Search

Preclinical biomedical research is limited by the predictiveness of in vivo and in vitro models. While in vivo models offer the most complex system for experimentation, they are also limited by ethical, financial, and experimental constraints. In vitro models are simplified models that do not offer the same complexity as living animals but do offer financial affordability and more experimental freedom; therefore, they are commonly used. Traditional 2D cell lines cannot fully simulate the complexity of the epithelium of healthy organs and limit scientific progress. The One Health Initiative was established to consolidate human, animal, and environmental health while also tackling complex and multifactorial medical problems. Reverse translational research allows for the sharing of knowledge between clinical research in veterinary and human medicine. Recently, organoid technology has been developed to mimic the original organs epithelial microstructure and function more reliably. While human and murine organoids are available, numerous other organoids have been derived from traditional veterinary animals and exotic species in the last decade. With these additional organoid models, species previously excluded from in vitro research are becoming accessible, therefore unlocking potential translational and reverse translational applications of animals with unique adaptations that overcome common problems in veterinary and human medicine.

Simple Summary: Chronic inflammatory enteropathy (CE) is a common cause for persistent or intermittent diarrhea and intestinal inflammation in dogs. Since there is evidence that imbalances in intestinal bacteria (dysbiosis) are associated with mucosal inflammation, probiotics, prebiotics, or a combination of the two (synbiotics) may reduce intestinal inflammation and decrease severity of dysbiosis. The goal of this study was to investigate the effects of dietary supplement synbiotic-IgY on clinical signs, inflammatory indices, and the mucosal microbiota in the dogs with CE. Twenty dogs with CE completed a prospective randomized clinical trial and were administered a hydrolyzed diet with the dietary supplement (synbiotic-IgY) or placebo (hydrolyzed diet) continuously for 6 weeks. At trial completion, results indicated that clinical disease activity and endoscopic scores decreased in both groups. Compared to dogs who were fed placebo, dogs administered supplement exhibited decreased levels of inflammatory markers fecal calprotectin and high-sensitivity C-reactive protein (hs-CRP) two weeks post-treatment, decreased levels of hs-CRP two- and six-weeks post-treatment, increased numbers of mucosal Clostridia and Bacteroides and decreased numbers of Enterobacteriaceae in colon biopsies at the completion of the trial. Results suggest that hydrolyzed diet and supplement effect favorable changes to host responses and the mucosal microbiota in dogs with CE. Chronic inflammatory enteropathy (CE) is a common cause of persistent gastrointestinal signs and intestinal inflammation in dogs. Since evidence links dysbiosis to mucosal inflammation, probiotics, prebiotics, or their combination (synbiotics) may reduce intestinal inflammation and ameliorate dysbiosis in affected dogs. This study's aim was to investigate the effects of the synbiotic-IgY supplement on clinical signs, inflammatory indices, and mucosal microbiota in dogs with CE. Dogs with CE were enrolled in a randomized prospective trial. Twenty-four client-owned dogs were fed a hydrolyzed diet and administered supplement or placebo (diet) for 6 weeks. Dogs were evaluated at diagnosis and 2- and 6-week post-treatment. Outcome measures included clinical activity, endoscopic and histologic scores, inflammatory markers (fecal calprotectin, C-reactive protein), and composition of the mucosal microbiota via FISH. Eleven supplement- and nine placebo-treated dogs completed the trial. After 6 weeks of therapy, clinical activity and endoscopic scores decreased in both groups. Compared to placebo-treated dogs, dogs administered supplement showed decreased calprotectin at 2-week post-treatment, decreased CRP at 2- and 6-week post-treatment increased mucosal Clostridia and Bacteroides and decreased Enterobacteriaceae in colonic biopsies at trial completion. Results suggest a beneficial effect of diet and supplements on host responses and mucosal microbiota in dogs with CE. [ABSTRACT FROM AUTHOR]

