Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.
Agmatine
/ metabolism
Animals
Caenorhabditis elegans
/ microbiology
Cyclic AMP Receptor Protein
Diabetes Mellitus, Type 2
/ drug therapy
Escherichia coli
/ drug effects
Gastrointestinal Microbiome
/ drug effects
Host Microbial Interactions
/ drug effects
Humans
Hypoglycemic Agents
/ pharmacology
Lipid Metabolism
/ drug effects
Longevity
/ drug effects
Metformin
/ pharmacology
Nutrients
/ metabolism
C. elegans
CRP signaling
Drosophila
aging
diet
humans
metabolic modeling
metformin
microbiome
type-2 diabetes
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
05 09 2019
05 09 2019
Historique:
received:
29
10
2018
revised:
08
07
2019
accepted:
02
08
2019
pubmed:
3
9
2019
medline:
17
6
2020
entrez:
3
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31474368
pii: S0092-8674(19)30891-8
doi: 10.1016/j.cell.2019.08.003
pmc: PMC6736778
pii:
doi:
Substances chimiques
Cyclic AMP Receptor Protein
0
Hypoglycemic Agents
0
Agmatine
70J407ZL5Q
Metformin
9100L32L2N
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1299-1312.e29Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1102/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1605/6
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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