RRC ID 59576
Author Pryor R, Norvaisas P, Marinos G, Best L, Thingholm LB, Quintaneiro LM, De Haes W, Esser D, Waschina S, Lujan C, Smith RL, Scott TA, Martinez-Martinez D, Woodward O, Bryson K, Laudes M, Lieb W, Houtkooper RH, Franke A, Temmerman L, Bjedov I, Cochemé HM, Kaleta C, Cabreiro F.
Title Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.
Journal Cell
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.
Volume 178(6)
Pages 1299-1312.e29
Published 2019-9-5
DOI 10.1016/j.cell.2019.08.003
PII S0092-8674(19)30891-8
PMID 31474368
PMC PMC6736778
MeSH Agmatine / metabolism Animals Caenorhabditis elegans / microbiology Cyclic AMP Receptor Protein Diabetes Mellitus, Type 2 / drug therapy* Escherichia coli / drug effects Escherichia coli / genetics Gastrointestinal Microbiome / drug effects* Host Microbial Interactions / drug effects* Humans Hypoglycemic Agents / pharmacology Hypoglycemic Agents / therapeutic use* Lipid Metabolism / drug effects Longevity / drug effects Metformin / pharmacology Metformin / therapeutic use* Nutrients / metabolism
IF 36.216
Times Cited 20
C.elegans tm1133 tm1108