Intestinal Permeability in Dogs with Chronic Enteropathy

Abstract

Dogs with chronic clinical signs of gastrointestinal disease such as diarrhea, vomiting, weight loss, and/or loss of appetite are often diagnosed with chronic enteropathy after infectious, parasitic, neoplasia, and extra-intestinal diseases have been excluded. Chronic enteropathy is a multifactorial disease for which the exact pathophysiology is not well elucidated, but it is believed that dysfunction of the intestinal barrier is involved, leading to increased intestinal permeability. The study aims were to, measure serum iohexol concentrations after oral ingestion of iohexol, measure serum lipopolysaccharide concentrations, evaluate the expression of apical junction complex proteins: zonula occludens-1, e-cadherin, claudin-1, and occludin in small intestine tissue by immunohistochemistry, and perform untargeted small RNA-sequencing of fecal samples of healthy dogs and dogs with chronic enteropathy.

Serum iohexol was increased in dogs with chronic enteropathy, more specifically in a subset of dogs with immunosuppressive-responsive enteropathy, classified based on treatment-response. Serum iohexol concentrations correlated with the canine chronic enteropathy activity index. E-cadherin immunostaining intensity in the small intestine was significantly increased in dogs with chronic enteropathy and correlated with serum iohexol concentrations. Occludin, claudin-1, and ZO-1 immunostaining intensity was not different between groups in this study population. Untargeted fecal small RNA-sequencing revealed 10 novel differentially expressed microRNAs in dogs with chronic enteropathy compared to healthy dogs. Among these, miR-21, miR-182, miR-184, miR- 200b, miR-221, and miR-320 were previously reported to correlate with gastrointestinal disorders or neoplasia in humans. miR-29a, which was upregulated in dogs with chronic enteropathy in this study, was previously reported to be upregulated in both humans and in pigs and described as an intestinal permeability regulator. Lastly, miR-Let7b, miR-8807, and miR-8842 are novel miRNAs that have not previously been studied in the human or veterinary fields. Interestingly, miR-8807 expression was increased in dogs with immunosuppressive-responsive enteropathy when compared to dogs with food-responsive enteropathy or healthy control dogs.

These results demonstrate that a subset of dogs with chronic gastrointestinal disease have altered intestinal permeability. Additional studies are needed to elucidate whether this dysfunction of the intestinal barrier plays an active role or is another sequalae to chronic gastrointestinal disease in dogs.