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

Kristoffer Forslund; Falk Hildebrand; Trine Nielsen; Gwen Falony; Emmanuelle Le Chatelier; Shinichi Sunagawa; Edi Prifti; Sara Vieira-Silva; Valborg Gudmundsdottir; Helle Krogh Pedersen; Manimozhiyan Arumugam; Karsten Kristiansen; Anita Yvonne Voigt; Henrik Vestergaard; Rajna Hercog; Paul Igor Costea; Jens Roat Kultima; Junhua Li; Torben Jørgensen; Florence Levenez; Joël Dore; Henrik Bjørn Nielsen; Søren Brunak; Jeroen Raes; Torben Hansen; Jun Wang; S. Dusko Ehrlich; Peer Bork; Oluf Borbye Pedersen

doi:10.1038/nature15766

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

Kristoffer Forslund, Falk Hildebrand, Trine Nielsen, Gwen Falony, Emmanuelle Le Chatelier, Shinichi Sunagawa, Edi Prifti, Sara Vieira-Silva, Valborg Gudmundsdottir, Helle Krogh Pedersen, Manimozhiyan Arumugam, Karsten Kristiansen, Anita Yvonne Voigt, Henrik Vestergaard, Rajna Hercog, Paul Igor Costea, Jens Roat Kultima, Junhua Li, Torben Jørgensen, Florence LevenezJoël Dore, Henrik Bjørn Nielsen, Søren Brunak, Jeroen Raes, Torben Hansen, Jun Wang, S. Dusko Ehrlich, Peer Bork, Oluf Borbye Pedersen

856 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	528
Udgave nummer	7581
Sider (fra-til)	262-266
Antal sider	5
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature15766
Status	Udgivet - 10 dec. 2015

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Forslund, K., Hildebrand, F., Nielsen, T., Falony, G., Le Chatelier, E., Sunagawa, S., Prifti, E., Vieira-Silva, S., Gudmundsdottir, V., Pedersen, H. K., Arumugam, M., Kristiansen, K., Yvonne Voigt, A., Vestergaard, H., Hercog, R., Igor Costea, P., Roat Kultima, J., Li, J., Jørgensen, T., ... Pedersen, O. B. (2015). Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature, 528(7581), 262-266. https://doi.org/10.1038/nature15766

Forslund, K, Hildebrand, F, Nielsen, T, Falony, G, Le Chatelier, E, Sunagawa, S, Prifti, E, Vieira-Silva, S, Gudmundsdottir, V, Pedersen, HK, Arumugam, M , Kristiansen, K, Yvonne Voigt, A, Vestergaard, H, Hercog, R, Igor Costea, P, Roat Kultima, J, Li, J, Jørgensen, T, Levenez, F, Dore, J, Nielsen, HB, Brunak, S, Raes, J, Hansen, T, Wang, J, Dusko Ehrlich, S, Bork, P & Pedersen, OB 2015, 'Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota', Nature, bind 528, nr. 7581, s. 262-266. https://doi.org/10.1038/nature15766

@article{ba868295ac1b49d5937002048700fa50,

title = "Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota",

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.",

author = "Kristoffer Forslund and Falk Hildebrand and Trine Nielsen and Gwen Falony and {Le Chatelier}, Emmanuelle and Shinichi Sunagawa and Edi Prifti and Sara Vieira-Silva and Valborg Gudmundsdottir and Pedersen, {Helle Krogh} and Manimozhiyan Arumugam and Karsten Kristiansen and {Yvonne Voigt}, Anita and Henrik Vestergaard and Rajna Hercog and {Igor Costea}, Paul and {Roat Kultima}, Jens and Junhua Li and Torben J{\o}rgensen and Florence Levenez and Jo{\"e}l Dore and Nielsen, {Henrik Bj{\o}rn} and S{\o}ren Brunak and Jeroen Raes and Torben Hansen and Jun Wang and {Dusko Ehrlich}, S. and Peer Bork and Pedersen, {Oluf Borbye}",

year = "2015",

month = dec,

day = "10",

doi = "10.1038/nature15766",

language = "English",

volume = "528",

pages = "262--266",

journal = "Nature",

issn = "0028-0836",

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T1 - Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota

AU - Forslund, Kristoffer

AU - Hildebrand, Falk

AU - Nielsen, Trine

AU - Falony, Gwen

AU - Le Chatelier, Emmanuelle

AU - Sunagawa, Shinichi

AU - Prifti, Edi

AU - Vieira-Silva, Sara

AU - Gudmundsdottir, Valborg

AU - Pedersen, Helle Krogh

AU - Arumugam, Manimozhiyan

AU - Kristiansen, Karsten

AU - Yvonne Voigt, Anita

AU - Vestergaard, Henrik

AU - Hercog, Rajna

AU - Igor Costea, Paul

AU - Roat Kultima, Jens

AU - Li, Junhua

AU - Jørgensen, Torben

AU - Levenez, Florence

AU - Dore, Joël

AU - Nielsen, Henrik Bjørn

AU - Brunak, Søren

AU - Raes, Jeroen

AU - Hansen, Torben

AU - Wang, Jun

AU - Dusko Ehrlich, S.

AU - Bork, Peer

AU - Pedersen, Oluf Borbye

PY - 2015/12/10

Y1 - 2015/12/10

N2 - 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.

AB - 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.

U2 - 10.1038/nature15766

DO - 10.1038/nature15766

M3 - Journal article

C2 - 26633628

SN - 0028-0836

VL - 528

SP - 262

EP - 266

JO - Nature

JF - Nature

IS - 7581

ER -

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

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