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

Heather Hulme, Lynsey M. Meikle, Nicole Strittmatter, Justin J. J. van der Hooft, John Swales, Ryan A. Bragg, Victor H. Villar, Michael J. Ormsby, Stephanie Barnes, Sheila L. Brown, Alex Dexter, Maya T. Kamat, Jasper C. Komen, Daniel Walker, Simon Milling, Emily K. Osterweil, Andrew S. MacDonald, Chris J. Schofield, Saverio Tardito, Josephine BunchGillian Douce, Julia M. Edgar, RuAngelie Edrada-Ebel, Richard J.A. Goodwin, Richard Burchmore, Daniel M. Wall

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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.

Original languageEnglish
Article numbereaax6328
Number of pages11
JournalScience Advances
Volume6
Issue number11
DOIs
Publication statusPublished - 11 Mar 2020

Keywords

  • gut microbiome
  • carnitine
  • microbial metabolites

Cite this

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., ... Wall, D. M. (2020). Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication. Science Advances, 6(11), [eaax6328]. https://doi.org/10.1126/sciadv.aax6328