Publications by authors named "Albert E Jergens"

61 Publications

Rules of Engagement: Epithelial-Microbe Interactions and Inflammatory Bowel Disease.

Front Med (Lausanne) 2021 27;8:669913. Epub 2021 Aug 27.

Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex, multifactorial disorders that lead to chronic and relapsing intestinal inflammation. The exact etiology remains unknown, however multiple factors including the environment, genetic, dietary, mucosal immunity, and altered microbiome structure and function play important roles in disease onset and progression. Supporting this notion that the gut microbiota plays a pivotal role in IBD pathogenesis, studies in gnotobiotic mice have shown that mouse models of intestinal inflammation require a microbial community to develop colitis. Additionally, antimicrobial therapy in some IBD patients will temporarily induce remission further demonstrating an association between gut microbes and intestinal inflammation. Finally, a dysfunctional intestinal epithelial barrier is also recognized as a key pathogenic factor in IBD. The intestinal epithelium serves as a barrier between the luminal environment and the mucosal immune system and guards against harmful molecules and microorganisms while being permeable to essential nutrients and solutes. Beneficial (i.e., mutualists) bacteria promote mucosal health by strengthening barrier integrity, increasing local defenses (mucin and IgA production) and inhibiting pro-inflammatory immune responses and apoptosis to promote mucosal homeostasis. In contrast, pathogenic bacteria and pathobionts suppress expression and localization of tight junction proteins, cause dysregulation of apoptosis/proliferation and increase pro-inflammatory signaling that directly damages the intestinal mucosa. This review article will focus on the role of intestinal epithelial cells (IECs) and the luminal environment acting as mediators of barrier function in IBD. We will also share some of our translational observations of interactions between IECs, immune cells, and environmental factors contributing to maintenance of mucosal homeostasis, as it relates to GI inflammation and IBD in different animal models.
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http://dx.doi.org/10.3389/fmed.2021.669913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432614PMC
August 2021

Temporal Dynamics of Chronic Inflammation on the Cecal Microbiota in IL-10 Mice.

Front Immunol 2020 16;11:585431. Epub 2021 Feb 16.

Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, United States.

The intestinal microbiota is a critical component of mucosal health as evidenced by the fact that alterations in the taxonomic composition of the gastrointestinal microbiota are associated with inflammatory bowel diseases. To better understand how the progression of inflammation impacts the composition of the gastrointestinal microbiota, we used culture independent taxonomic profiling to identify temporal changes in the cecal microbiota of C3Bir IL-10 mice concomitantly with the onset and progression of colitis. This analysis revealed that IL-10 mice displayed a biphasic progression in disease severity, as evidenced by histopathological scores and cytokine production. Beginning at 4 weeks of age, pro-inflammatory cytokines including TNF-α, IFN-γ, IL-6, G-CSF, and IL-1α as well as chemokines including RANTES and MIP-1α were elevated in the serum of IL-10 mice. By 19 weeks of age, the mice developed clinical signs of disease as evidenced by weight loss, which was accompanied by a significant increase in serum levels of KC and IL-17. While the overall diversity of the microbiota of both wild type and IL-10 were similar in young mice, the latter failed to increase in complexity as the mice matured and experienced changes in abundance of specific bacterial taxa that are associated with inflammatory bowel disease in humans. Collectively, these results reveal that there is a critical time in young mice between four to six weeks of age when inflammation and the associated immune responses adversely affect maturation of the microbiota.
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http://dx.doi.org/10.3389/fimmu.2020.585431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921487PMC
June 2021

Colonic mucosal and cytobrush sample cytokine mRNA expression in canine inflammatory bowel disease and their correlation with disease activity, endoscopic and histopathologic score.

PLoS One 2021 20;16(1):e0245713. Epub 2021 Jan 20.

Companion Animal Clinic (Medicine Unit), School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Canine inflammatory bowel disease (IBD) is a group of chronic gastrointestinal disorders, the pathogenesis of which remains elusive, but it possibly involves the interaction of the intestinal immune system with luminal microbiota and food-derived antigens. Mucosal cytokines profiles in canine IBD have been investigated mainly in small intestinal disease, while data on cytokine profiles in large intestinal IBD are limited. The objective of this study was to measure colonic mucosal and cytobrush sample messenger (m)RNA expression of interleukin (IL)-1β, IL-2, IL-12p40, IL-23p19, tumor necrosis factor-alpha (TNF-α) and chemokine C-C motif ligand (CCL28) in dogs with IBD and healthy controls using quantitative real-time polymerase chain reaction (PCR), and assess their correlation with clinical disease activity, endoscopic and histopathologic score. Dogs with IBD had a significantly increased mRNA expression of IL-1β, IL-23p19 and CCL28 in the colonic mucosa, compared to healthy controls. None of the selected cytokines had significantly different mRNA expression in the colonic cytobrush samples between the two groups or between the colonic mucosa and cytobrush samples of dogs with IBD. Finally, there was a statistically significant correlation of clinical disease activity with endoscopic activity score and fibrosis and atrophy of the colonic mucosa in dogs with large intestinal IBD. IL-1β, IL-23p19 and CCL28 could play a role in the pathogenesis of canine large intestinal IBD. Colonic cytokine expression does not correlate with clinical disease activity and/or endoscopic score. However, clinical signs reflect the severity of endoscopic lesions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245713PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817028PMC
June 2021

An initial genome-wide investigation of protein-losing enteropathy in Gordon setters: Exploratory observations.

Can J Vet Res 2021 Jan;85(1):51-60

Department of Veterinary Clinical Sciences (Donnini, Jergens, Allenspach), College of Veterinary Medicine, 1809 South Riverside Drive, Iowa State University, Ames, Iowa 50010, USA; Department of Animal Science (Walugembe, Rothschild), College of Agriculture and Life Sciences, 2255 H. Kildee Hall, Iowa State University, Ames, Iowa 20011, USA.

