Canine Chronic Enteropathy Clinical Activity Index Research Articles

In dogs with chronic enteropathy (idiopathic inflammatory bowel disease) is budesonide more effective than prednisolone or prednisone in resolving clinical signs?

PICO Question In dogs with chronic enteropathy (idiopathic inflammatory bowel disease) is budesonide more effective than prednisolone or prednisone in resolving clinical signs or improving the canine inflammatory bowel disease (IBD) activity index (CIBDAI) or the canine chronic enteropathy clinical activity index (CCECAI)? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed One double-blinded randomised control trial. Strength of evidence Moderate. Outcomes reported The outcome of this study identified that no significant differences in remission rates (> 75% decrease in CIBDAI scores) were observed between the prednisone and budesonide groups. Frequency of adverse effects were also similar between the two groups. Conclusion A single study with moderate power of evidence alongside some significant limitations, particularly population size, cannot be used as the sole provider of an answer to the PICO question. As such, further studies with greater power would be required before a definitive assessment of comparative treatment efficacy can be made. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Complete Blood Count-Derived Inflammatory Markers Changes in Dogs with Chronic Inflammatory Enteropathy Treated with Adipose-Derived Mesenchymal Stem Cells.

Simple SummaryMesenchymal stem cells exhibit anti-inflammatory properties, and their administration to dogs with chronic inflammatory enteropathy has been shown to be safe and effective. Neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and the systemic immuno-inflammation index are considered novel biomarkers to assess the inflammatory status of patients. The present study aimed to compare the clinical evolution and the changes in these inflammatory biomarkers in dogs with chronic enteropathy before and after cell therapy. The values of the three inflammatory biomarkers were higher in dogs with chronic enteropathy before the treatment compared to the values obtained from healthy dogs. After treatment, those values decreased significantly over time, and nine months later, no difference was observed between healthy dogs and dogs with chronic enteropathy in two of the three studied markers. A relationship between the amelioration of the clinical signs and the decrease in the blood inflammatory markers was also established. These results demonstrate that the clinical improvement of patients with chronic enteropathy treated with stem cells is accompanied by a normalization of the inflammatory biomarkers studied.Adipose-derived mesenchymal stem cells (Ad-MSCs) exhibit anti-inflammatory and immunomodulatory activities. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been reported as novel biomarkers of the inflammatory state; however, they have never been examined in dogs with chronic inflammatory enteropathy (CIE) treated with Ad-MSCs. This study aimed to compare the clinical evolution and the changes in the NLR, PLR, and SII in dogs with CIE before and after cell therapy. Sixteen dogs with CIE were administered a single intravenous dose of Ad-MSCs. The canine chronic enteropathy clinical activity index (CCECAI), NLR, PLR, and SII were assessed before treatment (T0) and at 2 (T2) and 9 (T9) months post-treatment and compared over time and with the reference values obtained from a group of healthy dogs. NLR, PLR, and SII were significantly increased at T0 compared to the reference values, decreasing significantly over time. At T9, the NLR and SII did not differ from the reference values, but PLR remained above the reference values. A correlation was observed between CCECAI and the three markers. These findings show that the clinical improvement of dogs with CIE treated with Ad-MSCs is accompanied by a normalization of the inflammatory status.

Machine Learning and Canine Chronic Enteropathies: A New Approach to Investigate FMT Effects.

