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

Hulme, H. et al. (2020) Microbiome-derived carnitine mimics as novel mediators of gut-brain axis communication. Science Advances, 6(11), eaax6328. (doi: 10.1126/sciadv.aax6328)

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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.

Item Type:Articles
Additional Information:Funding: This work was supported by a Biotechnology and Biological Sciences Research Council (BBSRC)–CASE studentship part funded by AstraZeneca (to R.B., D.M.W., and R.J.A.G.) and BBSRC grants BB/K008005/1 and BB/P003281/1 (to D.M.W.). E.K.O. was supported by a Wellcome Trust/Royal Society Sir Henry Dale fellowship 104116/Z/14/Z. S.T. was supported by the Cancer Research UK (C596/A17196, award 23982). J.M.E. was funded by the Multiple Sclerosis Society UK (Grant Ref 38). The Manchester Gnotobiotic Facility was established with the support of the Wellcome Trust (097820/Z/11/B).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio and Ormsby, Dr Michael and Wall, Dr Daniel and Milling, Professor Simon and HULME, Heather and Douce, Dr Gillian and Goodwin, Dr Richard and Walker, Professor Daniel and Burchmore, Dr Richard and Edgar, Dr Julia and Van Der Hooft, Mr Justin and Meikle, Dr Lynsey and Kamat, Miss Maya
Authors: Hulme, H., Meikle, L. M., Strittmatter, N., van der Hooft, J. J.J., Swales, J., Bragg, R. A., Villar, V. H., Ormsby, M. J., Barnes, S., Brown, S. L., Dexter, A., Kamat, M. T., Komen, J. C., Walker, D., Milling, S., Osterweil, E. K., MacDonald, A. S., Schofield, C. J., Tardito, S., Bunch, J., Douce, G., Edgar, J. M., Edrada-Ebel, R., Goodwin, R. J.A., Burchmore, R., and Wall, D. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Science Advances 6(11):eaax6328
Publisher Policy:Reproduced under a Creative Commons license
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167488Survival and dissemination of enteric pathogens through exploitation and inhibition of programmed cell death pathways in circulating immune cells.Daniel WallBiotechnology and Biological Sciences Research Council (BBSRC)BB/K008005/1III - Bacteriology
173261Propionic acid use in agriculture and food production is driving evolution of novel Escherichia coli pathotypesDaniel WallBiotechnology and Biological Sciences Research Council (BBSRC)BB/P003281/1III - Bacteriology