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      Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

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          Abstract

          Discovery of novel bacterial metabolites reveals an unprecedented role for the microbiome in gut-brain axis communication.

          Abstract

          Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen–free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.

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          Most cited references20

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          The Brain-Gut-Microbiome Axis

          Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases.
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            Recovery of gut microbiota of healthy adults following antibiotic exposure

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              Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations

              Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                March 2020
                11 March 2020
                : 6
                : 11
                : eaax6328
                Affiliations
                [1 ]Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
                [2 ]Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, UK.
                [3 ]Bioinformatics Group, Wageningen University, Wageningen 6708 PB, Netherlands.
                [4 ]Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, UK.
                [5 ]Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
                [6 ]Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, and The Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
                [7 ]Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9NT, UK.
                [8 ]National Physical Laboratory, Teddington, Middlesex TW11 0LW, UK.
                [9 ]Oncology Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, UK.
                [10 ]Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
                [11 ]Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
                [12 ]Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, UK.
                [13 ]Department of Neurogenetics, Max Planck Institute for Experimental Medicine, Hermann-Rein-Strasse 3, D-37075 Goettingen, Germany.
                [14 ]Natural Products Metabolomics Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
                Author notes
                [* ]Corresponding author. Email: donal.wall@ 123456glasgow.ac.uk
                Author information
                http://orcid.org/0000-0002-2987-7397
                http://orcid.org/0000-0003-1277-9608
                http://orcid.org/0000-0002-9340-5511
                http://orcid.org/0000-0002-4792-0037
                http://orcid.org/0000-0002-7545-8628
                http://orcid.org/0000-0003-2837-5018
                http://orcid.org/0000-0002-3991-2336
                http://orcid.org/0000-0001-8536-4417
                http://orcid.org/0000-0003-4384-5516
                http://orcid.org/0000-0003-0582-2284
                http://orcid.org/0000-0002-0290-6565
                http://orcid.org/0000-0002-5294-8683
                http://orcid.org/0000-0002-6654-7346
                http://orcid.org/0000-0002-3869-0962
                http://orcid.org/0000-0003-2420-1117
                http://orcid.org/0000-0003-1663-9004
                http://orcid.org/0000-0002-0421-1951
                Article
                aax6328
                10.1126/sciadv.aax6328
                7065903
                32195337
                7bb47b59-0b9f-4f9d-adc7-b14707b8f06b
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 April 2019
                : 13 December 2019
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: Sir Henry Dale fellowship 104116/Z/14/Z
                Funded by: doi http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 097820/Z/11/B
                Funded by: doi http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;
                Award ID: (BBSRC)-CASE studentship part funded by AstraZeneca
                Funded by: doi http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;
                Award ID: BB/K008005/1
                Funded by: doi http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;
                Award ID: BB/P003281/1
                Funded by: doi http://dx.doi.org/10.13039/501100000289, Cancer Research UK;
                Award ID: C596/A17196, Award 23982
                Funded by: Multiple Sclerosis Society UK;
                Award ID: Grant Reference 38
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Microbiology
                Life Sciences
                Microbiology
                Custom metadata
                Nielsen Marquez

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