Screen Identifies Bacterial Effectors of Metformin Therapy

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Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy
Rosina Pryor
Povilas Norvaisas
Georgios Marinos 12
Lena Best 12
Louise B. Thingholm 12
Leonor M. Quintaneiro 12
Wouter De Haes 12
Daniela Esser
Silvio Waschina
Celia Lujan
Reuben L. Smith
Timothy A. Scott
Daniel Martinez-Martinez
Orla Woodward
Kevin Bryson
Matthias Laudes
Wolfgang Lieb
Riekelt H. Houtkooper
Andre Franke
Liesbet Temmerman
Ivana Bjedov
Helena M. Cochemé
Christoph Kaleta 13
Filipe Cabreiro 13, 14
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Open AccessPublished:August 29, 2019DOI:https://doi.org/10.1016/j.cell.2019.08.003

Highlights
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A high-throughput method for investigating host-microbe-drug-nutrient interactions
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Metformin host effects are regulated by a bacterial nutrient signaling pathway
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Metabolic modeling of human gut microbiomes links metformin to microbial agmatine
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Metformin-bacterial interactions engage host lipid metabolism to extend lifespan
Summary
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.