Simple SummaryFecal microbiota transplantation (FMT) represents a very promising approach to decrease disease activity in chronic enteropathies (CE). Although CE and dysbiosis are undoubtedly connected, the relationship between remission mechanisms and microbiome changes has not been elucidated yet. Indeed, CE is a heterogeneous disease consisting of many different subtypes, and the dynamic of the microbial community is very complex. The aim of this study was to report the clinical effects of oral freeze-dried FMT in dogs affected by CE, analyzing the fecal microbiome before and after FMT, and comparing the microbial composition with a healthy population. Artificial intelligence algorithms were applied to address the high complexity of microbiomes. Clinical signs of improvement were observed in three-quarters of receivers, proving the effectiveness of the treatment in the freeze-dried form. Machine learning algorithms successfully predicted healthy and diseased animal categories, using microbial compositions. Every receiver showed microbiome variation after the transplant, but there was high heterogeneity in the response. These findings are the first step for further research on a larger dataset that could identify different healing patterns of microbiome changes.Fecal microbiota transplantation (FMT) represents a very promising approach to decreasing disease activity in canine chronic enteropathies (CE). However, the relationship between remission mechanisms and microbiome changes has not been elucidated yet. The main objective of this study was to report the clinical effects of oral freeze-dried FMT in CE dogs, comparing the fecal microbiomes of three groups: pre-FMT CE-affected dogs, post-FMT dogs, and healthy dogs. Diversity analysis, differential abundance analysis, and machine learning algorithms were applied to investigate the differences in microbiome composition between healthy and pre-FMT samples, while Canine Chronic Enteropathy Clinical Activity Index (CCECAI) changes and microbial diversity metrics were used to evaluate FMT effects. In the healthy/pre-FMT comparison, significant differences were noted in alpha and beta diversity and a list of differentially abundant taxa was identified, while machine learning algorithms predicted sample categories with 0.97 (random forest) and 0.87 (sPLS-DA) accuracy. Clinical signs of improvement were observed in 74% (20/27) of CE-affected dogs, together with a statistically significant decrease in CCECAI (median value from 5 to 2 median). Alpha and beta diversity variations between pre- and post-FMT were observed for each receiver, with a high heterogeneity in the response. This highlighted the necessity for further research on a larger dataset that could identify different healing patterns of microbiome changes.

Clinical efficacy of prebiotics and glycosaminoglycans versus placebo In dogs with food responsive enteropathy receiving a hydrolyzed diet: A pilot study.

Induction of remission is easily achieved with dietary treatment in dogs diagnosed with Food Responsive Chronic Diarrhea (FRD). Administration of prebiotics and glycosaminoglycans (GAGs) may improve epithelial cell integrity and therefore be useful as adjunct treatment. This study evaluated whether the relapse rate of FRD dogs that are switched back to a normal diet can be influenced using supplemental treatment with prebiotics and GAGs. A randomized, controlled clinical trial (RCCT) was performed in dogs diagnosed with FRD. Dogs were diagnosed based on clinical exclusion diagnosis, endoscopic biopsies showing predominantly lymphoplasmacytic infiltration, and response to dietary treatment. Dogs were randomized to be fed a combination of prebiotics and GAGs (group 1) or placebo (group 2) in addition to a hydrolyzed diet. At week 10, a second endoscopy was performed and dogs were switched back to normal diet. Relapse rate was monitored every 2 weeks after that until week 18. Statistical analysis was performed for each outcome (Canine Chronic Enteropathy Clinical Activity Index (CCECAI), clinicopathological data, endoscopic scoring, mWSAVA histological scoring index (mWSAVA), and number of relapses following switch to normal diet) using a linear mixed effects model for group comparison. Time, group, and their interactions were included as a fixed effect, whereas each dog was treated as a random effect. Of the 35 dogs enrolled into the clinical trial, 10 in each group reached the point of second endoscopy. A total of 13 dogs (n = 8 in group 1 and n = 5 in group 2) reached the trial endpoint of 18 weeks. After switching back to normal diet, none of the dogs in either group relapsed. No significant differences were found over time or between groups for CCECAI, endoscopy scoring and histological scoring. Although there was a clinical worsening in the placebo group after switching back to the original diet, this was not statistically significant (CCECAI p = 0.58). Post-hoc power calculation revealed that 63 dogs per group would have been needed to detect statistically significant differences in CIBDAI between treatment groups. Standard dietary treatment induced rapid clinical response in all cases, however, additional supplementation with prebiotics and GAGs did not significantly improve clinical outcome within 4 months after switching back to normal diet. Since there are very few RCCT published in CE in dogs, this pilot study provides important power analyses for planning of further studies.

Detection of Anti-Erythrocyte Antibodies in Dogs with Inflammatory Bowel Disease (IBD).

