@article {Ormsby2020.08.02.232447, author = {Michael J. Ormsby and Heather Hulme and Victor H. Villar and Gregory Hamm and Giovanny Rodriguez-Blanco and Ryan A. Bragg and Nicole Strittmatter and Christopher J. Schofield and Christian Delles and Ian P. Salt and Saverio Tardito and Richard Burchmore and Richard J. A. Goodwin and Daniel M. Wall}, title = {Microbiome-derived metabolites reproduce the mitochondrial dysfunction and decreased insulin sensitivity observed in type 2 diabetes}, elocation-id = {2020.08.02.232447}, year = {2020}, doi = {10.1101/2020.08.02.232447}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2020/08/02/2020.08.02.232447}, eprint = {https://www.biorxiv.org/content/early/2020/08/02/2020.08.02.232447.full.pdf}, journal = {bioRxiv} }