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      Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice

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          Abstract

          Background

          Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS.

          Results

          Here we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters.

          Conclusions

          In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.

          Electronic supplementary material

          The online version of this article (10.1186/s40168-018-0587-0) contains supplementary material, which is available to authorized users.

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          Most cited references58

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          FLASH: fast length adjustment of short reads to improve genome assemblies.

          Next-generation sequencing technologies generate very large numbers of short reads. Even with very deep genome coverage, short read lengths cause problems in de novo assemblies. The use of paired-end libraries with a fragment size shorter than twice the read length provides an opportunity to generate much longer reads by overlapping and merging read pairs before assembling a genome. We present FLASH, a fast computational tool to extend the length of short reads by overlapping paired-end reads from fragment libraries that are sufficiently short. We tested the correctness of the tool on one million simulated read pairs, and we then applied it as a pre-processor for genome assemblies of Illumina reads from the bacterium Staphylococcus aureus and human chromosome 14. FLASH correctly extended and merged reads >99% of the time on simulated reads with an error rate of <1%. With adequately set parameters, FLASH correctly merged reads over 90% of the time even when the reads contained up to 5% errors. When FLASH was used to extend reads prior to assembly, the resulting assemblies had substantially greater N50 lengths for both contigs and scaffolds. The FLASH system is implemented in C and is freely available as open-source code at http://www.cbcb.umd.edu/software/flash. t.magoc@gmail.com.
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            Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.

            The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 > zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 > genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.
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              The emergence of the metabolic syndrome with menopause.

              Women with the metabolic syndrome (central obesity, insulin resistance, and dyslipidemia) are known to be at especially high risk for cardiovascular disease (CVD). The prevalence of the metabolic syndrome increases with menopause and may partially explain the apparent acceleration in CVD after menopause. The transition from pre- to postmenopause is associated with the emergence of many features of the metabolic syndrome, including 1) increased central (intraabdominal) body fat; 2) a shift toward a more atherogenic lipid profile, with increased low density lipoprotein and triglycerides levels, reduced high density lipoprotein, and small, dense low density lipoprotein particles; 3) and increased glucose and insulin levels. The emergence of these risk factors may be a direct result of ovarian failure or, alternatively, an indirect result of the metabolic consequences of central fat redistribution with estrogen deficiency. It is unclear whether the transition to menopause increases CVD risk in all women or only those who develop features of the metabolic syndrome. This article will review the features of the metabolic syndrome that emerge with estrogen deficiency. A better understanding of these metabolic changes with menopause will aid in the recognition and treatment of women at risk for future CVD, leading to appropriate interventions.
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                Author and article information

                Contributors
                kkaliannan@mgh.harvard.edu
                ruairirobertson@gmail.com
                kiera.murphy@teagasc.ie
                catherine.stanton@teagasc.ie
                chao.kang_tmmu@hotmail.com
                yy_bwang@hotmail.com
                lei.hao@ttu.edu
                abhan@mgh.harvard.edu
                (617) 726-8509 , kang.jing@mgh.harvard.edu , jxkang@mgh.harvard.edu
                Journal
                Microbiome
                Microbiome
                Microbiome
                BioMed Central (London )
                2049-2618
                13 November 2018
                13 November 2018
                2018
                : 6
                : 205
                Affiliations
                [1 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Laboratory of Lipid Medicine and Technology, Department of Medicine, , Massachusetts General Hospital and Harvard Medical School, ; 149 -13th Street, Boston, MA 02129 USA
                [2 ]ISNI 0000000123318773, GRID grid.7872.a, School of Microbiology, , University College Cork, ; Cork, Ireland
                [3 ]Teagasc Moorepark Food Research Centre, Fermoy, Co., Cork, Ireland
                [4 ]ISNI 0000000123318773, GRID grid.7872.a, APC Microbiome Institute, , University College Cork, ; Cork, Ireland
                [5 ]ISNI 0000 0004 1760 6682, GRID grid.410570.7, Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, , Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, ; Chongqing, People’s Republic of China
                [6 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Pathology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA 02114 USA
                Article
                587
                10.1186/s40168-018-0587-0
                6234624
                30424806
                183b7114-202b-4a63-87bc-71d34386f8f9
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 June 2018
                : 30 October 2018
                Funding
                Funded by: Fortune Education Foundation
                Funded by: Sansun Life Sciences;
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                estrogen,gut microbiome,obesity,metabolic syndrome,isoflavones,chronic inflammation

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