Simple SummaryIn human patients with intestinal inflammation, many other diseases may occur due to it, but their presence in dogs is rarely described. The aim of the study was to prove if antibodies against red blood cells (RBC) were present in dogs with chronic intestinal inflammation (IBD), as it is demonstrated for humans, and to described other RBC abnormalities. IBD was diagnosed using the current consensus and a disease severity score was assessed for each dog, as well as score from endoscopy and intestinal histology. Our results showed that most of dogs had antibodies against RBC and 50% of dogs showed RBC regeneration in addition to chronic inflammation hematologic findings. In IBD dogs, the presence of anti-RBC antibodies and the other RBC alterations may suggest a subclinical RBC damaged (hemolysis).Several extra-intestinal manifestations, including immune-mediated cytopenias, are reported in human inflammatory bowel disease (IBD), whereas they are poorly documented in dogs. Hypothesizing that immune-mediated subclinical anemia can occur in canine IBD, the study aim was to evaluate the erythrogram and the presence of anti-RBC antibodies in dogs with IBD. IBD was diagnosed according to the following criteria: chronic gastrointestinal signs, ruling out of extra-intestinal diseases, no improvement with diet trial, histological evidence of inflammatory infiltration, and improvement after immunosuppressant therapy. Canine Chronic Enteropathy Clinical Activity Index (CCECAI) endoscopic and histopathological scores were assessed for each dog. Twenty-five dogs were enrolled, and each dog had a CBC evaluation prior to endoscopy. The CBC was performed using laser hematology analyzer and blood smears were carefully reviewed for the presence of nucleated RBC, anisocytosis, polychromasia, and Howell–Jolly bodies. IgG and IgM anti-RBC antibodies were evaluated with flow cytometry. A high frequency of positive cases for anti-RBC antibodies in dogs with IBD (17/25 dogs) was ascertained. Approximatively 50% of dogs showed some hematologic features of RBC regeneration in addition to hematologic findings consistent with chronic inflammation. Anti-RBC antibodies and signs of erythroid regeneration may suggest possible subclinical chronic immune-mediated hemolysis that can cause anemia in dogs with IBD, together with the chronic inflammation.

Upregulation of signal transducer and activator of transcription 3 in dogs with chronic inflammatory enteropathies.

BackgroundIn inflammatory bowel disease (IBD) in humans, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is upregulated in mucosal epithelial cells and correlates with clinical severity.Hypothesis/ObjectiveTo investigate the expression pattern of pSTAT3 in the mucosa of dogs with chronic inflammatory enteropathy (CIE) and explore correlations between its expression and clinical and histopathological severity scoring.AnimalsTwenty‐eight canine CIE patients grouped into food‐responsive enteropathy (FRE; 9), steroid‐responsive enteropathy (SRE; 10), and protein‐losing enteropathy (PLE; 9). Ten healthy beagle dogs served as controls (CO).MethodsRetrospective case control study. Immunohistochemistry was used to detect pSTAT3 in canine duodenal mucosa samples.ResultsCompared to CO, SRE (P < .001) and PLE (P < .001) dogs had significantly higher pSTAT3 expression in the villus epithelium. The SRE group had a significantly higher expression in the villus lamina propria (VLP) compared to controls (P = .009). In the crypt epithelium (CE), all CIE dogs had significantly higher pSTAT3 expression (FRE, P = .002; SRE, P = .003; PLE, P < .001) compared to CO. In the lamina propria crypt region (CLP), dogs with FRE (P = .04) and SRE (P = .03) had significantly upregulated pSTAT3 compared to controls. A positive correlation was found between canine chronic enteropathy clinical activity index (CCECAI) scoring and pSTAT3 expression for both epithelial (rho = .541; P < .001) and crypt regions (rho = .32; P = .02).Conclusions and Clinical ImportancepSTAT3 is upregulated in CIE in dogs, correlates with clinical severity, and may be helpful as a clinical marker in dogs with CIE.

Evaluation of duodenal endoscopic and histologic findings, including counts of forkhead box P3-positive regulatory T cells, in dogs with immunosuppressant-responsive enteropathy.

To prospectively evaluate the clinical and prognostic importance of duodenal endoscopic and histologic findings, including duodenal mucosal counts of forkhead box P3-positive regulatory T cells (Foxp3+ Tregs), in dogs with immunosuppressant-responsive enteropathy (IRE). 57 client-owned dogs with IRE. The canine chronic enteropathy clinical activity index (CCECAI) was used to assess each dog when IRE was diagnosed (T0) and 1, 3, 6, and 12 months later. Dogs were grouped on the basis of clinical response (responder group vs nonresponder group) and 12-month long-term outcome (responded to treatment and did not relapse [good outcome group] vs did not respond to treatment or had relapsed [bad outcome group]). At T0, dogs underwent gastrointestinal endoscopy and endoscopic biopsy, with results for variables of duodenal endoscopic and histologic evaluations scored and compared across groups. At T0, the overall median CCECAI score was 7; CCECAI score was not associated with clinical response or relapse. Dogs had significantly greater odds of being in the bad outcome group (vs the good outcome group) if they had a histologic score of 3 (OR, 3.5; 95% CI, 1.09 to 11.3). No differences in the counts of Foxp3+ Tregs were detected between groups. In dogs with IRE, results indicated that evaluation of Foxp3+ Tregs did not have prognostic value, whereas a duodenal histologic score of 3 could be a negative prognostic factor for response and relapse, and higher severity scores for intraepithelial lymphocytes and lamina propria lymphocytes and plasma cells in duodenal biopsy samples may be negatively associated with response.

