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      Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature

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          Abstract

          The rapid scientific interest in gut microbiota (GM) has coincided with a global increase in the prevalence of infectious and non-infectivous liver diseases. GM, which is also called “the new virtual metabolic organ”, makes axis with a number of extraintestinal organs, such as kidneys, brain, cardiovascular, and the bone system. The gut-liver axis has attracted greater attention in recent years. GM communication is bi-directional and involves endocrine and immunological mechanisms. In this way, gut-dysbiosis and composition of “ancient” microbiota could be linked to pathogenesis of numerous chronic liver diseases such as chronic hepatitis B (CHB), chronic hepatitis C (CHC), alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), development of liver cirrhosis, and hepatocellular carcinoma (HCC). In this paper, we discuss the current evidence supporting a GM role in the management of different chronic liver diseases and potential new therapeutic GM targets, like fecal transplantation, antibiotics, probiotics, prebiotics, and symbiotics. We conclude that population-level shifts in GM could play a regulatory role in the gut-liver axis and, consequently, etiopathogenesis of chronic liver diseases. This could have a positive impact on future therapeutic strategies.

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          Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.

          Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
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            A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

            Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
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              Towards the human intestinal microbiota phylogenetic core.

              The paradox of a host specificity of the human faecal microbiota otherwise acknowledged as characterized by global functionalities conserved between humans led us to explore the existence of a phylogenetic core. We investigated the presence of a set of bacterial molecular species that would be altogether dominant and prevalent within the faecal microbiota of healthy humans. A total of 10 456 non-chimeric bacterial 16S rRNA sequences were obtained after cloning of PCR-amplified rDNA from 17 human faecal DNA samples. Using alignment or tetranucleotide frequency-based methods, 3180 operational taxonomic units (OTUs) were detected. The 16S rRNA sequences mainly belonged to the phyla Firmicutes (79.4%), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%) and Verrumicrobia (0.1%). Interestingly, while most of OTUs appeared individual-specific, 2.1% were present in more than 50% of the samples and accounted for 35.8% of the total sequences. These 66 dominant and prevalent OTUs included members of the genera Faecalibacterium, Ruminococcus, Eubacterium, Dorea, Bacteroides, Alistipes and Bifidobacterium. Furthermore, 24 OTUs had cultured type strains representatives which should be subjected to genome sequence with a high degree of priority. Strikingly, 52 of these 66 OTUs were detected in at least three out of four recently published human faecal microbiota data sets, obtained with very different experimental procedures. A statistical model confirmed these OTUs prevalence. Despite the species richness and a high individual specificity, a limited number of OTUs is shared among individuals and might represent the phylogenetic core of the human intestinal microbiota. Its role in human health deserves further study.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                17 January 2019
                January 2019
                : 20
                : 2
                : 395
                Affiliations
                [1 ]Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; ankica.vujovic88@ 123456gmail.com (A.V.); aleksandrabarac85@ 123456gmail.com (A.B.); milos.korac@ 123456med.bg.ac.rs (M.K.); spurnic@ 123456yahoo.com (A.R.S.); stevanovicolja74@ 123456gmail.com (O.S.); vladimir.djordjevic@ 123456kcs.ac.rs (V.D.); nesalekic67@ 123456gmail.com (N.L.)
                [2 ]Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia; gmizic_ivana@ 123456yahoo.com
                [3 ]Faculty of Medicine, Universisty of Belgrade; Institute of Medical Physiology “Rihard Burijan”, 11000 Belgrade, Serbia; mdjelic011@ 123456gmail.com
                [4 ]Clinic for Digestive Surgery, Clinical Center of Serbia, 11000 Belgrade, Serbia
                [5 ]Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; edda.russo@ 123456unifi.it (E.R.); amedeo.amedei@ 123456unifi.it (A.A.)
                [6 ]Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), 50134 Florence, Italy
                Author notes
                [* ]Correspondence: ivana.s.milosevic@ 123456mfub.bg.ac.rs ; Tel.: +381-11-2683-366
                Author information
                https://orcid.org/0000-0003-3141-1091
                Article
                ijms-20-00395
                10.3390/ijms20020395
                6358912
                30658519
                03a7fbd1-8add-42e8-bf71-cc4885fdd4fb
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 December 2018
                : 14 January 2019
                Categories
                Review

                Molecular biology
                gut microbiota,gut-liver axis,chronic liver diseases,fecal transplantation,probiotics

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