. 2015;151:609-16.

20Whittemore JC, Mooney AP, Price JM, Thomason J. Clinical, clinicopathologic, and gastrointestinal changes from administration of clopidogrel, prednisone, or combination in healthy dogs: A double‐blind randomized trial. Journal of Veterinary Internal Medicine. 2019;33:2618-27.

21Swarte, J.C., Douwes, R.M., Hu, S., Vich Vila, A., Eisenga, M.F., van Londen, M., Gomes-Neto, A.W., Weersma, R.K., Harmsen, H.J. and Bakker, S.J., 2020. Characteristics and dysbiosis of the gut microbiome in renal transplant recipients. Journal of clinical medicine, 9(2), p.386.

22Flannigan, K.L., Taylor, M.R., Pereira, S.K., Rodriguez-Arguello, J., Moffat, A.W., Alston, L., Wang, X., Poon, K.K., Beck, P.L., Rioux, K.P. and Jonnalagadda, M., 2018. An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil. The Journal of Heart and Lung Transplantation, 37(9), pp.1047-1059.

23Robles-Vera, I., de la Visitación, N., Toral, M., Sánchez, M., Gómez-Guzmán, M., Jiménez, R., Romero, M. and Duarte, J., 2021. Mycophenolate mediated remodeling of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rats. Biomedicine & Pharmacotherapy135, p.111189.

24Klotsman, M., Sathyan, G., Anderson, W.H., Garden, O.A. and Shivanand, P., 2019. Mycophenolic acid in patients with immune‐mediated inflammatory diseases: From humans to dogs. Journal of veterinary pharmacology and therapeutics, 42(2), pp.127-138.

25Picard, N., Ratanasavanh, D., Prémaud, A., Le Meur, Y. and Marquet, P., 2005. Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug metabolism and disposition, 33(1), pp.139-146.

26Dandrieux JRS. Inflammatory bowel disease versus chronic enteropathy in dogs: are they one and the same? J Small Anim Pract. 2016;57: 589–599.

27Marsilio S, Pilla R, Sarawichitr B, Chow B, Hill SL, Ackermann MR, et al. Characterization of the fecal microbiome in cats with inflammatory bowel disease or alimentary small cell lymphoma. Sci Rep. 2019;9: 19208.

28Suchodolski JS, Markel ME, Garcia-Mazcorro JF, Unterer S, Heilmann RM, Dowd SE, et al. The fecal microbiome in dogs with acute diarrhea and idiopathic inflammatory bowel disease. PLoS One. 2012;7: e51907.

29Chaitman J, Jergens AE, Gaschen F, Garcia-Mazcorro JF, Marks SL, Marroquin-Cardona AG, et al. Commentary on key aspects of fecal microbiota transplantation in small animal practice. Vet Med (Auckl). 2016;7: 71–74.

30Niina A, Kibe R, Suzuki R, Yuchi Y, Teshima T, Matsumoto H, et al. Improvement in Clinical Symptoms and Fecal Microbiome After Fecal Microbiota Transplantation in a Dog with Inflammatory Bowel Disease. Vet Med (Auckl). 2019;10: 197–201.

31van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368: 407–415.

32Bajaj JS, Kakiyama G, Savidge T, Takei H, Kassam ZA, Fagan A, et al. Antibiotic‐Associated Disruption of Microbiota Composition and Function in Cirrhosis Is Restored by Fecal Transplant. Hepatology. 2018. pp. 1549–1558. doi:10.1002/hep.30037

33Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of Oral Capsule– vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection. JAMA. 2017. p. 1985. doi:10.1001/jama.2017.17077

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Dr. Holly Ganz is a microbiologist turned entrepreneur. In 2016, she left academic research at UC Davis to create AnimalBiome, a company that provides microbiome assessments for dogs and cats and creates restorative remedies to help promote healthy guts. Dr. Ganz received her PhD from UC Davis, where she studied co-evolution between microbes and animals. After receiving her doctorate, she was a post-doctoral fellow at UC Berkeley, where she studied how bacterial pathogens survive in soil to infect wildlife. She subsequently applied microbial genomics to study the canine oral microbiome, as a visiting scientist at the UC Davis School of Veterinary Medicine. Dr. Ganz is dedicated to improving animal health and wellness through applying the latest innovations in microbiology.
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Dr. Dawn Kingsbury has practiced general and specialty companion animal medicine around the world. She met Holly Ganz while studying for her PhD. Being chief veterinary officer at AnimalBiome aligns with Dr. Kingsburty’s interests -- host-microbe interactions, precision medicine, and One Health -- while allowing her to promote microbiome analysis as a non-invasive, clinically actionable tool and to cultivate evolving microbiome restoration strategies.
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Katherine Dahlhausen is a science writer for AnimalBiome. She was mentored by Holly Ganz during the beginning of her PhD at the University of California Davis and helped with the beginning of the KittyBiome project. Katherine has worked on a wide variety of microbiome-related projects to date, including ones about koalas, buildings, pollinators, and coral reefs.

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