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      Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment

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          Abstract

          Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.

          Abstract

          The authors examine the effects of antidiabetic medication on the gut microbiome and bile acid composition and show that these data can be used to stratify treatment regimens for type 2 diabetes.

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          Most cited references23

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          Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.

          Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.

            The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.
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              Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut.

              Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the key microbial functions influencing host energy metabolism and adiposity remain to be determined. Despite an increased understanding of the genetic content of the gastrointestinal microbiome, functional analyses of common microbial gene sets are required. We established a controlled expression system for the parallel functional analysis of microbial alleles in the murine gut. Using this approach we show that bacterial bile salt hydrolase (BSH) mediates a microbe-host dialogue that functionally regulates host lipid metabolism and plays a profound role in cholesterol metabolism and weight gain in the host. Expression of cloned BSH enzymes in the gastrointestinal tract of gnotobiotic or conventionally raised mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (Pparγ, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIγ), and circadian rhythm (Dbp, Per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in a significant reduction in host weight gain, plasma cholesterol, and liver triglycerides, demonstrating the overall impact of elevated BSH activity on host physiology. In addition, BSH activity in vivo varied according to BSH allele group, indicating that subtle differences in activity can have significant effects on the host. In summary, we demonstrate that bacterial BSH activity significantly impacts the systemic metabolic processes and adiposity in the host and represents a key mechanistic target for the control of obesity and hypercholesterolemia.
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                Author and article information

                Contributors
                kk@bio.ku.dk
                gning@sibs.ac.cn
                wqingw61@163.com
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                27 November 2017
                27 November 2017
                2017
                : 8
                : 1785
                Affiliations
                [1 ]GRID grid.415869.7, Shanghai National Research Centre for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, , Shanghai Jiaotong University School of Medicine, ; 200025 Shanghai, China
                [2 ]BGI-Shenzhen, China National GeneBank-Shenzhen, 518083 Shenzhen, China
                [3 ]BGI Education Centre, University of Chinese Academy of Sciences, 518083 Shenzhen, China
                [4 ]ISNI 0000 0001 2034 1839, GRID grid.21155.32, Shenzhen Key Laboratory of Human commensal microorganisms and Health Research, , BGI-Shenzhen, ; Shenzhen, 518083 China
                [5 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Laboratory of Genomics and Molecular Biomedicine, Department of Biology, , University of Copenhagen, ; 2100 Copenhagen, Denmark
                [6 ]ISNI 0000 0001 2034 1839, GRID grid.21155.32, Shenzhen Engineering Laboratory of Detection and Intervention of human intestinal microbiome, , BGI-Shenzhen, ; Shenzhen, 518083 China
                [7 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Renji Hospital affiliated to Shanghai Jiaotong University Medical School, ; 200127 Shanghai, China
                [8 ]ISNI 0000 0004 0630 1330, GRID grid.412987.1, Xinhua Hospital affiliated to Shanghai Jiaotong University Medical School, ; 200092 Shanghai, China
                [9 ]GRID grid.452544.6, MinHang Central Hospital affiliated to Fudan University Medical School, ; 201100 Shanghai, China
                [10 ]ISNI 0000000119573309, GRID grid.9227.e, Dalian Institute of Chemical Physics, , Chinese Academy of Science, ; 116011 Dalian, China
                [11 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Shanghai General Hospital, , Shanghai Jiaotong University, ; 200080 Shanghai, China
                [12 ]James D. Watson Institute of Genome Sciences, Hangzhou, 310008 China
                [13 ]ISNI 0000 0004 0428 2404, GRID grid.419612.9, National Institute of Nutrition and Seafood Research (NIFES), ; 5817 Bergen, Norway
                Author information
                http://orcid.org/0000-0002-4323-1648
                http://orcid.org/0000-0001-6784-1873
                http://orcid.org/0000-0001-9512-1750
                http://orcid.org/0000-0003-4298-3554
                http://orcid.org/0000-0003-4468-1947
                http://orcid.org/0000-0002-6024-0917
                Article
                1682
                10.1038/s41467-017-01682-2
                5702614
                29176714
                702a5607-8707-493b-bdbc-da8aeb65116d
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 29 March 2017
                : 9 October 2017
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