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      Role of the microbiota in ileitis of a mouse model of inflammatory bowel disease—Glutathione peroxide isoenzymes 1 and 2‐double knockout mice on a C57BL background

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          Abstract

          C57Bl6 (B6) mice devoid of glutathione peroxidases 1 and 2 (Gpx1/2‐DKO) develop ileitis after weaning. We previously showed germ‐free Gpx1/2‐DKO mice of mixed B6.129 background did not develop ileocolitis. Here, we examine the composition of the ileitis provoking microbiota in B6 Gpx1/2‐DKO mice. DNA was isolated from the ileum fecal stream and subjected to high‐throughput sequencing of the V3 and V4 regions of the 16S rRNA gene to determine the abundance of operational taxonomic units (OTUs). We analyzed the role of bacteria by comparing the microbiomes of the DKO and pathology‐free non‐DKO mice. Mice were treated with metronidazole, streptomycin, and vancomycin to alter pathology and correlate the OTU abundances with pathology levels. Principal component analysis based on Jaccard distance of abundance showed 3 distinct outcomes relative to the source Gpx1/2‐DKO microbiome. Association analyses of pathology and abundance of OTUs served to rule out 7–11 of 24 OTUs for involvement in the ileitis. Collections of OTUs were identified that appeared to be linked to ileitis in this animal model and would be classified as commensals. In Gpx1/2‐DKO mice, host oxidant generation from NOX1 and DUOX2 in response to commensals may compromise the ileum epithelial barrier, a role generally ascribed to oxidants generated from mitochondria, NOX2 and endoplasmic reticulum stress in response to presumptive pathogens in IBD. Elevated oxidant levels may contribute to epithelial cell shedding, which is strongly associated with progress toward inflammation in Gpx1/2‐DKO mice and predictive of relapse in IBD by allowing leakage of microbial components into the submucosa.

          Abstract

          Hydrogen peroxide (H 2O 2) and superoxide are generated by some bacterial genera and by the intestinal mucosa in response to bacteria. Gpx1/2‐double knockout mice are sensitive to intestinal H 2O 2 production, which causes crypt apoptosis and anoikis leading to inflammation. We investigate the normal ileum pathology inducing microbiota and use antibiotics to narrow down potential candidates. The principal candidate, Lactobacillus, stands out while not demonstrating unambiguous domination in provoking the pathology.

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          Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.

          Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.
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            Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches.

            Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.
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              The composition of the gut microbiota shapes the colon mucus barrier

              Two C57BL/6 mice colonies maintained in two rooms of the same specific pathogen-free (SPF) facility were found to have different gut microbiota and a mucus phenotype that was specific for each colony. The thickness and growth of the colon mucus were similar in the two colonies. However, one colony had mucus that was impenetrable to bacteria or beads the size of bacteria—which is comparable to what we observed in free-living wild mice—whereas the other colony had an inner mucus layer penetrable to bacteria and beads. The different properties of the mucus depended on the microbiota, as they were transmissible by transfer of caecal microbiota to germ-free mice. Mice with an impenetrable mucus layer had increased amounts of Erysipelotrichi, whereas mice with a penetrable mucus layer had higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus. Thus, our study shows that bacteria and their community structure affect mucus barrier properties in ways that can have implications for health and disease. It also highlights that genetically identical animals housed in the same facility can have rather distinct microbiotas and barrier structures.
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                Author and article information

                Contributors
                sesworthy@coh.org
                Journal
                Microbiologyopen
                Microbiologyopen
                10.1002/(ISSN)2045-8827
                MBO3
                MicrobiologyOpen
                John Wiley and Sons Inc. (Hoboken )
                2045-8827
                18 August 2020
                October 2020
                : 9
                : 10 ( doiID: 10.1002/mbo3.v9.10 )
                : e1107
                Affiliations
                [ 1 ] Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology Luoyang China
                [ 2 ] Department of Cancer Genetics and Epigenetics Beckman Research Institute City of Hope Duarte CA USA
                [ 3 ] Center for Cancer Research and Division of Cancer Treatment and Diagnosis National Cancer Institute Bethesda MD USA
                Author notes
                [*] [* ] Correspondence

                R. Steven Esworthy, Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, 1500 Duarte Road, Duarte, CA 91010‐3000, USA.

                Email: sesworthy@ 123456coh.org

                Author information
                https://orcid.org/0000-0002-0894-3033
                https://orcid.org/0000-0002-4111-3349
                https://orcid.org/0000-0002-4408-407X
                https://orcid.org/0000-0002-4463-1790
                Article
                MBO31107
                10.1002/mbo3.1107
                7568258
                32810389
                f9b2b016-5112-4b12-9caf-11ae1e73f15d
                © 2020 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 May 2020
                : 19 July 2020
                : 25 July 2020
                Page count
                Figures: 5, Tables: 1, Pages: 14, Words: 11388
                Funding
                Funded by: National Cancer Institute , open-funder-registry 10.13039/100000054;
                Award ID: P30CA33572
                Award ID: RO1CA085344
                Funded by: National Cancer Institute ‐ USA
                Award ID: HHSN261200800001E
                Award ID: R01CA233664
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:17.10.2020

                Microbiology & Virology
                ibd,ileitis,lactobacillus,microbiome,mouse model,reactive oxygen species
                Microbiology & Virology
                ibd, ileitis, lactobacillus, microbiome, mouse model, reactive oxygen species

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