Gastric mucosal pathology in Belgian Shepherd dogs with and without clinical signs of gastric disease

BackgroundGastric carcinoma (GC) is uncommon in dogs, except in predisposed breeds such as Belgian Shepherd dogs (BSD) of the Tervuren and Groenendael varieties. When GC is diagnosed in dogs it is often late in the disease, resulting in a poorer prognosis. The aim of this prospective clinical study was to investigate possible associations of gastric mucosal pathologies with clinical signs, laboratory test results and GC in BSD. An online survey gathered epidemiological data to generate potential risk factors for vomiting as the predominant gastric clinical sign, and supported patient recruitment for endoscopy. Canine Chronic Enteropathy Clinical Activity Index (CCECAI) score and signs of gastroesophageal reflux (GER) were used to allocate BSD older than five years to either Group A, with signs of gastric disease, or Group B, without signs. Findings in the clinical history, laboratory tests and gastric histopathology of endoscopic biopsies were statistically analysed in search of associations.ResultsThe online survey included 232 responses. Logistic regression analysis recognized an association of vomiting with gagging, poor appetite and change in attitude. Recruitment for endoscopy included 16 BSD in Group A (mean age 9.1 ± 1.8 years, mean CCECAI = 3.1 ± 2.2 and signs of GER); and 11 in Group B (mean age 9.8 ± 1.4 years, CCECAI = 0, no signs of GER). Seven (25.9%) of the 27 BSD (Group A 4/16, Group B 3/11) had leukopenia. Serum C-reactive protein tended to be increased with more advanced GC (P = 0.063). Frequency of GC, mucosal atrophy, mucous metaplasia, or glandular dysplasia did not differ between groups. GC was frequently diagnosed (6/27), even without clinical signs (2/11). The odds ratio for vomiting (OR = 9.9; P = 0.016) was increased only when glandular dysplasia was present. GC was associated with mucous metaplasia (P = 0.024) and glandular dysplasia (P = 0.006), but not with mucosal atrophy (P = 1).ConclusionsGC can develop as an occult disease, associated with metaplasia and dysplasia of the gastric mucosa. Suggestive clinical signs, notably vomiting, should warrant timely endoscopy in BSD. Extensive endoscopic screening of asymptomatic dogs remains, however, unrealistic. Therefore, biomarkers of mucosal pathology preceding clinical illness are needed to support an indication for endoscopy and enable early diagnosis of GC.

Platelet abnormalities and platelet-to-lymphocyte ratios in canine immunosuppressant-responsive and non-responsive enteropathy: A retrospective study in 41 dogs.

Few studies have examined platelet alterations in dogs with chronic enteropathy. Our aim was to investigate platelet count (PLT), mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) in dogs diagnosed with immunosuppressant-responsive enteropathy (IRE). In this retrospective study of 41 dogs, data regarding signalment, canine chronic enteropathy clinical activity index (CCECAI), endoscopic and histopathological scores, PLT, MPV, PLR, total serum protein concentrations, albumin, and iron were collected. Clinical response and relapse were assessed with the evaluation of CCECAI over time. One month after starting therapy, dogs with >25% CCECAI reduction were considered responders. During a three-month CCECAI evaluation as part of a twelve-month follow-up, a CCECAI >3 together with a ≥2 unit increase in responder dogs was considered a relapse. PLT and PLR displayed significant negative correlation with MPV. MPV was positively correlated with total protein and albumin levels and negatively correlated with CCECAI. Three dogs were classified as non-responders, and 14 relapsed within 12 months. No differences were observed in PLT, MPV, or PLR between responding/non-responding and relapsing/non-relapsing groups. PLT, MPV, and PLR correlated with total protein, albumin, and CCECAI, confirming PLT as a potential marker, and suggesting MPV as a new marker of clinical efficacy against canine IRE.

