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

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Title: Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy
Authors: Pryor, R
Norvaisas, P
Marinos, G
Best, L
Bruun Thingholm, L
Quintaneiro, L
De Haes, W
Esser, D
Waschina, S
Lujan, C
Smith, RL
Scott, T
Martinez-Martinez, D
Woodward, O
Bryson, K
Laudes, M
Lieb, W
Houtkooper, RH
Franke, A
Temmerman, L
Bjedov, I
Cocheme, HM
Kaleta, C
Gomes Cabreiro, F
Item Type: Journal Article
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, impact 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 signalling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modelling 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
Issue Date: 23-Aug-2019
Date of Acceptance: 2-Aug-2019
URI: http://hdl.handle.net/10044/1/72748
ISSN: 0092-8674
Publisher: Elsevier (Cell Press)
Journal / Book Title: Cell
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 102531/Z/13/A
Keywords: 06 Biological Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Online Publication Date: 2019-09-09
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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