The objective of this preliminary study was to identify genomic regions that may predispose Gordon setters from the United Kingdom to familial protein-losing enteropathy (PLE) at a young age. A total of 106 related Gordon setters was used, including 6 affected dogs from an affected litter, 6 case controls from the same litter, 10 related/affected dogs, and 84 related/unaffected dogs. Genomic DNA was collected from each Gordon setter and extracted from buccal mucosal swabs. Genotyping of affected and unaffected dogs was carried out using the Canine Illumina HD SNP array and data generated were analyzed with PLINK software, using fixation index (Fst) and runs of homozygosity (ROH) methods. Pairwise Fst analyses between the affected and unaffected Gordon setter dogs identified various regions of differentiation on chromosomes 10, 18, 21, and 23 that contained several important genes. These regions revealed 5 candidate genes, including , and , that are associated with human inflammatory bowel disease (IBD) and could potentially be associated with PLE in Gordon setters. Run of homozygosity (ROH) analyses revealed additional unique regions on chromosomes 15 and 17. These regions contained genes , and that could also be potential candidates for PLE in Gordon setters. The biological functions of the identified genes provided initial insights into the pathophysiology of PLE. Further large-scale studies are warranted to investigate the possible causality of these genomic regions and any possible genetic markers that could be used in predicting susceptibility to PLE syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747665PMC
January 2021

Effects of the Probiotic Mixture Slab51® (SivoMixx®) as Food Supplement in Healthy Dogs: Evaluation of Fecal Microbiota, Clinical Parameters and Immune Function.

Front Vet Sci 2020 4;7:613. Epub 2020 Sep 4.

Gastrointestinal Laboratory, Texas A&M University, College Station, TX, United States.

The gut microbiota plays a crucial role in several physiologic functions of the host. In humans and animals, manipulation of the intestinal microbiota by oral administration of probiotic lactic acid bacteria plays a significant role in modulating the immune system. The aim of this study was to evaluate the safety of the probiotic mixture Slab51® and the capacity of this mixture to stimulate immune function in healthy dogs. Twenty dogs were divided in two groups and received a control diet or the same diet supplemented with a dose of 400 billion cfu of lyophilized bacteria for a period of 60 days. Body weight, food intake, body condition score (BCS), fecal score (FSS), fecal immunoglobulin IgA concentration, plasma IgG concentration, and fecal microbiota composition were monitored. Weight, food intake, BCS, FSS, and biochemical parameters remained unchanged during the treatment in both groups of animals. The fecal microbiota showed a significant decrease in the abundance of and a significant increase in the abundance of beneficial Bifidobacterium and Lactobacillus organisms ( < 0.05). Fecal IgA and plasma IgG levels were significantly higher in the group receiving the probiotic compared to healthy controls. These data show that dietary supplementation with the probiotic mixture Slab51® is safe and well-tolerated, modulating the composition of the intestinal microbiota, and enhancing specific immune functions in healthy dogs.
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http://dx.doi.org/10.3389/fvets.2020.00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499176PMC
September 2020

Triaditis: Truth and Consequences.

Vet Clin North Am Small Anim Pract 2020 Sep 15;50(5):1135-1156. Epub 2020 Jul 15.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, L2565 Lloyd, 1809 South Riverside Drive, Ames, IA 50011, USA. Electronic address:

Clinical findings with triaditis and individual disease components overlap and may include hyporexia, weight loss, lethargy, vomiting, diarrhea, dehydration, icterus, abdominal pain, thickened bowel loops, pyrexia, dyspnea, and shock. A definitive diagnosis of triaditis requires histologic confirmation of inflammation in each organ, but this may not be possible because of financial or patient-related constraints. Evidence-based data indicate that histologic lesions of triaditis are present in 30% to 50% of cats diagnosed with pancreatitis and cholangitis/inflammatory liver disease. Treatment of triaditis is based on the overall health status of the patient and the type and severity of disease in component organs.
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http://dx.doi.org/10.1016/j.cvsm.2020.06.008DOI Listing
September 2020

Recapitulation of the accessible interface of biopsy-derived canine intestinal organoids to study epithelial-luminal interactions.

PLoS One 2020 17;15(4):e0231423. Epub 2020 Apr 17.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, United States of America.

Recent advances in canine intestinal organoids have expanded the option for building a better in vitro model to investigate translational science of intestinal physiology and pathology between humans and animals. However, the three-dimensional geometry and the enclosed lumen of canine intestinal organoids considerably hinder the access to the apical side of epithelium for investigating the nutrient and drug absorption, host-microbiome crosstalk, and pharmaceutical toxicity testing. Thus, the creation of a polarized epithelial interface accessible from apical or basolateral side is critical. Here, we demonstrated the generation of an intestinal epithelial monolayer using canine biopsy-derived colonic organoids (colonoids). We optimized the culture condition to form an intact monolayer of the canine colonic epithelium on a nanoporous membrane insert using the canine colonoids over 14 days. Transmission and scanning electron microscopy revealed a physiological brush border interface covered by the microvilli with glycocalyx, as well as the presence of mucin granules, tight junctions, and desmosomes. The population of stem cells as well as differentiated lineage-dependent epithelial cells were verified by immunofluorescence staining and RNA in situ hybridization. The polarized expression of P-glycoprotein efflux pump was confirmed at the apical membrane. Also, the epithelial monolayer formed tight- and adherence-junctional barrier within 4 days, where the transepithelial electrical resistance and apparent permeability were inversely correlated. Hence, we verified the stable creation, maintenance, differentiation, and physiological function of a canine intestinal epithelial barrier, which can be useful for pharmaceutical and biomedical researches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164685PMC
July 2020

Colonic mucosal and serum expression of microRNAs in canine large intestinal inflammatory bowel disease.

BMC Vet Res 2020 Feb 22;16(1):69. Epub 2020 Feb 22.

Departments of Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, USA.

Background: Canine inflammatory bowel disease (IBD) is a group of chronic gastrointestinal (GI) disorders of still largely unknown etiology. Canine IBD diagnosis is time-consuming and costly as other diseases with similar signs should be initially excluded. In human IBD microRNA (miR) expression changes have been reported in GI mucosa and blood. Thus, there is a possibility that miRs may provide insight into disease pathogenesis, diagnosis and even treatment of canine IBD. The aim of this study was to determine the colonic mucosal and serum relative expression of a miRs panel in dogs with large intestinal IBD and healthy control dogs.

