Inflammatory bowel disease

IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic i

nflammation of the stomach, intestine and/or colon of unknown pathogenesis and etiology.

Canine I.B.D. Pathogenesis, Diagnosis, and Therapy

Etiology – Inflammatory bowel disease (IBD) has been defined on the basis of clinical, histologic, immunologic, pathophysiologic, and genetic criteria.

Clinical Definition of IBD

IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic inflammation of the stomach, intestine and/or colon of unknown pathogenesis and etiology. A clinical diagnosis of IBD is considered only if affected animals have persistent (>3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucousy feces), failure to respond to dietary (novel protein, hydrolyzed-, anti-oxidant-, or highly digestible diets) or symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and histologic diagnosis of benign intestinal inflammation (Jergens et al., 2003). Small bowel and large bowel forms of IBD have been reported in both dogs and cats, although large bowel IBD appears to be more prevalent in the dog.

Histologic Definition of IBD

IBD has been defined histologically by the type of inflammatory infiltrate (neutrophilic, eosinophilic, lymphocytic, plasmacytic, granulomatous), associated mucosal pathology (villus atrophy, fusion, crypt collapse), distribution of the lesion (focal or generalized, superficial or deep), severity (mild, moderate, severe), mucosal thickness (mild, moderate, severe), and topography (gastric fundus, gastric antrum, duodenum, jejunum, ileum, cecum, ascending colon, descending colon). As with small intestinal IBD, the histologic assessment of large intestinal IBD lesions has been fraught with subjective interpretations. The lack of objective morphologic criteria has made it difficult to compare tissue findings between pathologists. Subjectivity in histologic assessments have led to the development of IBD grading systems (van der Gaag, 1988; van der Gaag, 1989; Spinato et al., 1990; Roth et al., 1990, Roth et al., 1992; Wilcock, 1992; Leib et al., 1992; Stonehewer et al., 1998). In more recent times, pathologists and internists are increasingly emphasizing architectural changes (villus atrophy, villus fusion, fibrosis) instead of lamina proprial cellularity.

Immunologic Definition of IBD

IBD has been defined immunologically by the innate and adaptive response of the mucosa to gastrointestinal antigens. Although the precise immunologic events of canine IBD remain to be determined, a prevailing hypothesis for the development of IBD is the loss of immunologic tolerance to the normal bacterial flora or food antigens, leading to abnormal T cell immune reactivity in the gut microenvironment. Genetically engineered animal models (e.g., IL-2, IL-10, and T cell receptor knockouts) that develop IBD involve alterations in T cell development and/or function suggesting that T cell populations are responsible for the homeostatic regulation of mucosal immune responses. Immunohistochemical studies of canine IBD have demonstrated an increase in the T cell population of the lamina propria, including CD3+ cells and CD4+ cells, as well as macrophages, neutrophils, and IgA-containing plasma cells. Many of the immunologic features of canine IBD can be explained as an indirect consequence of mucosal T cell activation. Enterocytes are also likely involved in the immunopathogenesis of IBD. Enterocytes are capable of behaving as antigen-presenting cells, and interleukins (e.g., IL-7 and IL-15) produced by enterocytes during acute inflammation activate mucosal lymphocytes. Up-regulation of Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expression contribute to the innate immune response of the colon. Thus, the pathogenesis and pathophysiology of IBD appears to involve the activation of a subset of CD4+ T cells within the intestinal epithelium that overproduce inflammatory cytokines with concomitant loss of a subset of CD4+ T cells, and their associated cytokines, which normally regulate the inflammatory response and protect the gut from injury. Enterocytes, behaving as antigen-presenting cells, contribute to the pathogenesis of this disease (Carding et al.).

Pathophysiologic Definition of IBD

IBD may be defined pathophysiologically in terms of transport, blood flow, and motility abnormalities. The clinical signs of IBD, whether small or large bowel, have long been attributed to the pathophysiology of malabsorption and hypersecretion, but experimental models of canine IBD have instead related clinical signs to the emergence of abnormality motility patterns..

