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      Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

      research-article
      1 , 2 , 1 , 2 , 1 , 3 , 1 , 1 , 2 , 4 , 4 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 1 , 11 , 1 , 1 , 1 , 1 , 1 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 17 , 18 , 19 , 20 , 1 , 2 , 21 , 22 , 21 , 23 , 12 , 7 , 1 , 10 , 24 , 25 , 8 , 9 , 6 , 26 , 1 , 11 , 27 , 4 , 1 , 2 , 27
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          Summary

          Chronic liver disease due to alcohol use disorder contributes markedly to the global burden of disease and mortality 13 . Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice 4 , but little is known about microbial factors responsible for this process. We identified cytolysin, a two-subunit exotoxin secreted by Enterococcus faecalis ( E. faecalis) 5, 6 , to cause hepatocyte death and liver injury. Compared with controls, patients with alcoholic hepatitis have increased fecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with liver disease severity and mortality in patients with alcoholic hepatitis. Using humanized mice colonized with bacteria from feces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found these phages to decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolysin-positive E. faecalis with worse clinical outcomes and mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, providing a method to precisely edit the intestinal microbiota. A prospective clinical trial with a larger cohort is required to validate human relevance of our findings and to test whether this new therapeutic approach is effective for patients with alcoholic hepatitis.

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          Most cited references61

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          Is Open Access

          RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies

          Motivation: Phylogenies are increasingly used in all fields of medical and biological research. Moreover, because of the next-generation sequencing revolution, datasets used for conducting phylogenetic analyses grow at an unprecedented pace. RAxML (Randomized Axelerated Maximum Likelihood) is a popular program for phylogenetic analyses of large datasets under maximum likelihood. Since the last RAxML paper in 2006, it has been continuously maintained and extended to accommodate the increasingly growing input datasets and to serve the needs of the user community. Results: I present some of the most notable new features and extensions of RAxML, such as a substantial extension of substitution models and supported data types, the introduction of SSE3, AVX and AVX2 vector intrinsics, techniques for reducing the memory requirements of the code and a plethora of operations for conducting post-analyses on sets of trees. In addition, an up-to-date 50-page user manual covering all new RAxML options is available. Availability and implementation: The code is available under GNU GPL at https://github.com/stamatak/standard-RAxML. Contact: alexandros.stamatakis@h-its.org Supplementary information: Supplementary data are available at Bioinformatics online.
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            Prokka: rapid prokaryotic genome annotation.

            T Seemann (2014)
            The multiplex capability and high yield of current day DNA-sequencing instruments has made bacterial whole genome sequencing a routine affair. The subsequent de novo assembly of reads into contigs has been well addressed. The final step of annotating all relevant genomic features on those contigs can be achieved slowly using existing web- and email-based systems, but these are not applicable for sensitive data or integrating into computational pipelines. Here we introduce Prokka, a command line software tool to fully annotate a draft bacterial genome in about 10 min on a typical desktop computer. It produces standards-compliant output files for further analysis or viewing in genome browsers. Prokka is implemented in Perl and is freely available under an open source GPLv2 license from http://vicbioinformatics.com/. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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              Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample.

              The ongoing revolution in high-throughput sequencing continues to democratize the ability of small groups of investigators to map the microbial component of the biosphere. In particular, the coevolution of new sequencing platforms and new software tools allows data acquisition and analysis on an unprecedented scale. Here we report the next stage in this coevolutionary arms race, using the Illumina GAIIx platform to sequence a diverse array of 25 environmental samples and three known "mock communities" at a depth averaging 3.1 million reads per sample. We demonstrate excellent consistency in taxonomic recovery and recapture diversity patterns that were previously reported on the basis of metaanalysis of many studies from the literature (notably, the saline/nonsaline split in environmental samples and the split between host-associated and free-living communities). We also demonstrate that 2,000 Illumina single-end reads are sufficient to recapture the same relationships among samples that we observe with the full dataset. The results thus open up the possibility of conducting large-scale studies analyzing thousands of samples simultaneously to survey microbial communities at an unprecedented spatial and temporal resolution.
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                Author and article information

                Journal
                0410462
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                03 October 2019
                13 November 2019
                November 2019
                13 May 2020
                : 575
                : 7783
                : 505-511
                Affiliations
                [1 ]Department of Medicine, University of California San Diego, La Jolla, CA, USA
                [2 ]Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
                [3 ]Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
                [4 ]J. Craig Venter Institute, Rockville, MD, USA
                [5 ]J. Craig Venter Institute, La Jolla, CA, USA
                [6 ]Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
                [7 ]Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
                [8 ]Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA
                [9 ]Center for Phage Technology, Texas A&M AgriLife Research and Texas A&M University, College Station, TX, USA
                [10 ]Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
                [11 ]Department of Pathology, University of California San Diego, La Jolla, CA, USA
                [12 ]Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
                [13 ]Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, México
                [14 ]Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
                [15 ]Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
                [16 ]Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA
                [17 ]Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
                [18 ]Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
                [19 ]Liver Unit, Hospital Clinic, Barcelona, Spain
                [20 ]Liver Sciences, Department of Inflammation Biology, School of Infectious Diseases and Microbial Sciences, King's College London, London, UK
                [21 ]Service des Maladies de L'appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France
                [22 ]Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, WI, USA
                [23 ]Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA, and Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT, USA
                [24 ]Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
                [25 ]Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA
                [26 ]St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
                [27 ]Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA
                Author notes
                Correspondence and requests for materials should be addressed to Bernd Schnabl, M.D., Department of Medicine, University of California San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA 92093, Phone 858-822-5311, Fax 858-822-5370, beschnabl@ 123456ucsd.edu
                Article
                EMS84533
                10.1038/s41586-019-1742-x
                6872939
                31723265
                1000e913-2015-43d3-9565-e44992e17a4d

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