Results: Compared to healthy control dogs, dogs with large intestinal IBD showed significantly increased relative expression of miR-16, miR-21, miR-122 and miR-147 in the colonic mucosa and serum, while the relative expression of miR-185, miR-192 and miR-223 was significantly decreased. Relative expression of miR-146a was significantly increased only in the serum of dogs with large intestinal IBD. Furthermore, serum miR-192 and miR-223 relative expression correlated to disease activity and endoscopic score, respectively.

Conclusion: Our data suggest the existence of dysregulated miRs expression patterns in canine IBD and support the potential future use of serum miRs as useful noninvasive biomarkers.
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http://dx.doi.org/10.1186/s12917-020-02287-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035774PMC
February 2020

Apparent total tract digestibility, fecal characteristics, and blood parameters of healthy adult dogs fed high-fat diets.

J Anim Sci 2020 Mar;98(3)

Department of Animal Science, Iowa State University, Ames, IA.

Pet foods may be formulated with decreased starch to meet consumer demands for less processed diets. Fats and oils may be added to low-starch diets to meet energy requirements, but little is known about its effects on canine health. The study objective was to evaluate the effects of feeding healthy adult dogs low carbohydrate, high-fat diets on apparent total tract digestibility, fecal characteristics, and overall health status. Eight adult Beagles were enrolled in a replicated 4 × 4 Latin Square design feeding trial. Dogs were randomly assigned to one of four dietary fat level treatments (T) within each period: 32% (T1), 37% (T2), 42% (T3), and 47% (T4) fat on a dry matter basis. Fat levels were adjusted with the inclusion of canola oil added to a commercial diet. Each dog was fed to exceed its energy requirement based on NRC (2006). Blood samples were analyzed for complete blood counts, chemistry profiles, and canine pancreatic lipase immunoreactivity levels. Apparent total tract digestibility improved (P < 0.05) as the fat level increased for dry matter, organic matter, fat, and gross energy. Fecal output decreased as levels of fat increased in the diet (P = 0.002). There was no effect of fat level on stool quality or short-chain fatty acid and ammonia concentrations in fecal samples (P ≥ 0.20). Blood urea nitrogen levels decreased with increased fat level (P = 0.035). No significant differences were seen in canine pancreatic lipase immunoreactivity (P = 0.110). All blood parameters remained within normal reference intervals. In summary, increased dietary fat improved apparent total tract digestibility, did not alter fecal characteristics, and maintained the health status of all dogs.
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http://dx.doi.org/10.1093/jas/skaa043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059695PMC
March 2020

Bacterial Biogeography of the Colon in Dogs With Chronic Inflammatory Enteropathy.

Vet Pathol 2020 03 9;57(2):258-265. Epub 2020 Jan 9.

Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.

The intestinal microbiota is believed to play a role in the pathogenesis of inflammatory bowel disease in humans and chronic inflammatory enteropathy (CIE) in dogs. While most previous studies have described the gut microbiota using sequencing methods, it is fundamental to assess the spatial distribution of the bacteria for a better understanding of their relationship with the host. The microbiota in the colonic mucosa of 22 dogs with CIE and 11 control dogs was investigated using fluorescence in situ hybridization (FISH) with a universal eubacterial probe (EUB338) and specific probes for select bacterial groups. The number of total bacteria labeled with EUB338 probe was lower within the colonic crypts of dogs with CIE compared to controls. spp. and spp. were decreased on the colonic surface and in the crypts of dogs with CIE. Dogs with CIE had increased number of spp. on the colonic surface and within the crypts compared to control dogs. In conclusion, the bacterial microbiota in the colonic mucosa differed between dogs with and without CIE, with depletion of the crypt bacteria in dogs with CIE. The crypt bacterial species that was intimately associated with the host mucosa in control dogs was composed mainly of spp.
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http://dx.doi.org/10.1177/0300985819891259DOI Listing
March 2020

Glucocorticoid and dietary effects on mucosal microbiota in canine inflammatory bowel disease.

PLoS One 2019 30;14(12):e0226780. Epub 2019 Dec 30.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America.

The pathogenesis of canine inflammatory bowel disease (IBD) involves complex interactions between mucosal immunity and the intestinal microbiota. Glucocorticoids are commonly administered to reduce mucosal inflammation and gastrointestinal signs. The study objective was to evaluate the effects of diet and oral prednisone on the spatial distribution of mucosal bacteria in IBD dogs. Eight dogs diagnosed with IBD were treated with immunosuppressive doses of prednisone. The mucosal microbiota from endoscopic biopsies of IBD dogs and healthy controls (HC; n = 15 dogs) was evaluated by fluorescence in situ hybridization (FISH) targeting the 16S rRNA genes of total bacteria and bacterial species relevant in canine/human IBD. Apicaljunction protein (AJP) expression using immunohistochemistry investigated the effect of medical therapy on intestinal barrier integrity. All IBD dogs had a reduction in GI signs following diet and prednisone therapy compared with baseline CIBDAI scores (P < 0.05). The mucosal microbiota of HC and diseased dogs was most abundant in free and adherent mucus. Only Lactobacilli were increased (P < 0.05) in the adherent mucus of IBD dogs compared to HC. The spatial distribution of mucosal bacteria was significantly different (P < 0.05) in IBD dogs following prednisone therapy, with higher numbers of Bifidobacteria and Streptococci detected across all mucosal compartments and increased numbers of Bifidobacterium spp., Faecalibacterium spp., and Streptococcus spp. present within adherent mucus. Differences in intestinal AJPs were detected with expression of occludin increased (P < 0.05) in IBD dogs versus HC. The expressions of occludin and E-cadherin were increased but zonulin decreased (P < 0.05 for each) in IBD dogs following prednisone therapy. In conclusion, the spatial distribution of mucosal bacteria differs between IBD and HC dogs, and in response to diet and glucocorticoid administration. Medical therapy was associated with beneficial changes in microbial community structure and enhanced mucosal epithelial AJP expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226780PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936794PMC
April 2020

Enterocolic increase of cannabinoid receptor type 1 and type 2 and clinical improvement after probiotic administration in dogs with chronic signs of colonic dysmotility without mucosal inflammatory changes.

Neurogastroenterol Motil 2020 01 8;32(1):e13717. Epub 2019 Sep 8.

School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy.