Neutrophil-to-Lymphocyte Ratio (NLR) in Canine Inflammatory Bowel Disease (IBD).

Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disorder leading to structural changes in the intestinal wall. In humans, the neutrophil-to-lymphocyte ratio (NLR) has been proposed as a promising marker of IBD. This study evaluated the possible clinical and prognostic significance of the NLR in dogs with IBD. This retrospective study enrolled 41 dogs diagnosed with IBD presented to University of Pisa from January 2017 to January 2018. For each dog, age, sex, canine chronic enteropathy clinical activity index (CCECAI), endoscopic and histopathological grading were recorded. Complete blood count, serum total protein, albumin, cholesterol, and C-reactive protein at the time of endoscopy were recorded. A control group (CG) of healthy dogs from a blood donor database was built. NLR was calculated for both IBD and CG as the ratio between absolute neutrophils and lymphocytes. Presence of crypt distension, lacteal dilation (LD), mucosal fibrosis, intraepithelial lymphocytes was recorded. Follow-up information was obtained from electronic medical records and dogs were classified as responders and non-responders based on CCECAI variation between admission and the first recheck. IRE dogs showed higher NLR compared to healthy dogs. NLR correlated negatively with total protein, albumin, and cholesterol and correlated positively with CCECAI. Dogs with LD showed higher NLR than dogs without LD. Non-responders showed higher NLR compared to responders. In conclusion, as in IBD human patients, the NLR acts as an inflammatory marker providing further information on severity of the disease and could be useful in predicting treatment response.

Serum amino acid profile in 51 dogs with immunosuppressant-responsive enteropathy (IRE): a pilot study on clinical aspects and outcomes

BackgroundLower levels of tryptophan (TRP) have been identified in people with inflammatory bowel disease and in dogs with protein-losing enteropathy (PLE). No data on serum amino acids (AAs) but some on plasma in canine immunosuppressant-responsive enteropathy (IRE) are available. The aim of this study is to compare serum AAs between healthy and IRE dogs, considering clinicopathological variables and follow-up.ResultsTwenty-six healthy control dogs (CD) and 51 IRE dogs were included. IRE was diagnosed after the exclusion of extra-intestinal diseases and food and antibiotic responsive enteropathies. The canine chronic enteropathy clinical activity index (CCECAI) was assessed at presentation and during the clinical follow-up. In CD and IRE dogs, 19 different serum AAs were measured. IRE dogs were classified into responders, partial responders and non-responders, based on CCECAI after 1 month, and divided into PLE and non-PLE, based on albumin level. IRE dogs showed lower L-Tyrosine (TYR), L-Phenylalanine (PHE) and TRP (p < 0.001) and higher L-Serine (SER), L-Glutamic acid (GLU), L-Arginine (p < 0.001), L-Threonine (p = 0.013), Proline (p = 0.044), L-Cysteine (p = 0.003), L-Valine (p = 0.018), L-Lysine (p = 0.01) and L-Isoleucine (p = 0.005) than CDs. PLE dogs showed lower L-Histidine (HIS) (p = 0.008), PHE (p = 0.005) and TRP (p = 0.005) than non-PLE dogs. In IRE dogs, median GLU was significantly lower in dogs with BCS 3/9 than BCS 5/9 category (p = 0.036). Total protein was positively correlated with PHE and TRP (both p = 0.031, r = 0.30) and albumin was positively correlated with HIS (p = 0.025, r = 0.31), PHE and TRP (both p = 0.001, r = 0.46). HIS (p = 0.041), PHE (p = 0.047) and TRP (p = 0.044) concentrations were significantly lower in non-responders than in responders and partial responders.ConclusionsThis study may suggest further investigation on serum, HIS, PHE, TRP and TYR as markers of intestinal disease and proposed HIS, PHE and TRP as prognostic marker for response to therapy.

Clinical characteristics of dogs with food-responsive protein-losing enteropathy.

