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      Interaction between microbiota and immunity in health and disease

      review-article

      1 , 2 , 1 , 3 , 1 , 4 ,

      Cell Research

      Springer Singapore

      Immunology, Molecular biology

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          Abstract

          The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host’s innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.

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          Most cited references 160

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

             S Almer,  S Lesage,  J Hugot (2001)
            Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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              An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

              The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial molecules mediating symbiosis remain undefined. Here we show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and T(H)1/T(H)2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunologic functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine production. These findings provide a molecular basis for host-bacterial symbiosis and reveal the archetypal molecule of commensal bacteria that mediates development of the host immune system.
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                Author and article information

                Contributors
                eran.elinav@weizmann.ac.il
                Journal
                Cell Res
                Cell Res
                Cell Research
                Springer Singapore (Singapore )
                1001-0602
                1748-7838
                20 May 2020
                20 May 2020
                June 2020
                : 30
                : 6
                : 492-506
                Affiliations
                [1 ]ISNI 0000 0004 0604 7563, GRID grid.13992.30, Immunology Department, , Weizmann Institute of Science, ; 234 Herzl Street, 7610001 Rehovot, Israel
                [2 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Gastroenterology, The First Affiliated Hospital, , Sun Yat-sen University, ; Guangzhou, Guangdong China
                [3 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, 1st Department of Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
                [4 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Cancer-Microbiome Division, Deutsches Krebsforschungszentrum (DKFZ), ; Neuenheimer Feld 280, 69120 Heidelberg, Germany
                Article
                332
                10.1038/s41422-020-0332-7
                7264227
                32433595
                7cff6c16-fb26-4ff2-a206-6e49d4175d13
                © The Author(s) 2020

                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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                Review Article
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                © Center for Excellence in Molecular Cell Science, CAS 2020

                Cell biology

                immunology, molecular biology

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