Background: Colonic dysmotility in dogs can cause different GI signs. Sometimes, histology of enterocolic biopsies does not reveal inflammatory infiltrates or mucosal lesions that are typically associated with clinical disease activity. It is speculated that, similarly to humans, colonic dysmotility may be anxiety-based, although recent data demonstrate that irritable bowel syndrome (IBS) could result from acute infectious enteritis. Specific Lactobacillus spp. strains administered orally in humans induced the expression of μ-opioid and cannabinoid receptors in mucosal enterocytes, modulating intestinal morphine-like analgesic functions. We investigated the potential association of GI signs caused by colonic dysmotility and mucosal expression of cannabinoid receptors in intestinal epithelial cells and the number of mucosal mast cells.

Methods: Ten to 15 endoscopic biopsies were collected from colonic mucosa of 20 dogs diagnosed with dysmotility disturbances before and after probiotic (Slab51 bacterial blend; Sivoy ) administration (3-month period). Number and distribution of mast cells (MCs), and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated by immunohistochemistry and PCR. Results were compared to data obtained from five clinically healthy dogs (archive samples).

Key Results: Decreased numbers of MCs (P < .0001) and increased CB1- and CB2-positive epithelial cells (P < .0001) in diseased dogs were positively associated with post-treatment CCECAI scores (P < .0001).

Conclusions And Inferences: Our results suggest that probiotic administration can reduce signs of colonic dysmotility, possibly due to microbiota modulation and epithelial cell receptor-mediated signaling in intestinal mucosa.
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http://dx.doi.org/10.1111/nmo.13717DOI Listing
January 2020

Microbiota-Related Changes in Unconjugated Fecal Bile Acids Are Associated With Naturally Occurring, Insulin-Dependent Diabetes Mellitus in Dogs.

Front Vet Sci 2019 27;6:199. Epub 2019 Jun 27.

Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States.

Diabetes mellitus (DM) in humans has recently been associated with altered intestinal microbiota. The consequences of intestinal dysbiosis, such as increased intestinal permeability and altered microbial metabolites, are suspected to contribute to the host inflammatory state and peripheral insulin resistance. Human diabetics have been shown to have changes in bile acid (BA) metabolism which may be detrimental to glycemic control. The purpose of this study was to examine BA metabolism in dogs with naturally-occurring, insulin-dependent DM and to relate these findings to changes in the intestinal microbiota. A prospective observational study of adult dogs with a clinical diagnosis of DM ( = 10) and healthy controls (HC, = 10) was performed. The fecal microbiota were analyzed by 16S rRNA gene next-generation (Illumina) sequencing. Concentrations of fecal unconjugated BA (fUBA) were measured using gas chromatography and mass spectrometry. Analysis of bacterial communities showed no significant difference for any of the alpha-diversity measures between DM vs. HC dogs. Principal coordinate analysis based on unweighted Unifrac distance metric failed to show significant clustering between dog groups (ANOSIM: = 0.084; = 0.114). However, linear discriminate analysis effects size (LEfSe) detected differentially abundant bacterial taxa (α = 0.01, LDA score >2.0) on various phylogenetic levels. While was overrepresented in dogs with DM, the proportions of Erysipelotrichia, , and were increased in HC dogs. Dogs with DM had increased concentration of total primary fUBA compared to HC dogs ( = 0.028). The concentrations of cholic acid and the cholic acid percentage of the total fUBA were increased ( = 0.028 and = 0.035, respectively) in the feces of DM dogs relative to HC dogs. The levels of lithocholic acid (both absolute value and percentage of the total fUBA) were decreased ( = 0.043 and < 0.01, respectively) in DM dogs vs. HC dogs. Results indicate that dogs with DM have both intestinal dysbiosis and associated fUBA alterations. The pattern of dysbiosis and altered BA composition is similar to that seen in humans with Type 2 DM. The dog represents a novel large animal model for advancing translational medicine research efforts (e.g., investigating pathogenesis and therapeutics) in DM affecting humans.
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http://dx.doi.org/10.3389/fvets.2019.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610424PMC
June 2019

Indoleamine-pyrrole 2,3-dioxygenase-1 (IDO-1) mRNA is over-expressed in the duodenal mucosa and is negatively correlated with serum tryptophan concentrations in dogs with protein-losing enteropathy.

PLoS One 2019 10;14(6):e0218218. Epub 2019 Jun 10.

College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America.

Introduction: Dogs with protein-losing enteropathy (PLE) have decreased serum tryptophan concentrations, which may contribute to disease pathogenesis. Indoleamine-pyrrole 2,3-dioxygenase-1 (IDO-1) expression is associated with low serum tryptophan concentrations and is increased in the gastrointestinal tract of humans with inflammatory bowel disease (IBD). Therefore, the objective of our study was to determine if the mRNA expression of IDO-1 is increased in the duodenal mucosa of dogs with PLE as compared to dogs with chronic enteropathy (CE) and healthy dogs, and whether this expression is correlated with changes in serum tryptophan concentration.

Methods: Our study was a retrospective study using archived paraffin-embedded duodenal biopsy specimens from 8 healthy Beagle dogs from the Iowa State University Canine Service Colony and 18 and 6 client-owned dogs diagnosed with CE and PLE, respectively at the Bristol Veterinary School. A novel RNA in situ hybridization (ISH) technology, RNAscope, was used to identify IDO-1 mRNA mucosal expression in duodenal tissues. An IDO-1 specific probe was hybridized onto 10 duodenal biopsy sections from each dog whereby RNAscope signal (mRNA expression) was quantified by a single operator using light microscopy.

Results: Dogs with PLE had significantly higher mRNA expression of IDO-1 in the duodenal mucosa compared to healthy dogs (mucosal percentage IDO-1 positive: P = 0.0093, (mean ± S.D) control: 19.36 ± 7.08, PLE: 34.12 ± 5.98, average fold difference: 1.76 and mucosal IDO-1 H-score: P = 0.0356, (mean ± S.D) control: 45.26 ± 19.33, PLE: 84.37 ± 19.86, average fold difference: 1.86). The duodenal mucosal mRNA expression of IDO-1 was negatively correlated with serum tryptophan concentrations in dogs with PLE (mucosal IDO-1 H-score: Spearman's rank correlation coefficient = -0.94, P = 0.0048).