BackgroundIn dogs with protein‐losing enteropathy (PLE), data on the clinical characteristics of food‐responsive PLE (FR‐PLE) remain scarce.ObjectiveTo determine the clinical characteristics of FR‐PLE in dogs responsive to ultralow‐fat diet (ULFD) management.AnimalsThirty‐three dogs diagnosed with PLE based on standard diagnostic criteria.MethodsRetrospective review of medical records. Clinical findings were compared between dogs with FR‐PLE (FR‐PLE group) and those with immunosuppressant‐responsive PLE (IR‐PLE) or nonresponsive PLE (NR‐PLE) (IR/NR‐PLE group). The area under the curve (AUC) of a receiver operating characteristic curve was used to evaluate the ability of factors to differentiate the FR‐PLE and IR/NR‐PLE groups. Survival time was compared between the FR‐PLE and IR/NR‐PLE groups.ResultsTwenty‐three dogs responded to ULFD management and were diagnosed with FR‐PLE. The canine chronic enteropathy clinical activity index (CCECAI) was significantly lower in the FR‐PLE group than in the IR/NR‐PLE group (P < .001). The AUC of CCECAI for differentiating the FR‐PLE group was 0.935 (95% confidence interval [CI], 0.845‐1.000) with an optimal cutoff value of 8 (sensitivity, 0.826; specificity, 0.889). Survival times were significantly longer in the FR‐PLE group (median, not reached) than in the IR/NR‐PLE group (median, 432 days; P < .001).Conclusions and Clinical ImportanceDogs that respond to ULFD management and are diagnosed with FR‐PLE are expected to have a favorable prognosis. Clinical scores, specifically the CCECAI, could be useful for differentiating FR‐PLE from IR‐PLE or NR‐PLE.

Rapid Resolution of Large Bowel Diarrhea after the Administration of a Combination of a High-Fiber Diet and a Probiotic Mixture in 30 Dogs.

Canine fiber responsive diarrhea is a form of chronic colitis that improves clinically after adding fiber to the diet. In the present study, we investigated the effect of a combination of a high-fiber, highly digestible, hypoallergenic diet with a probiotic mixture in 30 dogs with chronic colitis that were unresponsive to various dietary and/or pharmacological interventions. Fecal scores, canine chronic enteropathy clinical activity index (CCECAI) scores, the dysbiosis index (DI), and histologic images of colonic biopsies were evaluated. At baseline (day 0; T0) and after 30 days of treatment (T1), all variables evaluated in our patients (i.e., fecal and CCECAI scores and histopathology) improved significantly at T1, with the exception of DI. However, there was a numerical shift from a state of dysbiosis to one of normobiosis. The combination of the diet and the probiotic used in the present study induced the resolution of clinical signs in a mean of 8.5 days (maximum 15 days) and did not necessitate any other treatments or the further addition of alimentary fiber.

Ki-67/CD3 ratio in the diagnosis of chronic inflammatory enteropathy in dogs.

BackgroundT cells play a key role in the pathogenesis of chronic inflammatory enteropathy (CIE) in dogs. Cluster of differentiation 3 (CD3) antigen serves as a marker for T cells. In human medicine, Ki‐67 is an indicator for cell growth but there are only a few studies in dogs with CIE.ObjectiveTo investigate Ki‐67 in relation to T cells as a marker for CIE in dogs.AnimalsEleven dogs with CIE and 6 healthy beagle controls (CO).MethodsRetrospective case‐control study. Dogs were clinically assessed by the Canine Chronic Enteropathy Clinical Activity Index (CCECAI). Duodenal mucosal biopsy samples were endoscopically obtained for histopathologic examination by means of the World Small Animal Veterinary Association score. Double‐labeled immunofluorescence was used to investigate colocalization of Ki‐67 and CD3 in epithelium and lamina propria (LP) of villi and crypts.ResultsDogs with CIE had significantly higher clinical score (median, 5.0; interquartile range [IQR], 3‐7) compared to CO (all 0; P < .001). The Ki‐67/CD3 double‐positive cells were significantly increased in the LP of the crypt region of CIE dogs (0.63 cells/mm2; IQR, 0‐0.54) versus CO (0.08 cells/mm2; IQR, 0‐0.26; P = .044). A significant correlation was found between CCECAI and the Ki‐67/CD3 ratio in the LP of the crypt region (r = 0.670; P = .012) in dogs with CIE.Conclusions and Clinical ImportanceThe Ki‐67/CD3 ratio is upregulated in the LP crypt region of dogs with CIE and it correlates with clinical severity. Therefore, Ki‐67/CD3 could be a useful tool for detection of CIE.

Plasma amino acid profiles in dogs with inflammatory bowel disease.

