Graduate Thesis Or Dissertation

Expression of serotonin, chromogranin-A, serotonin receptor-2B, tryptophan hydroxylase-1, and serotonin reuptake transporter in the small intestine of dogs with inflammatory bowel disease

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  • The neuroendocrine system of the gut plays a significant role in regulating intestinal motor and sensory functions, as well as modulating inflammation in the intestine. The intestinal mucosa is the dominant site of serotonin (5HT) synthesis in mammals, with more than 95% of the intestinal 5HT being present in the enterochromaffin cells (ECC). When released from these cells, 5HT acts locally on the intestinal tract, affecting intestinal motility and nociception. 5HT excess is associated with autonomic hyperactivity of the intestinal tract and has been shown to be modulated in the gut of dogs with inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal (GI) tract of dogs that commonly causes chronic vomiting, diarrhea, weight loss, and/or anorexia. Because IBD is commonly diagnosed and treated in companion animals, continuing to identify avenues by which therapy can be enhanced is relevant. Therefore, the first objective of this study was to retrospectively compare the expression of 5HT and Chromogranin-A (CgA) in the intestine between dogs with IBD and a group of healthy dogs (CG1). A second objective was to prospectively quantify and compare the expression of serotonin receptor 2B (5HT2B), tryptophan hydroxylase-1 (THP-1), and serotonin transporter (SERT), in the intestine between IBD dogs and a group of healthy dogs (CG2). For the retrospective aspect of the study, a search of the medical record database at Lois Bates Acheson Veterinary Teaching Hospital at Oregon State University College of Veterinary Medicine revealed nine client-owned dogs diagnosed with IBD that were included. Histologic grading of eleven specimens from the nine dogs was determined based on WSAVA guidelines and disease severity was determined via inflammatory bowel index scores. 5HT and CgA expression was determined by immunohistochemistry (IHC). CG1 included nine healthy control dogs from an unrelated project. For the second part of the study, GI samples were prospectively collected from seven dogs with a clinical history consistent with that of IBD with histopathologic evidence of mucosal inflammation consistent with IBD. 5HT[subscript 2B], THP-1, and SERT expression was determined by quantitative reverse transcriptase polymerase chain reaction (QRT-PCR), and compared to expression of 5HT[subscript 2B], THP-1, and SERT in CG2, which included eight healthy dogs. Both the IBD group and CG1 showed enterocytes with strong staining for 5HT and CgA. The mean positive cells/hpf were significantly increased for both 5HT and CgA immunopositive cells in the IBD dogs compared to the control group (5HT mean 2.3 cells/hpf vs. 1.0 cells/hpf, p<0.01; CgA 2.7 cells/hpf vs. 1.7 cells/hpf, p<0.05). There was a significant correlation between 5HT and CgA positive cells/hpf across all dogs (Pearson r²=0.2433, p=0.016). 5HT[subscript 2B] expression was significantly lower in the IBD dogs (p<0.05). The RQ values in the IBD group overall were approximately 0.5 times those of CG2 (mean relative target sequence expression value: IBD group 0.5; CG2 1.1). There was no significant difference in the amount of THP-1 expressed in the IBD dogs versus CG2 (p=0.7413). Although there was a trend towards a lower relative target sequence expression value for SERT in the dogs with IBD, there is no significant difference found (p=0.34). Overall, in this study we were able to demonstrate that there was increased expression of 5HT and CgA in the small intestine of IBD dogs versus that of CG1, that correlated with previous studies in humans. There was a decrease in the relative target sequence expression of 5HT[subscript 2B] in the IBD dogs. We were unable to establish a significant difference in the expression of THP-1 and SERT between the two groups.
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