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      Microbiome–microglia connections via the gut–brain axis

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          Abstract

          A role for the gut microbiome in facilitating microglial maturation and shaping microglial physiology has emerged in recent years. This review highlights evidence demonstrating the various mechanisms by which the gut microbiota can influence microglia in both homeostatic and disease conditions.

          Abstract

          Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract. Recent preclinical findings suggest that the gut microbiome plays a pivotal role in regulating microglial maturation and function, and altered microbial community composition has been reported in neurological disorders with known microglial involvement in humans. Collectively, these findings suggest that bidirectional crosstalk between the gut and the brain may influence disease pathogenesis. Herein, we discuss recent studies showing a role for the gut microbiome in modulating microglial development and function in homeostatic and disease conditions and highlight possible future research to develop novel microbial treatments for disorders of the brain.

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          Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

          Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
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            Stages in the development of Parkinson's disease-related pathology.

            The synucleinopathy, idiopathic Parkinson's disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged. During presymptomatic stages 1-2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3-4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5-6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.
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              The Microglial Sensome Revealed by Direct RNA Sequencing

              Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                Rockefeller University Press
                0022-1007
                1540-9538
                07 January 2019
                : 216
                : 1
                : 41-59
                Affiliations
                [1 ]Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA
                [2 ]Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA
                Author notes
                Correspondence to Sarkis K. Mazmanian: sarkis@ 123456caltech.edu
                Author information
                http://orcid.org/0000-0002-7418-5736
                http://orcid.org/0000-0003-4344-3592
                http://orcid.org/0000-0003-2713-1513
                Article
                20180794
                10.1084/jem.20180794
                6314531
                30385457
                31b1d9d6-17ee-40ac-b932-8db65f1cba3f
                © 2018 Abdel-Haq et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 29 April 2018
                : 08 July 2018
                : 03 October 2018
                Funding
                Funded by: U.S. Department of Defense, DOI https://doi.org/10.13039/100000005;
                Funded by: Donna and Benjamin M. Rosen Bioengineering Center, DOI https://doi.org/10.13039/100012614;
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: AG057706
                Award ID: NS096170
                Funded by: Heritage Medical Research Institute
                Funded by: Simons Foundation, DOI https://doi.org/10.13039/100000893;
                Award ID: 322839
                Funded by: U.S. Department of Defense, DOI https://doi.org/10.13039/100000005;
                Award ID: PD160030
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: MH100556
                Award ID: NS085910
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                Medicine
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