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      No Effect in Alcoholic Hepatitis of Gut-Selective, Broad-Spectrum Antibiotics on Bacterial Translocation or Hepatic and Systemic Inflammation

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          Abstract

          INTRODUCTION:

          In alcoholic hepatitis (AH), translocation of gut bacteria may drive hepatic macrophage activation and systemic inflammation. We investigated the effect of oral non-absorbable, broad-spectrum antibiotic treatment on bacterial translocation and liver and systemic inflammation in AH.

          METHODS:

          We consecutively recruited 31 patients with AH. Fourteen were given vancomycin 500 mg, gentamycin 40 mg, and meropenem 500 mg once daily for 7 days. Seventeen patients were a reference group receiving standard-of-care. Circulating markers of bacterial translocation and inflammation were measured at baseline, by day 7 and 90. Gut bacteriome profiling was performed before the intervention and at day 7.

          RESULTS:

          At study entry, blood lipopolysaccharide-binding protein was multifold higher than normal, remained unchanged at day 7, but decreased at day 90 ( P < 0.001) with no difference between the study groups. The macrophage activation markers sCD163 and sCD206 showed the same pattern ( P < 0.001, day 90), still without group differences. The systemic inflammation markers tumor necrosis factor—alpha, interleukin (IL)-6, IL-8, and IL-10 showed similar dynamics without group differences. There was no difference in 90-day mortality (total of 6 deaths) between the groups. The remnant gut bacteriome was markedly diversified by the intervention with growth of bacterial species rare for human flora.

          DISCUSSION:

          In patients with AH, gut-targeted antibiotic treatment does not change markers of bacterial translocation and liver and systemic inflammation. This suggests that bacterial translocation is less important once the inflammatory process is established or that bacteriome reduction is less important than composition.

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          Most cited references25

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          Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

          Summary Chronic liver disease due to alcohol use disorder contributes markedly to the global burden of disease and mortality 1–3 . 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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            Altered profile of human gut microbiome is associated with cirrhosis and its complications.

            The gut microbiome is altered in cirrhosis; however its evolution with disease progression is only partly understood. We aimed to study changes in the microbiome over cirrhosis severity, its stability over time and its longitudinal alterations with decompensation.
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              Enteric dysbiosis associated with a mouse model of alcoholic liver disease.

              The translocation of bacteria and bacterial products into the circulation contributes to alcoholic liver disease. Intestinal bacterial overgrowth is common in patients with alcoholic liver disease. The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in alcoholic liver disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation occurred prior to changes observed in the microbiome. Quantitative changes in the intestinal microflora of these animals were assessed first using conventional culture techniques in the small and large intestine. Although we found no difference after 1 day or 1 week, intestinal bacterial overgrowth was observed in the gastrointestinal tract of mice fed alcohol for 3 weeks compared with control mice fed an isocaloric liquid diet. Because <20% of all gastrointestinal bacteria can be cultured using conventional methodologies, we performed massively parallel pyrosequencing to further assess the qualitative changes in the intestinal microbiome following alcohol exposure. Sequencing of 16S ribosomal RNA genes revealed a relative abundance of Bacteroidetes and Verrucomicrobia bacteria in mice fed alcohol compared with a relative predominance of Firmicutes bacteria in control mice. With respect to the host's transcriptome, alcohol feeding was associated with down-regulation in gene and protein expression of bactericidal c-type lectins Reg3b and Reg3g in the small intestine. Treatment with prebiotics partially restored Reg3g protein levels, reduced bacterial overgrowth, and lessened alcoholic steatohepatitis. Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis. Intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to alcoholic steatohepatitis. Copyright © 2010 American Association for the Study of Liver Diseases.
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                Author and article information

                Contributors
                Journal
                Clin Transl Gastroenterol
                Clin Transl Gastroenterol
                CLTG
                CT9
                CT9
                Clinical and Translational Gastroenterology
                Wolters Kluwer (Philadelphia, PA )
                2155-384X
                February 2021
                27 January 2021
                : 12
                : 2
                : e00306
                Affiliations
                [1 ]Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
                Author notes
                Correspondence: Thomas Damgaard Sandahl, MD, PhD. E-mail: thomsand@ 123456rm.dk .
                Article
                CTG-20-0378 00001
                10.14309/ctg.0000000000000306
                7846454
                33566559
                d57a7496-225e-4758-8fa8-55ac5ba54d04
                © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 09 July 2020
                : 18 December 2020
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                Liver
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                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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