Conclusions: In conclusion, our study suggests that decreased serum tryptophan concentrations in dogs with PLE is associated with increased intestinal IDO-1 expression. Further studies are needed to determine potential inflammatory pathways responsible for increased expression of IDO-1 in the intestinal tract of dogs with PLE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557522PMC
February 2020

Interleukin-13 and interleukin-33 mRNA are underexpressed in the duodenal mucosa of German Shepherd dogs with chronic enteropathy.

J Vet Intern Med 2019 Jul 6;33(4):1660-1668. Epub 2019 Jun 6.

College of Veterinary Medicine, Iowa State University, Ames, Iowa.

Background: A recent genome-wide association study in German Shepherd dogs (GSDs) with chronic enteropathy (CE) has identified polymorphisms in the Th2 cytokine genes.

Hypothesis/objective: To determine if the expression of the Th2 cytokines, interleukin-13 (IL-13) and interleukin-33 (IL-33), is altered in the duodenal mucosa of GSDs with CE compared to non-GSDs with CE and healthy dogs.

Animals: Twenty client-owned dogs diagnosed with CE (10 GSDs and 10 non-GSDs) at the Bristol Veterinary School and 8 healthy Beagle dogs from the Iowa State University Service Colony.

Methods: Retrospective study using archived paraffin-embedded duodenal biopsy samples. A novel RNA in situ hybridization technology (RNAscope) was used to hybridize IL-13 and IL-33 mRNA probes onto at least 10 sections from duodenal biopsy samples for each dog. RNAscope signals were visualized using a microscope and semi-quantitative assessment was performed by a single operator.

Results: Based on duodenal villus, subvillus, epithelial, and lamina propria average expression scores, GSDs with CE had significantly lower IL-13 and IL-33 mRNA expression compared to non-GSDs with CE (IL-13, P < .04; IL-33, P < .02) and healthy Beagle dogs (IL-13, P < .02; IL-33, P < .004).

Conclusions And Clinical Importance: Similar to human patients with ulcerative colitis, a subtype of human inflammatory bowel disease, these data indicate that Th2 cytokines may be involved in the pathogenesis of CE in GSDs.
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http://dx.doi.org/10.1111/jvim.15544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639532PMC
July 2019

Derivation of adult canine intestinal organoids for translational research in gastroenterology.

BMC Biol 2019 04 11;17(1):33. Epub 2019 Apr 11.

Departments of Veterinary Clinical Sciences, Iowa State University, Ames, IA, USA.

Background: Large animal models, such as the dog, are increasingly being used for studying diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between commonly used animal models, such as rodents, and humans, and expand the translational potential of the dog model, we developed a three-dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures.

Results: Organoids were derived from tissue of more than 40 healthy dogs and dogs with GI conditions, including inflammatory bowel disease (IBD) and intestinal carcinomas. Adult intestinal stem cells (ISC) were isolated from whole jejunal tissue as well as endoscopically obtained duodenal, ileal, and colonic biopsy samples using an optimized culture protocol. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization, and transmission electron microscopy, to determine the extent to which they recapitulated the in vivo tissue characteristics. Physiological relevance of the enteroid system was defined using functional assays such as optical metabolic imaging (OMI), the cystic fibrosis transmembrane conductance regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research. We have furthermore created a collection of cryopreserved organoids to facilitate future research.

Conclusions: We establish the canine GI organoid systems as a model to study naturally occurring intestinal diseases in dogs and humans, and that can be used for toxicology studies, for analysis of host-pathogen interactions, and for other translational applications.
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http://dx.doi.org/10.1186/s12915-019-0652-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460554PMC
April 2019

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies.

AAPS J 2019 04 8;21(3):50. Epub 2019 Apr 8.

Department of Medicine, Mayo Clinic Division of Hematology, Rochester, Minnesota, 55905, USA.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin's lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.
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http://dx.doi.org/10.1208/s12248-019-0322-1DOI Listing
April 2019

Longitudinal assessment of microbial dysbiosis, fecal unconjugated bile acid concentrations, and disease activity in dogs with steroid-responsive chronic inflammatory enteropathy.

J Vet Intern Med 2019 May 7;33(3):1295-1305. Epub 2019 Apr 7.

Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas.

Background: Mounting evidence from human studies suggests that bile acid dysmetabolism might play a role in various human chronic gastrointestinal diseases. It is unknown whether fecal bile acid dysmetabolism occurs in dogs with chronic inflammatory enteropathy (CE).

Objective: To assess microbial dysbiosis, fecal unconjugated bile acids (fUBA), and disease activity in dogs with steroid-responsive CE.

Animals: Twenty-four healthy control dogs and 23 dogs with steroid-responsive CE.

Methods: In this retrospective study, fUBA were measured and analyzed. Fecal microbiota were assessed using a dysbiosis index. The canine inflammatory bowel disease activity index was used to evaluate remission of clinical signs. This was a multi-institutional study where dogs with steroid-responsive CE were evaluated over time.

Results: The dysbiosis index was increased in dogs with CE (median, 2.5; range, -6.2 to 6.5) at baseline compared with healthy dogs (median, -4.5; range, -6.5 to -2.6; P = .002) but did not change in dogs with CE over time. Secondary fUBA were decreased in dogs with CE (median, 29%; range, 1%-99%) compared with healthy dogs (median, 88%; 4%-96%; P = .049). The percent of secondary fUBA in dogs with CE increased from baseline values (median, 28%; range, 1%-99%) after 2-3 months of treatment (median, 94%; range, 1%-99%; P = 0.0183).

Conclusions And Clinical Importance: These findings suggest that corticosteroids regulate fecal bile acids in dogs with CE. Additionally, resolution of clinical activity index in dogs with therapeutically managed CE and bile acid dysmetabolism are likely correlated. However, subclinical disease (i.e., microbial dysbiosis) can persist in dogs with steroid-responsive CE.
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http://dx.doi.org/10.1111/jvim.15493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524081PMC
May 2019

Correlating Gastrointestinal Histopathologic Changes to Clinical Disease Activity in Dogs With Idiopathic Inflammatory Bowel Disease.

Vet Pathol 2019 05 18;56(3):435-443. Epub 2018 Dec 18.

1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.

