RT Journal Article SR Electronic T1 Microbiome-derived metabolites reproduce the mitochondrial dysfunction and decreased insulin sensitivity observed in type 2 diabetes JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.08.02.232447 DO 10.1101/2020.08.02.232447 A1 Michael J. Ormsby A1 Heather Hulme A1 Victor H. Villar A1 Gregory Hamm A1 Giovanny Rodriguez-Blanco A1 Ryan A. Bragg A1 Nicole Strittmatter A1 Christopher J. Schofield A1 Christian Delles A1 Ian P. Salt A1 Saverio Tardito A1 Richard Burchmore A1 Richard J. A. Goodwin A1 Daniel M. Wall YR 2020 UL http://biorxiv.org/content/early/2020/08/02/2020.08.02.232447.abstract AB Diabetes is a global health problem that was estimated to be the 7th leading cause of death worldwide in 2016. Type 2 diabetes mellitus (T2DM) is classically associated with genetic and environmental factors, however recent studies have demonstrated that the gut microbiome, which is altered in T2DM patients, is also likely to play a significant role in disease development. Despite this, the identity of microbiome-derived metabolites that influence T2DM onset and/or progression remain elusive. Here we demonstrate that a serum biomarker for T2DM, previously of unknown structure and origin, is actually two microbiome-derived metabolites, 3-methyl-4-(trimethylammonio)butanoate (3M-4-TMAB) and 4-(trimethylammonio)pentanoate (4-TMAP). These metabolites are produced by the Lachnospiraceae family of bacteria, which are highly prevalent in the gut microbiome of T2DM patients and are associated with high dietary fat intake. Treatment of human liver cells with 3M-4-TMAB and 4-TMAP results in a distinct change in the acylcarnitine profile in these cells and significantly reduced their insulin sensitivity; both indicators of T2DM. These results provide evidence of a mechanistic link between gut microbiome derived metabolites and T2DM.Competing Interest StatementThe authors have declared no competing interest.