BackgroundLymphocytic‐plasmacytic enteritis is the common form of idiopathic inflammatory bowel disease (IBD) in dogs. In human IBD, disturbances of amino acid metabolism have been demonstrated to be involved in the pathophysiology of IBD. Therefore, plasma amino acid profile might represent a novel marker of human IBD.ObjectivesTo determine the plasma amino acid profiles of dogs with IBD and its usefulness as a novel marker of IBD in dogs.AnimalsFasting blood plasma was obtained from 10 dogs with IBD and 12 healthy dogs.MethodsAll IBD dogs were prospectively included in this study, and heparinized blood samples were collected. The plasma concentrations of 21 amino acids were determined using the ninhydrin method. The relationships among the plasma amino acid concentrations and plasma C‐reactive protein (CRP) concentration, canine chronic enteropathy clinical activity index (CCECAI), and overall World Small Animal Veterinary Association (WSAVA) score were investigated.ResultsMedian concentration (nmol/mL) of methionine [46.2; range, 30.0‐59.3], proline [119.4; range, 76.7‐189.2], serine [115.1; range, 61.4‐155.9], and tryptophan [17.4; range, 11.9‐56.3]) were significantly lower than in control dogs [62.6; range, 51.0‐83.6, 199.1; range, 132.5‐376.7, 164.3; range, 124.7‐222.9, and 68.3; range, 35.7‐94.8, respectively]. A negative correlation was identified between the plasma serine concentration and CCECAI (r s = −.67, P = .03), but there were no correlations between plasma amino acid concentrations and CRP concentration or overall WSAVA score.Conclusions and Clinical ImportancePlasma serine concentration might represent a novel maker of IBD in dogs.

Platelet indices as biomarkers for characterization and determination of severity in canine chronic enteropathy

Human studies have shown an association between certain platelet indices and active inflammatory bowel disease when compared to healthy controls. The objectives of this retrospective study were to determine if any platelet indices differ between dogs with chronic enteropathies and healthy age- and sex-matched control dogs and are predictive of the severity of chronic enteropathy based on canine chronic enteropathy clinical activity index (CCECAI) scores. Medical records for 22 chronic enteropathy-positive dogs and 22 healthy control dogs were reviewed for historical and physical examination findings, platelet indices, and histologic diagnoses of chronic enteropathy. Platelet indices were compared between the groups, and an association between platelet indices and CCECAI scores in dogs with chronic enteropathy was investigated.Chronic diarrhea and weight loss were common clinical signs associated with chronic enteropathy. Lymphoplasmacytic enteritis was the most common histologic diagnosis. Only one platelet index, platelet component distribution width (P = 0.045), was found to be significantly different between the groups. For predicting severity of disease, determined by CCECAI score, statistically significant differences in indices associated with higher scores were platelet count (P = 0.024) and platelet dry mass distribution width (P = 0.036). Only platelet component distribution width showed potential in characterizing dogs with chronic enteropathy compared to normal dogs. Elevated platelet count and decreased platelet dry mass distribution width had a significant effect on total CCECAI scores. These findings suggest further investigation into the utility of platelet indices as predictors of disease presence and severity in dogs with chronic enteropathy is warranted.

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

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.

Association of fecal calprotectin concentrations with disease severity, response to treatment, and other biomarkers in dogs with chronic inflammatory enteropathies.

BackgroundCalprotectin is a marker of inflammation, but its clinical utility in dogs with chronic inflammatory enteropathies (CIE) is unknown.ObjectiveEvaluation of fecal calprotectin in dogs with biopsy‐confirmed CIE.Animals127 dogs.MethodsProspective case‐control study. Dogs were assigned a canine chronic enteropathy clinical activity index (CCECAI) score, and histologic lesions severity was assessed. Fecal calprotectin, fecal S100A12, and serum C‐reactive protein (CRP) were measured. Food‐ or antibiotic‐responsive cases (FRE/ARE, n = 13) were distinguished from steroid‐/immunosuppressant‐responsive or ‐refractory cases (SRE/IRE, n = 20). Clinical response to treatment in SRE/IRE dogs was classified as complete remission (CR), partial response (PR), or no response (NR).ResultsFecal calprotectin correlated with CCECAI (ρ = 0.27, P = .0065) and fecal S100A12 (ρ = 0.90, P < .0001), some inflammatory criteria, and cumulative inflammation scores, but not serum CRP (ρ = 0.16, P = .12). Dogs with SRE/IRE had higher fecal calprotectin concentrations (median: 2.0 μg/g) than FRE/ARE dogs (median: 1.4 μg/g), and within the SRE/IRE group, dogs with PR/NR had higher fecal calprotectin (median: 37.0 μg/g) than dogs with CR (median: 1.6 μg/g). However, both differences did not reach statistical significance (both P = .10). A fecal calprotectin ≥15.2 μg/g separated both groups with 80% sensitivity (95% confidence interval [95%CI]: 28%‐100%) and 75% specificity (95%CI: 43%‐95%).Conclusions and Clinical ImportanceFecal calprotectin could be a useful surrogate marker of disease severity in dogs with CIE, but larger longitudinal studies are needed to evaluate its utility in predicting the response to treatment.