For decades, two-dimensional (2D) cell cultures have been used as the gold standard in vitro models for basic research, drug discovery and preclinical screening applications. However, since 2009, the field has quickly shifted towards the use of three-dimensional (3D) stem cell-derived organoids. Organoids offer a variety of advantages compared with conventional 2D models, including being selforganized, retaining their cellular polarity, and being simplified versions of organs in vitro. Adult stem cells can self-renew, differentiate into multiple cell types, and are genomically stable over multiple passage lines, providing a variety of technical benefits and offering the closest recapitulation of the in vivo environment. Our laboratory has focused on expanding, characterizing, and utilizing animal-derived 3D organoid models, specifically focusing on canines; but also including other animals such as swine, turtles, snakes, and squirrels to study their unique adaptations. Practically, we can use 3D canine colonoids for the screening of antiinflammatory candidates using our tumor necrosis factor (TNF)-α stimulation model. Additionally, we have grown and used swine lung organoids as a model for studying H1N1 viral uptake. Furthermore, we have grown and bio-banked tumor organoids/spheroids from a variety of canine cancers, including urothelial carcinoma (derived from urine and biopsies) and nasal carcinoma, among others, with future applications in precision veterinary medicine and comparative oncology. To accomplish this goal, we have carried out in vitro screening of a variety of chemotherapies and combination therapies at different concentrations across patients to predict in vivo responses and demonstrate the predictive ability of the organoid model. Finally, our laboratory has derived and characterized a variety of healthy organoid lines from canines including the pancreas, lung, liver, bladder, colon, and pituitary to act as healthy controls in mechanistic studies looking at disease pathogenesis and for uses in basic biology. In summary, in vitro organoid models from various animal species and tissues can be used in a variety of basic and applied research fields, including virology, toxicology, and oncology, with the potential to broaden our scientific understanding of disease and overall improve human and veterinary medicine [ABSTRACT FROM AUTHOR]

Human consumption of Western diets (WD) has been strongly associated with increased central obesity, adipocyte hypertrophy, intestinal epithelial stemness/proliferation, dyslipidemia, and blood pressure. These changes reflect metabolic dysfunction and contribute to increased risk of type 2 diabetes mellitus and colorectal cancer. As comprehensive molecular/clinical comparisons have not been performed, the objective of this study was to evaluate diet-induced changes in dogs as a clinically-responsive model for human WD-related disease research. Methods: In a crossover design, 10 dogs were fed either a 1.) control diet (CON) formulated based on the Acceptable Macronutrient Distribution Ranges and fiber recommendations for humans; or 2.) Western diet (WD) formulated based on National Health and Nutrition Examination Survey dataset parameters. Diets were prepared cooked with the same ingredients and formulated to meet/exceed nutrient/energy requirements for both humans/dogs and fed isocalorically based on calculated metabolizable energy (ME). Following each period (~7-8 weeks), experimental parameters were measured. Results/Conclusions: Mean body weights were 8.83 and 9.28kg for CON and WD diets, respectively (P = 0.0018). Fasted (10-hour) blood samples differed significantly (P < 0.01) for mean fasting bile acids (CON=0.79, WD=8.94µmol/L), serum triglycerides (CON=45.70, WD=67.80mg/dL), and serum cholesterol (CON=140.10, WD=175.40mg/dL) demonstrating diet-dependent alterations in lipid profiles. Mean systolic blood pressures were 131.66 and 140.02mmHg for CON and WD, respectively (P < 0.0001). Histological analysis revealed dietdependent changes in colonic epithelial villus height (CON=182, WD=207µm) and villus:crypt ratio (CON=2.61, WD=3.89). Preliminary RNA-ISH analysis (n = 3 dogs) showed increased LGR5+ expression (intestinal stem-cell marker) in WD compared to CON group (P = 0.0019) suggesting an increased "stemnness" of colonic epithelium. Further, mean adipocyte diameters were increased in omental fat biopsies (CON=58.6, WD=62.5µm; P < 0.0001) but not subcutaneous fat biopsies (P >0.05) following WD feeding, consistent with centralized obesity. Collectively, these results demonstrate effects of diet-induced changes in dogs as a clinically-responsive model for human WD-related disease research. [ABSTRACT FROM AUTHOR]