Prior studies have failed to detect a convincing association between histologic lesions of inflammation and clinical activity in dogs with inflammatory bowel disease (IBD). We hypothesized that use of a simplified histopathologic scoring system would improve the consistency of interpretation among pathologists when describing histologic lesions of gastrointestinal inflammation. Our aim was to evaluate the correlation of histopathologic changes to clinical activity in dogs with IBD using this new system. Forty-two dogs with IBD and 19 healthy control dogs were enrolled in this retrospective study. Endoscopic biopsies from the stomach, duodenum, ileum, and colon were independently scored by 8 pathologists. Clinical disease activity was scored using the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) or the Canine Chronic Enteropathy Clinical Activity Index (CCECAI), depending on the individual study center. Summative histopathological scores and clinical activity were calculated for each tissue (stomach, duodenum, ileum, and colon) and each tissue histologic score (inflammatory/morphologic feature). The correlation between CCECAI/CIBDAI and summative histopathologic score was significant ( P < .05) for duodenum ( r = 0.42) and colon ( r = 0.33). In evaluating the relationship between histopathologic scores and clinical activity, significant ( P < .05) correlations were observed for crypt dilation ( r = 0.42), lamina propria (LP) lymphocytes ( r = 0.40), LP neutrophils ( r = 0.45), mucosal fibrosis ( r = 0.47), lacteal dilation ( r = 0.39), and villus stunting ( r = 0.43). Compared to earlier grading schemes, the simplified scoring system shows improved utility in correlating histopathologic features (both summative histology scores and select histologic scores) to IBD clinical activity.
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http://dx.doi.org/10.1177/0300985818813090DOI Listing
May 2019

Narrative review of therapies for chronic enteropathies in dogs and cats.

J Vet Intern Med 2019 Jan 6;33(1):11-22. Epub 2018 Dec 6.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa.

Background: The optimal medical treatment for chronic enteropathy (CE) in dogs and cats is controversial. Sequential treatment using diet, antimicrobials, and immunosuppressive drugs is the most common strategy used by clinicians.

Objectives: To review the evidence for the effectiveness of dietary, drug, and alternative health interventions for inducing clinical remission in dogs and cats with CE.

Animals: Retrospective study of dogs and cats with a diagnosis of chronic enteropathy.

Methods: MEDLINE and Centre for Agriculture and Bioscience International (CABI) databases (1950 to March 2017) were searched for randomized controlled trials (RCTs), observational studies, and case series. The primary outcome was induction of clinical remission. All studies were evaluated using the quality of evidence grading guidelines (I-IV), which assign a score defining the strength and quality of the evidence.

Results: Twenty-two studies (11 RCTs in dogs and 2 in cats and 9 cohort studies or case series) met the inclusion criteria for inducing remission of gastrointestinal (GI) signs. Of the 13 RCTs achieving grade I scores, 10 studies (totaling 218 dogs and 65 cats) compared single treatment: diet (n = 3), immunosuppressives (n = 3), antimicrobials (n = 2), anti-inflammatory drugs (n = 1), and probiotics (n = 1). Three case series (grade III) reported clinical remission using an elimination diet fed to 55 cats and use of enrofloxacin to induce remission in dogs with granulomatous colitis (2 studies totaling 16 dogs).

Conclusions And Clinical Importance: The current evidence for treatment of CE is much greater in dogs than in cats. There is sufficient strong evidence to recommend the use of therapeutic GI diets, glucocorticoids, enrofloxacin, or some combination of these in dogs with CE. Therapeutic GI diets and glucocorticoids are most useful in cats with CE.
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http://dx.doi.org/10.1111/jvim.15345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335544PMC
January 2019

Retrospective evaluation of toceranib phosphate (Palladia®) use in the treatment of gastrointestinal stromal tumors of dogs.

J Vet Intern Med 2018 Nov 11;32(6):2045-2053. Epub 2018 Oct 11.

Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, Ames, Iowa.

Background: Gastrointestinal stromal tumors (GISTs) are uncommon intestinal neoplasms in the dog. Literature regarding adjunctive therapy for GISTs in dogs is sparse. High-risk GISTs in humans respond to tyrosine kinase inhibition in the adjuvant setting.

Objectives: To review cases of toceranib phosphate use in dogs with GISTs and provide initial assessment of possible biological activity. A secondary aim was to evaluate patient and tumor characteristics for possible prognostic value.

Animals: Twenty-seven dogs with confirmed GISTs based on histopathology and immunohistochemistry treated with toceranib.

Methods: Retrospective study in which cases of toceranib use in dogs with GIST were solicited using the American College of Veterinary Internal Medicine Oncology and Small Animal Internal Medicine listservs.

Results: Five of 7 dogs with gross disease experienced clinical benefit (71%; 3 complete responses, 1 partial response, 1 stable disease). These included 2 dogs with durable responses after toceranib discontinuation. Median progression-free interval (PFI) in dogs with gross disease was 110 weeks (range, 36-155 weeks). Median PFI in dogs with microscopic disease was 67 weeks (range, 9-257 weeks). Metastasis at diagnosis (P = 0.04) and high mitotic index (P < 0.001) were associated with shorter PFI in toceranib-treated dogs.

Conclusions And Clinical Importance: Biological activity of toceranib is evident in dogs with gross disease. Metastasis of GIST at diagnosis, as well as high tumor mitotic index, was associated with shorter PFI in toceranib-treated dogs. Larger studies are needed to define postsurgical risk and refine the use of toceranib in dogs with gross and microscopic GIST.
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http://dx.doi.org/10.1111/jvim.15335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271363PMC
November 2018

Relationship of the mucosal microbiota to gastrointestinal inflammation and small cell intestinal lymphoma in cats.

J Vet Intern Med 2018 Sep 7;32(5):1692-1702. Epub 2018 Aug 7.

College of Veterinary Medicine, Iowa State University.

Background: The gastrointestinal (GI) microbiota in healthy cats is altered in IBD. Little research has been performed to identify whether specific bacterial groups are associated with small cell GI lymphoma (LSA).

Hypothesis: Mucosal bacteria, including Enterobacteriaceae and Fusobacterium spp., are abundant in intestinal biopsies of cats with small cell GI LSA compared to cats with IBD.

Animals: Fourteen cats with IBD and 14 cats with small cell GI LSA.

