Inflammatory Bowel Disease

Chapter 131

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) describes a group of idiopathic disorders characterized by chronic persistent or recurrent gastrointestinal (GI) signs, with histologic evidence of inflammation in the lamina propria of the small intestine, large intestine, or both. The diagnosis of IBD is one of exclusion, and a full diagnostic workup is necessary to rule out all known causes of GI inflammation. Currently, endoscopic evaluation and histopathology of intestinal biopsies is the preferred way to diagnose IBD definitively. Although the exact etiology of IBD is unknown, it is widely accepted that the pathogenesis involves a complex interplay among host genetics, the intestinal mucosal immune system, the environment, and the intestinal microbiota. This chapter briefly examines the current understanding of the pathogenesis and diagnosis of IBD and then concentrates in more detail on the current therapeutic practice, drawing from the most recent work conducted in this field.


IBD is classified according to the inflammatory cell infiltrate present, the most common of which is lymphoplasmacytic enteritis in dogs and cats. Eosinophilic enteritis is thought to be the second most common, whereas granulomatous enteritis is rare and most commonly diagnosed in young boxers and French bulldogs. Neutrophilic infiltration also is rare in canine and feline IBD. Furthermore, IBD patients can be classified retrospectively depending on their response to treatment. Those responding to an elimination diet or hydrolyzed diet are diagnosed with food-responsive diarrhea (FRD), whereas those responding to antibiotic treatment are diagnosed with antibiotic-responsive diarrhea (ARD). IBD patients that do not fall into either of the two latter categories require immunosuppressive medication to treat their clinical signs and are classified commonly as having steroid-responsive diarrhea. Finally, certain breeds are highly susceptible to developing specific unique forms of IBD; examples include the immunoproliferative enteropathy of basenjis, the protein-losing enteropathy (PLE) and protein-losing nephropathy (PLN) complex in soft-coated wheaten terriers, IBD in Norwegian lundehunds, and granulomatous colitis in boxer dogs.


In the last few decades the study of human IBD and animal models of this disease has led to many significant advances in understanding the pathogenesis of IBD. These studies have shown that the pathogenesis of IBD is complex, involving an overly aggressive cell-mediated response resulting from the loss of tolerance to antigens of the microbiome in genetically susceptible hosts.


The genetic inheritance of human IBD is not understood fully. A classical Mendelian inheritance attributable to a single locus has not been demonstrated, but rather a more complex polygenic model of inheritance with evidence of epistasis between genetic loci. Mutations in pattern-recognition receptors of the innate immunity, such as Toll-like receptors and NOD-like receptors as well as in genes coding for autophagy proteins, have been associated with the development of IBD in people.

A number of breed predispositions have been described in canine IBD, thus strongly supporting a role for host genetics. Using candidate gene analysis, polymorphisms in Toll-like receptor (TLR) 4 and TLR5 were shown recently to be significantly associated with IBD in German shepherds. Furthermore, the same polymorphisms in TLR5 were associated with IBD in a heterogeneous population of dogs consisting of 38 different breeds. These mutations could well play an important role in the pathogenesis of IBD in dogs: a mutated receptor leads to misrepresentation of commensal bacteria as pathogens, therefore signaling “danger” to the host and initiating the characteristic inflammatory response seen in this disease. Further studies must focus on genome-wide association studies in specific breeds of dogs and cats and take into account environmental factors likely to be instrumental in the development of disease in individual susceptible animals.

Intestinal Mucosal Immune System

The concept of impaired immunoregulation in IBD is supported by observations of increased numbers of CD4+ T cells in people and increased numbers of immunoglobulin-producing plasma cells and T cell subsets in canine and feline IBD. Inflammation seen in IBD is thought to result from the inappropriate cytokine production by these different T cell subsets. Specifically, Crohn’s disease (CD) is associated with a Th1 and Th17 cytokine profile and ulcerative colitis (UC) with a Th2 profile. In cats, a similar cytokine profile skewed toward a Th1 profile has been found. However, in dogs, no specific pattern of cytokines has been detected using real-time PCR on intestinal biopsies. It therefore is plausible that other immunologic components may play a role in the inappropriate inflammation seen in a subset of dogs with IBD. Indeed one study demonstrated that CD11c-positive dendritic cells (DCs) were decreased significantly in the intestinal mucosa of dogs with IBD. DCs are important in regulating the immunologic balance and are responsible for eliciting either an inflammatory or a tolerant immune response to an antigen. Thus a decrease in the number of DCs in the inflamed mucosa of dogs with IBD may explain the exaggerated inflammation seen in this disease. Moreover, cytokines such as the Th17 cytokine family have not been evaluated in dogs and cats with IBD and could, similarly to IBD in people, play a significant role in the pathogenesis of the disease.

Alterations of expression of TLR3 and TLR4 by intestinal epithelial cells have been described in human IBD. Similarly, TLR 2, 4, and 9 have been shown to be upregulated in the duodenum and colonic mucosa in dogs with IBD at the mRNA level, and TLR2 expression specifically was shown to be correlated with the severity of disease. This dysregulation of TLRs in human and canine IBD patients may be a pathologic consequence or the underlying cause of inflammation. However, if the latter applies, this may explain the chronic inflammation seen in these diseases.

Intestinal Microbiota

The importance of the commensal bacteria in the pathogenesis of IBD has been well documented in animal models and in people with IBD. Chronic intestinal inflammation does not develop in mice reared in germ-free environments; however, reconstitution of germ-free mice with commensal bacteria can be enough to induce IBD in several gene-deficient as well as T cell transfer models of IBD. The role of luminal bacteria in the pathogenesis of human IBD is supported strongly by the fact that clinical symptoms of CD improve after intestinal washes and antibacterial treatment. Similarly, a subset of canine IBD patients (ARD patients) responds solely to antibiotics with subsequent relapse of clinical signs on withdrawal of treatment.

Investigating DNA libraries of mucosal-associated microbiota using molecular methods has revolutionized our understanding of the microbiome in animals and human beings. In patients with CD and UC, a decreased complexity of the microbiome has been found. Most notably, members of the phyla Bacteroidetes and Firmicutes are reduced significantly in CD and UC, whereas E. coli is abundant in CD. Similarly, the species richness within the microbiome in the duodenal lumen of dogs with IBD was reduced. Dogs with IBD also exhibit dysbiosis, with an abundance of members belonging to the Enterobacteriaceae family and a significantly lower number of Clostridia spp. Such dysbiosis may well be breed specific because German shepherds with IBD have been shown to harbor increased numbers of sequences belonging to Erysipelotrichaceae and Lactobacillales. In cats, the number of Enterobacteriaceae, E. coli, and Clostridium spp. correlates with abnormalities in mucosal architecture, up-regulation of Th1-cytokines, and the number of clinical signs exhibited by the affected cats. Such dysbiosis is thought to contribute to the inflammation seen in dogs and cats with IBD, in that inflammatory signals from the microbes (so-called pathogen-associated patterns) are recognized by the innate immune system of the host (such as Toll-like receptors) and could lead to an exaggerated adaptive immune response in the lamina propria of the mucosa, therefore leading to clinical signs.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Inflammatory Bowel Disease

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