Inflammation

Inflammatory bowel disease (IBD) may be defined using clinical, pathogenetic, imaging, histologic, immunologic, pathophysiologic, and genetic criteria.

Clinical Criteria

IBD has been defined clinically as a spectrum of gastrointestinal disorders associated with chronic inflammation of the stomach, intestine and/or colon of unknown etiology. A clinical diagnosis of IBD is considered only if affected animals have: 1) persistent (>3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucoid feces), 2) failure to respond to symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, 3) failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and 4) histologic diagnosis of benign intestinal inflammation.

Pathogenetic Criteria

Known causes of intestinal diarrhea should first be considered: food sensitivity reaction, bacterial infection, parasitic infection, fungal infection, pancreatic insufficiency, intestinal neoplasia, lymphangiectasia (canine), and hyperthyroidism (feline). Most current hypotheses on the pathogenesis of IBD hold that the gut has sustained reactivity to endogenous bacterial antigens.

Histologic Criteria

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 large intestinal IBD, subjective interpretation of small intestinal IBD lesions has made it difficult to compare tissue findings between pathologists. Subjectivity in histologic assessments has led to the development of several IBD grading systems.

Immunologic Criteria

IBD has been defined immunologically by the innate and adaptive response of the mucosa to gastrointestinal antigens. Although the precise immunologic events of canine and feline 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.

Pathophysiologic Criteria

IBD may be defined pathophysiologically in terms of changes in transport, blood flow, and motility. 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. The pathophysiology of small intestinal IBD is explained by at least two interdependent mechanisms: the mucosal immune response, and accompanying 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-γ, TNF-α, 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 whereas IBD of the canine colon may be more of a Th1 type response with elaboration of IL-2, IL-12, INF-γ, and TNF-α.

Motility Changes: 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. 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, 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 (K_Ca) partially attenuate this effect. 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. PKC α, β, and ε isoenzyme expression is down-regulated, PKC ι and λ isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. 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-κB which further suppresses cell contractility.

New Findings in Inflammatory Bowel Disease

Histopathology of the gastrointestinal tract is an important tool for the diagnosis of chronic gastrointestinal disorders of dogs and cats although internationally accepted standards for diagnosis and therapy have not yet been achieved. During the first phase of its work (2004-2008), the WSAVA Gastrointestinal Standardization Group produced: 1) standard guidelines for the endoscopic examination of the stomach, duodenum and colon (http://www.wsava.org/standardizationgroup.htm); 2) standard criteria for the histologic assessment of endoscopic biopsies of the stomach, duodenum and colon (Day et al., Journal of Comparative Pathology 2008; 138: S1-S43); 3) an ACVIM Consensus Statement on the diagnosis of inflammatory enteropathies (Washabau et al., ACVIM Forum, San Antonio, 2008); and, 4) guidelines on biopsy number and quality in the detection of gastrointestinal pathology in endoscopic biopsies (Willard et al., Journal of Veterinary Internal Medicine, 2008; 22: 1084-1089). 5) Other studies relating histologic changes to clinical symptomatology are in preparation, and one was presented as an abstract at the 2008 ECVIM Congress in Ghent, Belgium (Willard et al. Use of the WSAVA Gastrointestinal Standardization Guidelines in the assessment of correlation between pathologists in the interpretation of gastric and intestinal endoscopic biopsies. J. Vet. Intern. Med. 2008). 6) An Atlas of Gastrointestinal Endoscopic and Related Histopathologic Findings is planned for 2009-2010. By creating endoscopic, biopsy, and histologic standards for gastrointestinal disease, these advances have improved our ability to diagnose common gastrointestinal disorders as well as provide standards that will permit meaningful comparison of different studies. Moreover, veterinarians around the world will now have access to one reference standard for inflammatory bowel disease in the diagnosis of gastrointestinal disease.

New Findings in Inflammatory Bowel Disease

 Endoscopy: http://www.wsava.org, 2008

 Biopsies: Journal of Veterinary Internal Medicine 2008; 22: 1084-1089

 Histology: Journal of Comparative Pathology 2008; 138: S1-S43

 Inflammation: Journal of Veterinary Internal Medicine 2009: Consensus Statement, pending

 Correlations: ECVIM Congress 2008, abstract

 Atlas: Atlas of Endoscopy and Related Pathology, Blackwell Publishing, 2009-2010