Genetic Definition of IBD

IBD may be defined in genetic terms in several animal species. Crohn’s disease and ulcerative colitis are more common in certain human genotypes, and a mutation in the NOD2 gene (nucleotide-binding oligomerization domain2) has been found in a sub-group of patients with Crohn’s disease (Strober). Genetic influences have not yet been identified in canine or feline IBD, but certain breeds (e.g., German shepherd, Boxers) appear to be at increased risk for the disease.


The pathophysiology of colitis-type IBD is explained by at least two interdependent phenomena: the mucosal immune response, and associated changes in motility.

Immune Responses

A generic inflammatory response involving cellular elements (B and T lymphocytes, plasma cells, macrophages, and dendritic cells), secretomotor neurons (e.g., VIP, substance P, and cholinergic neurons), cytokines and interleukins, and inflammatory mediators (e.g., leukotrienes, prostanoids, reactive oxygen metabolites, nitric oxide, 5-HT, IFN-? TNF-? and platelet-activating factor) is typical of canine and feline inflammatory bowel disease. There are many similarities between the inflammatory response of the small and large intestine, but recent immunologic studies suggest that IBD of the canine small intestine is a mixed Th1/Th2 response (German et al. 2001) whereas IBD of the canine colon may be more of a Th1 type response with elaboration of IL-2, IL-12, INF-?, and TNF-a (Ridyard et al. 2001). Other studies of canine colonic IBD have demonstrated increased numbers of mucosal IgA- and IgG-containing cells, CD3+ T cells, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) in the inflamed colonic mucosa. Increases in the CD3+ positive T cell population of the inflamed colon are consistent with increases previously reported in the inflamed canine small intestine. Thus, there are important similarities and differences between small and large bowel IBD.

Motility Changes

Experimental studies of canine IBD have shown that many of the clinical signs (diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and urgency of defecation) are related to motor abnormalities of the colon. Ethanol and acetic acid perfusion of the canine colon induces a colitis-type IBD syndrome indistinguishable from the natural condition (Sethi and Sarna, 1991). Inflammation in this model suppresses the normal phasic contractions of the colon, including the migrating motility complex, and triggers the emergence of giant migrating contractions (GMCs). The appearance of these GMCs in association with inflammation is a major factor in producing diarrhea, abdominal cramping, and urgency of defecation. GMCs are powerful lumen-occluding contractions that rapidly propel pancreatic, biliary, and intestinal secretions in the fasting state, and undigested food in the fed state, to the colon to increase its osmotic load (Sethi and Sarna, 1991). Malabsorption results from direct injury to the epithelial cells and from ultrarapid propulsion of intestinal contents by giant migrating contractions (GMCs) so that sufficient mucosal contact time is not allowed for digestion and absorption to take place.

Inflammation impairs the regulation of the colonic motility patterns at several levels, i.e., enteric neurons, interstitial cells of Cajal, and circular smooth muscle cells. Inflammation-induced changes in the amplitude and duration of the smooth muscle slow wave plateau potentials contribute to the suppression of rhythmic phasic contractions (RPCs). These alterations likely have their origin in structural as well as functional damage to the interstitial cells of Cajal (Lu et al.). At the same time that inflammation suppresses the (RPCs), inflammation sensitizes the colon to the stimulation of GMCs by the neurotransmitter substance P. These findings suggest that SP increases the frequency of GMCs during inflammation, and that selective inhibition of GMCs during inflammation may minimize the symptoms of diarrhea, abdominal discomfort, and urgency of defecation associated with these contractions.

Inflammation suppresses the generation of tone and phasic contractions in the circular smooth muscle cells through multiple molecular mechanisms. Inflammation shifts muscarinic receptor expression in circular smooth muscles from the M3 to the M2 subtype (Jadcherla et al.). This shift has the effect of reducing the overall contractility of the smooth muscle cell. Inflammation also impairs calcium influx and down-regulates the expression of the L-type calcium channel (Liu et al.), which may be important in suppressing phasic contractions and tone while concurrently stimulating GMCs in the inflamed colon. Changes in the open-state probability of the large conductance calcium-activated potassium channels (KCa) partially attenuate this effect (Lu et al.). Inflammation also modifies the signal transduction pathways of circular smooth muscle cells. Phospholipase A2 and protein kinase C (PKC) expression and activation are significantly altered by colonic inflammation and this may partially account for the suppression of tone and phasic contractions (Ali et al.). PKC a, ? and e isoenzyme expression is down-regulated, PKC i and l isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. To worsen matters, the L-type calcium channel (already reduced in its expression) is one of the molecular targets of PKC. Inflammation also activates the transcription factor NF-kB which further suppresses cell contractility (Shi et al.)

