Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota

MetaHIT Consortium

Research output: Contribution to journalArticlepeer-review

1205 Citations (Scopus)

Abstract

In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.

Original languageEnglish
Pages (from-to)262-266
Number of pages5
JournalNature
Volume528
Issue number7581
DOIs
Publication statusPublished - 10 Dec 2015

Bibliographical note

Funding Information:
Acknowledgements The authors wish to thank A. Forman, T. Lorentzen, B. Andreasen, G. J. Klavsen and M. J. Nielsen for technical assistance, and T. F. Toldsted and G. Lademann for management assistance. J. Nielsen and F. Bäckhed are thanked for providing access to T2D metagenome data and metformin treatment status before publication4. V. Benes and the GeneCore facility of EMBL Heidelberg are thanked for their assistance with the metformin signature validation experiments, as is Y. Yuan for assistance with computer infrastructure. This research has received funding from European Community’s Seventh Framework Program (FP7/2007-2013): MetaHIT, grant agreement HEALTH-F4-2007-201052, MetaCardis, grant agreement HEALTH-2012-305312, International Human Microbiome Standards, grant agreement HEALTH-2010-261376, as well as from the Metagenopolis grant ANR-11-DPBS-0001, from the European Research Council CancerBiome project, contract number 268985, and from the European Union HORIZON 2020 programme, under Marie Skłodowska-Curie grant agreement 600375. Additional funding came from The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCamp, http://www.lucamp.org), the Novo Nordisk Foundation (grant NNF14CC0001), and the European Molecular Biology Laboratory (EMBL). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk). Additional funding for the validation experiments was provided by the Innovation Fund Denmark through the MicrobDiab project.

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

Fingerprint

Dive into the research topics of 'Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota'. Together they form a unique fingerprint.

Cite this