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

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


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.