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Cell. 2019 Sep 5;178(6):1299-1312.e29. doi: 10.1016/j.cell.2019.08.003. Epub 2019 Aug 29.

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Author information

1
MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK.
2
Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK.
3
Institute for Experimental Medicine, Kiel University, 24105 Kiel, Germany.
4
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, 24105 Kiel, Germany.
5
Molecular and Functional Neurobiology, Department of Biology, KU Leuven, 3000 Leuven, Belgium.
6
UCL Cancer Institute, University College London, London WC1E 6JD, UK.
7
Laboratory of Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
8
MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
9
Department of Computer Science, University College London, London WC1E 6BT, UK.
10
Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
11
Institute of Epidemiology, Christian Albrechts University Kiel, 24105 Kiel, Germany.
12
Institute for Experimental Medicine, Kiel University, 24105 Kiel, Germany. Electronic address: c.kaleta@iem.uni-kiel.de.
13
MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK. Electronic address: f.cabreiro@lms.mrc.ac.uk.

Abstract

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.

KEYWORDS:

C. elegans; CRP signaling; Drosophila; aging; diet; humans; metabolic modeling; metformin; microbiome; type-2 diabetes

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