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      Gut-associated IgA + immune cells regulate obesity-related insulin resistance

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          Abstract

          The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA + immune cells and that IgA is a critical immune regulator of glucose homeostasis. Obese mice have fewer IgA + immune cells and less secretory IgA and IgA-promoting immune mediators. HFD-fed IgA-deficient mice have dysfunctional glucose metabolism, a phenotype that can be recapitulated by adoptive transfer of intestinal-associated pan-B cells. Mechanistically, IgA is a crucial link that controls intestinal and adipose tissue inflammation, intestinal permeability, microbial encroachment and the composition of the intestinal microbiome during HFD. Current glucose-lowering therapies, including metformin, affect intestinal-related IgA + B cell populations in mice, while bariatric surgery regimen alters the level of fecal secretory IgA in humans. These findings identify intestinal IgA + immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease.

          Abstract

          The effect of diet-induced obesity on intestinal B cell populations is not well understood despite emerging evidence of a critical role for the intestinal immune system in contributing to insulin resistance. Here, the authors show important functions of IgA in regulating metabolic disease and for intestinal immunity in modulating systemic glucose metabolism.

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          Most cited references75

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          QIIME allows analysis of high-throughput community sequencing data.

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            Metagenomic biomarker discovery and explanation

            This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.
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              UPARSE: highly accurate OTU sequences from microbial amplicon reads.

              Amplified marker-gene sequences can be used to understand microbial community structure, but they suffer from a high level of sequencing and amplification artifacts. The UPARSE pipeline reports operational taxonomic unit (OTU) sequences with ≤1% incorrect bases in artificial microbial community tests, compared with >3% incorrect bases commonly reported by other methods. The improved accuracy results in far fewer OTUs, consistently closer to the expected number of species in a community.
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                Author and article information

                Contributors
                dan.winer@uhn.ca
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                13 August 2019
                13 August 2019
                2019
                : 10
                : 3650
                Affiliations
                [1 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), , University Health Network, ; Toronto, ON M5G 2C4 Canada
                [2 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Immunology, , University of Toronto, ; Toronto, ON M5S 1A8 Canada
                [3 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Centre for the Analysis of Genome Evolution and Function, , University of Toronto, ; Toronto, ON M5S 3B2 Canada
                [4 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Integrative Biology and Physiology, , University of Minnesota, ; Minneapolis, MN 55455 USA
                [5 ]ISNI 0000000419368657, GRID grid.17635.36, Center for Immunology, , University of Minnesota, ; Minneapolis, MN 55455 USA
                [6 ]GRID grid.17089.37, Department of Medical Microbiology and Immunology, , University of Alberta, ; Edmonton, AB T6G 2R3 Canada
                [7 ]GRID grid.145695.a, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, School of Traditional Chinese Medicine and Graduate Institute of Clinical Medical Sciences, College of Medicine, , Chang Gung University, ; Taoyuan, 333 Taiwan
                [8 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Department of Medicine, Division of Infectious Diseases, , University Health Network, ; Toronto, ON M5G 2N2 Canada
                [9 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Laboratory Medicine and Pathobiology, , University of Toronto, ; Toronto, ON M5S 1A8 Canada
                [10 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Toronto Western Hospital, , University Health Network, ; Toronto, ON M5T 2S8 Canada
                [11 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Surgery, , University of Toronto, ; Toronto, ON M5T 1P5 Canada
                [12 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Medicine, , University of Toronto, ; Toronto, ON M5S 1A8 Canada
                [13 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Department of Microbiology, , University Health Network/Sinai Health System, ; Toronto, ON M5G 2M9 Canada
                [14 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Toronto General Hospital, , University Health Network, ; Toronto, ON M5G 2C4 Canada
                [15 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Virology and Microbiology, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [16 ]GRID grid.415502.7, Department of Laboratory Medicine, , St. Michael’s Hospital, ; Toronto, ON M5B 1W8 Canada
                [17 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Department of Pathology, , University Health Network, ; 200 Elizabeth Street, Toronto, ON M5G 2C4 Canada
                [18 ]ISNI 0000 0000 8687 5377, GRID grid.272799.0, Buck Institute for Research on Aging, ; 8001 Redwood Boulevard, Novato, CA 94945 USA
                [19 ]Present Address: 10-352 Toronto Medical Discovery Tower, 101 College Street, Toronto, ON M5G 1L7 Canada
                Author information
                http://orcid.org/0000-0003-4747-2550
                http://orcid.org/0000-0001-8479-3869
                Article
                11370
                10.1038/s41467-019-11370-y
                6692361
                31409776
                674809a8-6b78-491e-b8c1-0a3f4338fbfb
                © The Author(s) 2019

                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/.

                History
                : 3 April 2018
                : 8 July 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100007202, Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre);
                Award ID: 119414
                Award ID: 142708
                Award ID: 148385
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100013528, Diabetes Canada (DC);
                Award ID: OG-3-15-5014
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                mucosal immunology,diabetes,b cells,obesity
                Uncategorized
                mucosal immunology, diabetes, b cells, obesity

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