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

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          Abstract

          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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          Most cited references22

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          Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

          Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.
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            Intestinal transport and metabolism of bile acids.

            In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling.
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              16S rRNA Gene Pyrosequencing Reveals Bacterial Dysbiosis in the Duodenum of Dogs with Idiopathic Inflammatory Bowel Disease

              Background Canine idiopathic inflammatory bowel disease (IBD) is believed to be caused by a complex interaction of genetic, immunologic, and microbial factors. While mucosa-associated bacteria have been implicated in the pathogenesis of canine IBD, detailed studies investigating the enteric microbiota using deep sequencing techniques are lacking. The objective of this study was to evaluate mucosa-adherent microbiota in the duodenum of dogs with spontaneous idiopathic IBD using 16 S rRNA gene pyrosequencing. Methodology/Principal Findings Biopsy samples of small intestinal mucosa were collected endoscopically from healthy dogs (n = 6) and dogs with moderate IBD (n = 7) or severe IBD (n = 7) as assessed by a clinical disease activity index. Total RNA was extracted from biopsy specimens and 454-pyrosequencing of the 16 S rRNA gene was performed on aliquots of cDNA from each dog. Intestinal inflammation was associated with significant differences in the composition of the intestinal microbiota when compared to healthy dogs. PCoA plots based on the unweighted UniFrac distance metric indicated clustering of samples between healthy dogs and dogs with IBD (ANOSIM, p<0.001). Proportions of Fusobacteria (p = 0.010), Bacteroidaceae (p = 0.015), Prevotellaceae (p = 0.022), and Clostridiales (p = 0.019) were significantly more abundant in healthy dogs. In contrast, specific bacterial genera within Proteobacteria, including Diaphorobacter (p = 0.044) and Acinetobacter (p = 0.040), were either more abundant or more frequently identified in IBD dogs. Conclusions/Significance In conclusion, dogs with spontaneous IBD exhibit alterations in microbial groups, which bear resemblance to dysbiosis reported in humans with chronic intestinal inflammation. These bacterial groups may serve as useful targets for monitoring intestinal inflammation.
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                Author and article information

                Contributors
                bguard@cvm.tamu.edu
                Journal
                J Vet Intern Med
                J. Vet. Intern. Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                0891-6640
                1939-1676
                07 April 2019
                May-Jun 2019
                : 33
                : 3 ( doiID: 10.1111/jvim.2019.33.issue-3 )
                : 1295-1305
                Affiliations
                [ 1 ] Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences Texas A&M University College Station Texas
                [ 2 ] Department of Veterinary Clinical Sciences, College of Veterinary Medicine Iowa State University Ames Iowa
                [ 3 ] Evidensia Specialist Animal Hospital Helsingborg Sweden
                [ 4 ] Helsinki University Helsinki Finland
                [ 5 ] Clinical Sciences Department Colorado State University Fort Collins Colorado
                [ 6 ] Veterinary Specialty Hospital San Diego California
                Author notes
                [*] [* ] Correspondence

                Blake C. Guard, Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, 4474 TAMU, Texas A&M University, College Station, TX 77843.

                Email: bguard@ 123456cvm.tamu.edu

                Author information
                https://orcid.org/0000-0002-3545-7778
                https://orcid.org/0000-0001-8804-3539
                https://orcid.org/0000-0003-2375-8685
                https://orcid.org/0000-0001-9078-2293
                https://orcid.org/0000-0001-5107-4577
                https://orcid.org/0000-0003-3336-2086
                Article
                JVIM15493
                10.1111/jvim.15493
                6524081
                30957301
                3b14964f-a84f-4429-847b-54d7ac3dbb69
                © 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 08 September 2018
                : 21 March 2019
                Page count
                Figures: 6, Tables: 4, Pages: 11, Words: 6662
                Funding
                Funded by: Texas A and M University Gastrointestinal Laboratory
                Categories
                Standard Article
                SMALL ANIMAL
                Standard Articles
                Gastroenterology
                Custom metadata
                2.0
                jvim15493
                May/June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.3 mode:remove_FC converted:17.05.2019

                Veterinary medicine
                chenodeoxycholic acid,bile acid dysmetabolism,cholic acid,deoxycholic acid,inflammatory bowel disease,lithocholic acid

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