Does canine inflammatory bowel disease influence gut microbial profile and host metabolism?

BackgroundInflammatory bowel disease (IBD) refers to a diverse group of chronic gastrointestinal diseases, and gut microbial dysbiosis has been proposed as a modulating factor in its pathogenesis. Several studies have investigated the gut microbial ecology of dogs with IBD but it is yet unclear if this microbial profile can alter the nutrient metabolism of the host. The aim of the present study was to characterize the faecal bacterial profile and functionality as well as to determine host metabolic changes in IBD dogs.Twenty-three dogs diagnosed with IBD and ten healthy control dogs were included. Dogs with IBD were given a clinical score using the canine chronic enteropathy clinical activity index (CCECAI). Faecal short-chain fatty acids (SCFA) and ammonia concentrations were measured and quantitative PCR was performed. The concentration of plasma amino acids, acylcarnitines, serum folate, cobalamin, and indoxyl sulfate was determined.ResultsNo significant differences in the abundance of a selection of bacterial groups and fermentation metabolites were observed between the IBD and control groups. However, significant negative correlations were found between CCECAI and the faecal proportion of Lactobacillus as well as between CCECAI and total SCFA concentration. Serum folate and plasma citrulline were decreased and plasma valine was increased in IBD compared to control dogs. Increased plasma free carnitine and total acylcarnitines were observed in IBD compared with control dogs, whereas short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and, methylmalonylcarnitine) to free carnitine ratios decreased. Dogs with IBD had a higher 3-hydroxyisovalerylcarnitine + isovalerylcarnitine to leucine ratio compared to control dogs.ConclusionsCanine IBD induced a wide range of changes in metabolic profile, especially for the plasma concentrations of short-chain acylcarnitines and amino acids, which could have evolved from tissue damage and alteration in host metabolism. In addition, dogs with more severe IBD were characterised by a decrease in faecal proportion of Lactobacillus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0736-2) contains supplementary material, which is available to authorized users.

Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Clinical and laboratory outcomes

Mesenchymal stem cells (MSCs) have shown immunomodulatory and anti-inflammatory effects in experimental colitis, and promising clinical results have been obtained in humans with Crohn's disease and ulcerative colitis. The aim of this study was to determine the safety and feasibility of adipose tissue-derived MSC (ASC) therapy in dogs with inflammatory bowel disease (IBD). Eleven dogs with confirmed IBD received one ASC intravascular (IV) infusion (2 × 106 cells/kg bodyweight). The outcome measures were clinical response based on percentage reduction of the validated Clinical Inflammatory Bowel Disease Activity Index (CIBDAI) and Canine Chronic Enteropathy Clinical Activity Index (CCECAI), as well as normalisation of C-reactive protein (CRP), albumin, folate and cobalamin serum concentrations at day 42 post-treatment. The Wilcoxon test was used to compare variables before and after treatment.No acute reaction to ASC infusion and no side effects were reported during follow-up in any dog. Six weeks post-treatment, the CIBDAI and CCECAI decreased significantly and albumin, cobalamin and folate concentrations increased substantially. Differences in CRP concentrations pre- and post-treatment were not significant (P = 0.050). Clinical remission (defined by a reduction of initial CIBDAI and CCECAI >75%) occurred in 9/11 dogs at day 42. The two remaining dogs showed a partial response with reduction percentages of 69.2% and 71.4%. In conclusion, a single IV infusion of allogeneic ASCs was well tolerated and appeared to produce clinical benefits in dogs with severe IBD.