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      Microbiome and PCOS: State-of-Art and Future Aspects

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          Abstract

          Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.

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          An obesity-associated gut microbiome with increased capacity for energy harvest.

          The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.
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            A human gut microbial gene catalogue established by metagenomic sequencing.

            To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
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              Metabolic endotoxemia initiates obesity and insulin resistance.

              Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                19 February 2021
                February 2021
                : 22
                : 4
                : 2048
                Affiliations
                [1 ]Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; pgiampaolino@ 123456gmail.com (P.G.); alessandra_gallo@ 123456hotmail.it (A.G.); francescopaolo.improda@ 123456gmail.com (F.P.I.); paoloverrazzo@ 123456gmail.com (P.V.); cirabuonfantino@ 123456gmail.com (C.B.); maria_borgo@ 123456hotmail.it (M.B.); m.chiaradeangelis@ 123456gmail.com (C.D.A.); brunella.zizolfi@ 123456hotmail.it (B.Z.)
                [2 ]Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; virgi.foreste@ 123456hotmail.it (V.F.); claudifilippo@ 123456gmail.com (C.D.F.); antoniomercorio@ 123456gmail.com (A.M.); paolo.serafino1992@ 123456gmail.com (P.S.); giuseppe.zara1404@ 123456gmail.com (G.Z.); giuseppe.bifulco@ 123456unina.it (G.B.)
                [3 ]Obstetrics and Gynecology Unit, Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; gaetano.riemma7@ 123456gmail.com
                Author notes
                [* ]Correspondence: dellacorte.luigi25@ 123456gmail.com ; Tel.: +39-081-746-2905
                Author information
                https://orcid.org/0000-0001-6660-0955
                https://orcid.org/0000-0003-3676-7716
                https://orcid.org/0000-0002-0584-2181
                Article
                ijms-22-02048
                10.3390/ijms22042048
                7922491
                33669557
                986b813a-2c5f-4610-b96c-48176ed629d2
                © 2021 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
                : 04 January 2021
                : 15 February 2021
                Categories
                Review

                Molecular biology
                pcos,microbiome,insulin-resistance,sexual hormones,therapeutic strategies
                Molecular biology
                pcos, microbiome, insulin-resistance, sexual hormones, therapeutic strategies

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