Methods: Retrospective case control study. A search of the medical records was performed to identify cats diagnosed with IBD and with GI LSA. Bacterial groups identified by FISH in GI biopsies were compared between cohorts and correlated to CD11b and NF-κB expression.

Results: Fusobacterium spp. (median; IQR bacteria/region) were higher in cats with small cell GI LSA in ileal (527; 455.5 - 661.5; P = .046) and colonic (404.5; 328.8 - 455.5; P = .016) adherent mucus, and combined colonic compartments (free mucus, adherent mucus, attaching to epithelium) (8; 0 - 336; P = .017) compared to cats with IBD (ileum: 67; 31.5 - 259; colon: 142.5; 82.3 - 434.5; combined: 3; 0 - 34). Bacteroides spp. were higher in ileal adherent mucus (P = .036) and 3 combined ileal compartments (P = .034) of cats with small cell GI LSA. There were significant correlations between Fusobacterium spp. totals and CD11b cell (P = .009; rs .476) and NF-κB expression (P = .004; rs .523).

Conclusions: The bacterial alterations appreciated might be influential in development of small cell GI LSA, and should drive further studies to elucidate the effects of microbial-mediated inflammation on GI cancer progression.
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http://dx.doi.org/10.1111/jvim.15291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189339PMC
September 2018

Genome-wide association studies of inflammatory bowel disease in German shepherd dogs.

PLoS One 2018 20;13(7):e0200685. Epub 2018 Jul 20.

Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, North Mymms, United Kingdom.

Canine Inflammatory Bowel Disease (IBD) is considered a multifactorial disease caused by complex interactions between the intestinal immune system, intestinal microbiota and environmental factors in genetically susceptible individuals. Although IBD can affect any breed, German shepherd dogs (GSD) in the UK are at increased risk of developing the disease. Based on previous evidence, the aim of the present study was to identify single nucleotide polymorphisms (SNPs), which may confer genetic susceptibility or resistance to IBD using a genome-wide association study (GWAS). Genomic DNA was extracted from EDTA blood or saliva samples of 96 cases and 98 controls. Genotyping of cases and controls was performed on the Canine Illumina HD SNP array and data generated was analyzed using PLINK. Several SNPs and regions on chromosomes 7,9,11 and 13 were detected to be associated with IBD using different SNP-by-SNP association methods and FST windows approach. Searching one Mb up-and down-stream of the most significant SNPs, as identified by single SNP analysis as well as 200Kb before and after the start and the end position of the associated regions identified by FST windows approach, we identified 63 genes. Using a combination of pathways analysis and a list of genes that have been reported to be involved in human IBD, we identified 16 candidate genes potentially associated with IBD in GSD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054420PMC
January 2019

Is irritable bowel syndrome also present in dogs?

Tierarztl Prax Ausg K Kleintiere Heimtiere 2018 Jun 13;46(3):176-180. Epub 2018 Jun 13.

Irritable bowel syndrome (IBS) in humans is described as the recurrent presence of gastrointestinal signs, without gross histopathologic evidence of inflammation and of other morphologic lesions; however, it is a syndrome not unanimously defined in veterinary medicine. There is some evidence that dysmotility could be related to stressors in some dogs that present with clinical signs (e.g. chronic idiopathic large-bowel diarrhea) that share overlapping aspects with human IBS. The authors hypothesize that an IBS-like condition, similar to that described in humans, might also be present in dogs. Nevertheless, the diagnostic path for canine IBS needs to be further elucidated and its pathogenesis better defined for a more rational therapeutic approach.
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http://dx.doi.org/10.15654/TPK-170590DOI Listing
June 2018

Serologic and fecal markers to predict response to induction therapy in dogs with idiopathic inflammatory bowel disease.

J Vet Intern Med 2018 May 6;32(3):999-1008. Epub 2018 Apr 6.

Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa.

Background: Little information is available of markers that assess the disease course in dogs with idiopathic inflammatory bowel disease (IBD).

Objectives: Evaluate relationship between disease severity and serum and fecal biomarkers in dogs with idiopathic IBD before and after treatment.

Animals: Sixteen dogs with idioptahic IBD and 13 healthy dogs.

Methods: Prospective case control study. Canine IBD activity index (CIBDAI) clinical score, serum concentrations of C-reactive protein (CRP), perinuclear antineutrophil cytoplasmic antibodies (pANCA), and serum and fecal canine calprotectin (cCP) were measured before and after 21 days of treatment.

Results: Serum CRP (median 3.5 mg/L; range: 0.1-52.4 mg/L), fecal cCP (median 92.3 μg/g; range: 0.03-637.5 μg/g), and CIBDAI scores significantly increased in dogs with IBD before treatment compared with serum CRP (median 0.2 mg/L; range: 0.1-11.8 mg/L; P < .001), fecal cCP (median 0.67 μg/g; range: 0.03-27.9 μg/g; P < .001) and CIBDAI (P < .001) after treatment. No significant associations between CIBDAI scores and before or after treatment serum biomarkers. There was a significant association between fecal cCP and CIBDAI scores before treatment (rho = 0.60, P = .01). CRP and fecal cCP significantly decreased after treatment (median 3.5 mg/L v. 0.2 mg/L; P < .001 and 92.3 μg/g v. 0.67 μg/g; P = .001, respectively).

Conclusions And Clinical Importance: Our data indicate that measurement of fecal cCP concentration is a useful biomarker for noninvasive evaluation of intestinal inflammation. Dogs with severe signs of GI disease more often have abnormal markers than dogs having less severe disease.
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http://dx.doi.org/10.1111/jvim.15123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980281PMC
May 2018

Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research.

AAPS J 2017 12 12;20(1):17. Epub 2017 Dec 12.

Department of Veterinary Clinical Sciences, Iowa State University College of Veterinary Medicine, 50011-1250 Ames, Iowa, USA.

Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies. Importantly, because they are derived from individuals with different genotypes, environmental risk factors and drug sensitivity profiles, organoids are a highly relevant screening system for personalized therapy in both human and veterinary medicine. Lastly, and in the context of patient-specific congenital diseases, orthotopic transplantation of engineered organoids could repair and/or replace damaged epithelial tissues reported in various GI diseases, such as inflammatory bowel disease, cystic fibrosis, and tuft enteropathy. Ongoing translational research on organoids derived from dogs with naturally occurring digestive disorders has the potential to improve the predictability of preclinical models used for optimizing the therapeutic management of severe chronic enteropathies in human patients.
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http://dx.doi.org/10.1208/s12248-017-0178-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044282PMC
December 2017

Model-Based Reverse Translation Between Veterinary and Human Medicine: The One Health Initiative.

