Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy

Pryor, R. et al. (2019) Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy. Cell, 178(6), 1299-1312.e29. (doi: 10.1016/j.cell.2019.08.003) (PMID:31474368) (PMCID:PMC6736778)

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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.

Item Type:Articles
Additional Information:F.C. acknowledges funding from the Wellcome Trust/Royal Society (102531/Z/13/Z and 102531/Z/13/A), C.K. from the German Research Foundation (CRC 1182 “Metaorganisms,” Excellence Cluster “Inflammation at Interfaces [EXC306]), H.M.C. from the MRC (MC-A654-5QB90), W.D.H. and L.T. from FWO Flanders, and I.B. from ERC StG 311331 and ERC PoC 842174.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bryson, Dr Kevin
Creator Roles:
Bryson, K.Software, Formal analysis, Supervision
Authors: Pryor, R., Norvaisas, P., Marinos, G., Best, L., Thingholm, L. B., Quintaneiro, L. M., De Haes, W., Esser, D., Waschina, S., Lujan, C., Smith, R. L., Scott, T. A., Martinez-Martinez, D., Woodward, O., Bryson, K., Laudes, M., Lieb, W., Houtkooper, R. H., Franke, A., Temmerman, L., Bjedov, I., Cochemé, H. M., Kaleta, C., and Cabreiro, F.
College/School:College of Science and Engineering > School of Computing Science
Journal Name:Cell
Publisher:Elsevier
ISSN:0092-8674
ISSN (Online):1097-4172
Published Online:29 August 2019
Copyright Holders:Copyright: © 2019 The Authors
First Published:First published in Cell 178(6): 1299-1312.e29
Publisher Policy:Reproduced under a Creative Commons licence

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