Clinical Examination

The clinical signs of colitis-type IBD are those of a large-bowel type diarrhea, i.e., marked increased frequency, reduced fecal volume per defecation, red blood pigments and mucous in feces, and tenesmus. Anorexia, weight loss, and vomiting are occasionally reported in animals with severe IBD of the colon or concurrent IBD of the stomach and/or small intestine. Clinical signs usually wax and wane in their severity. A transient response to symptomatic therapy may occur during the initial stages of IBD. As the condition progresses, diarrhea gradually increases in its frequency and intensity, and may become continuous. In some cases the first bowel movement of the day may be normal or nearly normal, whereas successive bowel movements are reduced in volume and progressively more urgent and painful. During severe episodes, mild fever, depression, and anorexia may occur.

There does not appear to be any sex predilection, but age may be a risk factor with IBD appearing more frequently in middle aged animals (mean age approximately 6 years with a range of 6 months to 20 years). German shepherd and Boxer dogs are at increased risk for IBD, and pure-breed cats appear to be at greater risk. Cats more often present with an upper gastrointestinal form of IBD, whereas dogs are at risk for both small and large bowel IBD.

Physical examination is unremarkable in most cases. Thickened bowel loops may be detected during abdominal palpation if the small bowel is concurrently involved. Digital examination of the anorecturm may evoke pain or reveal irregular mucosa, and blood pigments and mucous may be evident on the exam glove.


Complete blood counts, serum chemistries, and urinalyses are often normal in mild cases of large bowel IBD. Chronic cases may have one or more subtle abnormalities. One review of canine and feline IBD reported several hematologic abnormalities including mild anemia, leukocytosis, neutrophilia with and without a left shift, eosinophilia, eosinopenia, lymphocytopenia, monocytosis, and basophilia (Jergens). The same study reported several biochemical abnormalities including increased activities of serum alanine aminotransferase and alkaline phosphatase, hypoalbuminemia, hypoproteinemia, hyperamylasemia, hyperglobulinemia, hypokalemia, hypocholesterolemia, and hyperglycemia. No consistent abnormality in the complete blood count or serum chemistry has been identified.

A scoring index for disease activity in canine IBD was recently developed that relates severity of clinical signs to serum acute-phase protein concentrations (C-reactive protein, serum amyloid A – Jergens et al., 2003). The canine IBD activity index (CIBDAI) assigns levels of severity to each of several gastroenterologic signs (e.g., anorexia, vomiting, weight loss, diarrhea), and it appears to be a reliable index of mucosal inflammation in canine IBD. Interestingly, both the CIBDAI and serum concentrations of C-reactive protein (CRP) improve with successful treatment, suggesting that serum CRP is suitable for the laboratory evaluation of therapy in canine IBD. Other acute-phase proteins were less specific than CRP. One important caveat that should be emphasized is that altered CRP is not prima facie evidence of gastrointestinal inflammation. Concurrent infections or other inflammatory conditions could cause an acute-phase response, including CRP, in affected patients.

Treatment The treatment of canine I.B.D. has eight components of therapy: (1) Dietary Management, (2) Exercise, (3) Antibiotics, (4) Probiotics, (5) Anti-Diarrheal Therapy, (6) Restoration of G.I. Motility, (7) Immunosuppressive Therapy, and (8) Behavioral Modification.

