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Microbiome-derived metabolites reproduce the mitochondrial dysfunction and decreased insulin sensitivity observed in type 2 diabetes

Michael J. Ormsby, Heather Hulme, Victor H. Villar, Gregory Hamm, Giovanny Rodriguez-Blanco, Ryan A. Bragg, Nicole Strittmatter, Christopher J. Schofield, Christian Delles, Ian P. Salt, Saverio Tardito, Richard Burchmore, Richard J. A. Goodwin, View ORCID ProfileDaniel M. Wall
doi: https://doi.org/10.1101/2020.08.02.232447
Michael J. Ormsby
1Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, United Kingdom
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Heather Hulme
2Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
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Victor H. Villar
3Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom
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Gregory Hamm
2Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
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Giovanny Rodriguez-Blanco
3Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom
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Ryan A. Bragg
4Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
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Nicole Strittmatter
2Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
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Christopher J. Schofield
5Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom
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Christian Delles
6Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom
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Ian P. Salt
6Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom
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Saverio Tardito
3Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom
7Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom
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Richard Burchmore
1Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, United Kingdom
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Richard J. A. Goodwin
2Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
1Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, United Kingdom
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Daniel M. Wall
1Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, United Kingdom
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  • ORCID record for Daniel M. Wall
  • For correspondence: donal.wall@glasgow.ac.uk
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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 Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Lead contact email: Donal.Wall{at}glasgow.ac.uk, Lead contact address: Dr. Daniel M. Wall, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 02, 2020.
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Microbiome-derived metabolites reproduce the mitochondrial dysfunction and decreased insulin sensitivity observed in type 2 diabetes
Michael J. Ormsby, Heather Hulme, Victor H. Villar, Gregory Hamm, Giovanny Rodriguez-Blanco, Ryan A. Bragg, Nicole Strittmatter, Christopher J. Schofield, Christian Delles, Ian P. Salt, Saverio Tardito, Richard Burchmore, Richard J. A. Goodwin, Daniel M. Wall
bioRxiv 2020.08.02.232447; doi: https://doi.org/10.1101/2020.08.02.232447
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Microbiome-derived metabolites reproduce the mitochondrial dysfunction and decreased insulin sensitivity observed in type 2 diabetes
Michael J. Ormsby, Heather Hulme, Victor H. Villar, Gregory Hamm, Giovanny Rodriguez-Blanco, Ryan A. Bragg, Nicole Strittmatter, Christopher J. Schofield, Christian Delles, Ian P. Salt, Saverio Tardito, Richard Burchmore, Richard J. A. Goodwin, Daniel M. Wall
bioRxiv 2020.08.02.232447; doi: https://doi.org/10.1101/2020.08.02.232447

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