CPT Pharmacometrics Syst Pharmacol 2018 02 27;7(2):65-68. Epub 2017 Nov 27.

Department of Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, Iowa, USA.

There is growing concern about the limitations of rodent models with regard to recapitulation of human disease pathogenesis. Computational modeling of data from humans and animals sharing similar diseases provides an opportunity for parallel drug development in human and veterinary medicine. This "reverse translational" approach needs to be supported by continuing efforts to refine the in silico tools that allow extrapolation of results between species.
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http://dx.doi.org/10.1002/psp4.12262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824107PMC
February 2018

Randomized, controlled trial evaluating the effect of multi-strain probiotic on the mucosal microbiota in canine idiopathic inflammatory bowel disease.

Gut Microbes 2017 09 5;8(5):451-466. Epub 2017 Jul 5.

a Department of Veterinary Clinical Sciences, College of Veterinary Medicine , Iowa State University , Ames , Iowa , USA.

The intestinal microbiota is increasingly linked to the pathogenesis of idiopathic inflammatory bowel disease (IBD) in dogs. While studies have reported alterations in fecal (luminal) microbial populations, only limited information is available about the mucosal microbiota of IBD dogs at diagnosis and following medical therapy. Our aim was to characterize the mucosal microbiota and determine the clinical, microbiological, and mucosal homeostatic effects of probiotic treatment in dogs with IBD. Thirty four IBD dogs were randomized to receive standard therapy (ST = diet + prednisone) with or without probiotic. Tissue sections from endoscopic biopsies were evaluated by fluorescence in situ hybridization (FISH) on a quantifiable basis. Disease activity and changes in mucosal microbiota and tight junction protein (TJP) expression were assessed before and after 8 weeks of IBD therapy. ST and ST/probiotic therapy modulated the number of mucosal bacteria of IBD dogs in a similar fashion. Both treatments increased the numbers of total bacteria and individual species residing within adherent mucus, with ST therapy increasing Bifidobacterium spp. and ST/probiotic therapy increasing Lactobacillus spp (P < 0.05 for both), respectively. Both treatments were associated with rapid clinical remission but not improvement in histopathologic inflammation. Probiotic therapy was associated with upregulated (P < 0.05) expression of TJPs E-cadherin, occludin, and zonulin versus ST. The probiotic effect on mucosal bacteria is similar to that of IBD dogs receiving ST. IBD dogs fed probiotic had increased TJP expression suggesting that probiotic may have beneficial effects on mucosal homeostasis.
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http://dx.doi.org/10.1080/19490976.2017.1334754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628651PMC
September 2017

Multilaboratory Survey To Evaluate Salmonella Prevalence in Diarrheic and Nondiarrheic Dogs and Cats in the United States between 2012 and 2014.

J Clin Microbiol 2017 05 15;55(5):1350-1368. Epub 2017 Feb 15.

Washington Animal Disease Diagnostic Laboratory, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.

Eleven laboratories collaborated to determine the periodic prevalence of in a population of dogs and cats in the United States visiting veterinary clinics. Fecal samples (2,965) solicited from 11 geographically dispersed veterinary testing laboratories were collected in 36 states between January 2012 and April 2014 and tested using a harmonized method. The overall study prevalence of in cats (3 of 542) was <1%. The prevalence in dogs (60 of 2,422) was 2.5%. Diarrhea was present in only 55% of positive dogs; however, 3.8% of the all diarrheic dogs were positive, compared with 1.8% of the nondiarrheic dogs. -positive dogs were significantly more likely to have consumed raw food ( = 0.01), to have consumed probiotics ( = 0.002), or to have been given antibiotics ( = 0.01). Rural dogs were also more likely to be positive than urban ( = 0.002) or suburban ( = 0.001) dogs. In the 67 isolates, 27 unique serovars were identified, with three dogs having two serovars present. Antimicrobial susceptibility testing of 66 isolates revealed that only four of the isolates were resistant to one or more antibiotics. Additional characterization of the 66 isolates was done using pulsed-field gel electrophoresis and whole-genome sequencing (WGS). Sequence data compared well to resistance phenotypic data and were submitted to the National Center for Biotechnology Information (NCBI). This study suggests an overall decline in prevalence of -positive dogs and cats over the last decades and identifies consumption of raw food as a major risk factor for infection. Of note is that almost half of the -positive animals were clinically nondiarrheic.
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http://dx.doi.org/10.1128/JCM.02137-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405253PMC
May 2017

The Association of Specific Constituents of the Fecal Microbiota with Immune-Mediated Brain Disease in Dogs.

PLoS One 2017 26;12(1):e0170589. Epub 2017 Jan 26.

Department of Small Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, United State of America.

Meningoencephalomyelitis of unknown origin (MUO) is a common, naturally-occurring, clinical disease of pet dogs. It is an immune-mediated condition that has many similarities with experimental autoimmune encephalitis (EAE) in rodents and so investigation of its pathogenesis may aid in understanding factors that contribute to development of multiple sclerosis in people. Gut microbiota are known to modulate immune responses that influence susceptibility to immune-mediated brain disease. In this study we aimed to compare abundance of specific constituents of the fecal microbiota, namely Faecalibacterium prausnitzii and Prevotellaceae, between dogs diagnosed with MUO and matched controls. Fecal samples were obtained from 20 dogs diagnosed with MUO and 20 control dogs matched for breed, age and gender. Bacterial abundance was measured using qPCR and 16S rRNA sequencing. We found that Prevotellaceae were significantly less abundant in cases compared with controls (p = 0.003) but there was no difference in abundance of F.prausnitzii. There was no evidence of other differences in gut microbiota between groups. These data, derived from this naturally-occurring canine clinical model, provide strong corroborative evidence that high abundance of Prevotellaceae in the gut is associated with reduced risk for developing immune-mediated brain disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170589PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268494PMC
August 2017
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