Dietary Management

The precise immunologic mechanisms of canine and feline IBD have not yet been determined, but a prevailing hypothesis for the development of IBD is the loss of immunologic tolerance to the normal bacterial flora or food antigens. Accordingly, dietary modification may prove useful in the management of canine and feline IBD. Several nutritional strategies have been proposed including novel proteins, hydrolyzed diets, anti-oxidant diets, medium chain triglyceride supplementation, low fat diets, modifications in the omega-6/omega-3 (w-6/w-3) fatty acid ratio, and fiber supplementation. Of these strategies, some evidence-based medicine has emerged for the use of novel protein, hydrolyzed, and fiber-supplemented diets.

Food sensitivity reactions were suspected or documented in 49% of cats presented because of gastroenterologic problems (with or without concurrent dermatologic problems) in a prospective study of adverse food reactions in cats. Beef, wheat, and corn gluten were the primary ingredients responsible for food sensitivity reactions in that study, and most of the cats responded to the feeding of a chicken- or venison-based selected-protein diet for a minimum of 4 weeks. The authors concluded that adverse reactions to dietary staples are common in cats with chronic gastrointestinal problems and that they can be successfully managed by feeded selected-protein diets. Further support for this concept comes from studies in which gastroenterologic or dermatologic clinical signs were significantly improved by the feeding of novel proteins.

Evidence is accruing that hydrolyzed diets may be useful in the nutritional management of canine IBD. The conceptual basis of the hydrolyzed diet is that oligopeptides are of insufficient size and structure to induce antigen recognition or presentation. In one preliminary study, dogs with inflammatory bowel disease showed significant improvement following the feeding of a hydrolyzed diet although they had failed to respond to the feeding of a novel protein. Clinical improvement could not be solely attributed to the hydrolyzed nature of the protein source because the test diet had other modified features, i.e., high digestibility, cornstarch rather than intact grains, medium chain triglycerides, and an altered ratio of w-6 to w-3 polyunsaturated fatty acids. Additional studies will be required to ascertain the efficacy of this nutritional strategy in the management of IBD.

Fiber-supplemented diets may be useful in the management of irritable bowel syndrome (IBS) in the dog. IBS is a poorly defined syndrome in the dog that may or may not bear resemblance to IBS in humans. Canine IBS has been defined as a chronic large-bowel type diarrhea without known cause and without evidence of colonic inflammation on colonoscopy or biopsy. Dogs fulfilling these criteria were successfully managed with soluble fiber (psyllium hydrophilic mucilloid) supplementation of a highly digestible diet.


Experimental IBD in the dog is accompanied by significant abnormalities in the normal colonic motility patterns. Physical exercise has been shown to disrupt the colonic MMCs and to increase the total duration of contractions that are organized as non-migrating motor complexes during the fed state. Exercise also induces GMCs, defecation, and mass movement in both the fasted and fed states. The increased motor activity of the colon and extra GMCs that result from physical exercise may aid in normal colonic motor function.


Three types of antibiotics (tylosin, metronidazole, oxytetracycline) have been used with some success for the management of small intestinal bacterial overgrowth (SIBO) in dogs. SIBO has not been documented in cats, however, so it’s not clear whether these antibiotics will be as useful in the management of chronic diarrheal states. One study has shown a reduction in the indigenous microflora and an increase in serum cobalamin and albumin concentrations in cats treated with metronidazole.


Probiotics are living organisms with low or no pathogenicity that exert beneficial effects (e.g., stimulation of innate and acquired immunity) on the health of the host. The Gram-positive commensal lactic acid bacteria (e.g., Lactobacilli) have many beneficial health effects, including enhanced lymphocyte proliferation, innate and acquired immunity, and anti-inflammatory cytokine production. Lactobacillus rhamnosus GG, a bacterium used in the production of yogurt, is effective in preventing and treating diarrhea, recurrent Clostridia difficile infection, primary rotavirus infection, and atopic dermatitis in humans. Lactobacillus rhamnosus GG has been safely colonized in the canine gastrointestinal tract, although probiotic effects in the canine intestine have not been firmly established. The probiotic organism, Enterococcus faecium (SF68), has been safely colonized in the canine gastrointestinal tract, and it has been shown to increase fecal IgA content and circulating mature B (CD21+/MHC class II+) cells in young puppies. It has been suggested that this probiotic may be useful in the prevention or treatment of canine gastrointestinal disease. This organism may, however, enhance Campylobacter jejuni adhesion and colonization of the dog intestine, perhaps conferring carrier status on colonized dogs.

Two recent studies have shown that many commercial veterinary probiotic preparations are not accurately represented by label claims. Quality control appears to be deficient for many of these formulations. Until these products are more tightly regulated, veterinarians should probably view product claims with some skepticism.

Anti-Diarrheal Therapy

Four major classes of anti-diarrheal agents are available for use in canine I.B.D. These drugs directly inhibit crypt epithelial secretion or they directly promote villus epithelial absorption.

Prostaglandin Synthetase Inhibitors

1. Sulfasalazine – 10-25 mg/kg TID-QID, PO

2. Olsalazine – 5-10 mg/kg PO, TID-QID (dog)

Opioid Agonists  These drugs stimulate absorption, and inhibit secretion of, fluid and electrolytes.

1. Loperamide 0.08 mg/kg TID, PO-preferred drug

2. Diphenoxylate 0.05-0.10 mg/kg TID-QID, PO-available in Lomotil

5-HT3 Serotonin Antagonists – Antagonists of the neuronal 5-HT3 receptor inhibit Cl- and H2O secretion from intestinal epithelial cells.

1. Ondansetron (Zofran, Glaxo) – 0.5-1.0 mg/kg BID, PO

2. Granisetron (Kytril, SmithKline Beecham) – 0.5-1.0 mg/kg BID, PO

Adrenergic Antagonists – These drugs must be used carefully as they can activate -adrenergic receptors in the chemoreceptor trigger zone and cause vomiting.

1. Clonidine 5-10 ?/kg BID-TID, SQ/PO

Restoration of G.I. Motility

The mixed m,d-opioid agonist, loperamide, stimulates colonic fluid and electrolyte absorption while inhibiting colonic propulsive motility. Loperamide (0.08 mg/kg PO TID-QID) may be beneficial in the treatment of difficult or refractory cases of large bowel-type IBD.

Immunosuppressive Therapy

Sulfasalazine  Sulfasalazine is a highly effective prostaglandin synthetase inhibitor that has proven efficacy in the therapy of large bowel IBD in the dog. Sulfasalazine is a compound molecule of 5-aminosalicylate (meselamine) and sulfapyridine linked in an azo chemical bond. Following oral dosing, most of the sulfasalazine is transported to the distal gastrointestinal tract where cecal and colonic bacteria metabolize the drug to its component parts. Sulfapyridine is largely absorbed by the colonic mucosa but much of the 5-aminosalicylate remains in the colonic lumen where it inhibits mucosal lipoxygenase and the inflammatory cascade. Sulfasalazine has been recommended for the treatment of canine large bowel IBD at doses of 10-25 mg/kg PO TID for 4-6 weeks. With resolution of clinical signs, sulfasalazine dosages are gradually decreased by 25 per cent at 2-week intervals and eventually discontinued while maintaining dietary management. Salicylates are readily absorbed and induce toxicity in cats, therefore this drug classification should be used with great caution in cats. If used in cats, some authors have recommended using half of the recommended dog dose (i.e., 5-12.5 mg/kg PO TID. Sulfasalazine usage has been associated with the development of keratoconjunctivitis sicca in the dog, so tear production should be assessed subjectively (by the pet owner) and objectively (by the veterinarian) during usage.

Other 5-Aminosalicylates  This drug classification was developed to reduce the toxicity of the sulfapyridine portion of the parent molecule (sulfasalazine) and to enhance the efficacy of the 5-aminosalicylate portion. Meselamine (Dipentum, Asachol) and dimeselamine (Olsalazine) are available for use in the treatment of canine large bowel IBD. Olsalazine has been used at a dosage of 5-10 mg/kg PO TID in the dog. Despite the formulation of sulfa-free 5-aminosalicylate preparations, instances of keratoconjunctivitis sicca have still been reported in the dog.

Treatment with Flagyl

Metronidazole (10-20 mg/kg PO BID-TID) has been used in the treatment of mild to moderate cases of large bowel IBD in both dogs and cats. Metronidazole has been used either as a single agent or in conjunction with 5-aminosalicylates or glucocorticoids. Metronidazole is believed to have several beneficial properties, including anti-bacterial, anti-protozoal, and immunomodulatory effects. Side effects include anorexia, hypersalivation, and vomiting at recommended doses and neurotoxicity (ataxia, nystagmus, head title, and seizures) at higher doses. Side effects usually resolve with discontinuation of therapy but diazepam may accelerate recovery of individual patients.


Anti-inflammatory doses of prednisone or prednisolone (1-2 mg/kg PO SID) may be used to treat IBD in dogs that have failed to respond to dietary management, sulfasalazine, or metronidazole, and as adjunctive therapy to dietary modification in feline IBD. Prednisone or prednisolone is used most frequently, as both have short durations of action, are cost-effective, and are widely available. Equipotent doses of dexamethasone are equally effective but may have more deleterious effects on brush border enzyme activity. Prednisone should be used for 2-4 weeks depending upon the severity of the clinical signs. Higher doses of prednisone (e.g., 2-4 mg/kg PO SID) may be needed to control severe forms of eosinophilic colitis or hypereosinophilic syndrome in cats. Combination therapy with sulfasalazine, metronidazole, or azothioprine may reduce the overall dosage of prednisone needed to achieve remission of clinical signs. As with sulfasalazine, the dose of glucocorticoid may be reduced by 25% at 1-2 week intervals while hopefully maintaining remission with dietary modification.

Because of steroid side effects and suppression of the hypothalamic-pituitary-adrenal axis, several alternative glucocorticoids have been developed that have excellent topical (i.e., mucosal) anti-inflammatory activity but are significantly metabolized during first pass hepatic metabolism. Budesonide has been used for many years as an inhaled medication for asthma, and an enteric-coated form of the drug is now available for treatment of IBD in humans (and animals). There is little evidence-based medicine in support of the use of this medication in canine or feline IBD, but doses of 1 mg/cat or 1 mg/dog per day have been used with some success in anecdotal cases.

Azathioprine  Azathioprine is a purine analog that, following DNA incorporation, inhibits lymphocyte activation and proliferation. It is rarely effective as a single agent, and it should instead be used as adjunctive therapy with glucocorticoids. Azathioprine may have a significant steroid-sparing effect in IBD. Doses of 2 mg/kg PO q 24 hours in dogs and 0.3 mg/kg PO q 48 hours in cats have been used with some success in IBD. It may take several weeks or months of therapy for azathioprine to become maximally effective. Cats particularly should be monitored for side effects, including myelosuppression, hepatic disease, and acute pancreatic necrosis.


Cyclosporine has been used in the renal transplantation patient for its inhibitory effect on T cell function. In more recent times, cyclosporine has been used in a number of immune-mediated disorders, including keratoconjunctivitis sicca, perianal fistula (anal furunculosis), and IMHA. Anecdotal reports suggest that cyclosporine (3-7 mg/kg PO BID) may be useful in the treatment of some cases of refractory IBD. Evidence-based medicine studies will be needed to establish efficacy, but anecdotal experience would suggest that cyclosporine may be useful in some of the more difficult or refractory cases of IBD.


Chlorambucil (2 mg/m2 PO every other day) has been used in place of azathioprine in some difficult or refractory cases of feline IBD.

Behavioral Modification

Inflammatory bowel disease and irritable bowel syndrome very likely have underlying behavioral components. Abnormal personality traits and potential environmental stress factors were identified in 38% of dogs in one study. Multiple factors were present in affected households, including travel, re-location, house construction, separation anxiety, submissive urination, noise sensitivity, and aggression. The role of behavior in the pathogenesis and therapy of canine and feline gastrointestinal disorders remains largely unexplored.

References  Available upon request.

Minnesota Veterinary Medical Association Gastroenterology

Robert J. Washabau, VMD, PhD, Dipl. ACVIM
Professor of Medicine and Department Chair
Department of Veterinary Clinical Sciences
College of Veterinary Medicine, University of Minnesota
St. Paul, Minnesota 55108 U.S.A.
(612) 625-5273 Office; (612) 624-0751 FAX<