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

Kristoffer Forslund (1) , Falk Hildebrand (2, 1, 3) , Trine Nielsen (4) , Gwen Falony (2, 5) , Emmanuelle Le Chatelier (6, 7) , Shinichi Sunagawa (1) , Edi Prifti (6, 7, 8) , Sara Vieira-Silva (2, 5) , Valborg Gudmundsdottir (9) , Helle Krogh Pedersen (9) , Manimozhiyan Arumugam (4) , Karsten Kristiansen (10) , Anita Yvonne Voigt (1, 11, 12) , Henrik Vestergaard (4) , Rajna Hercog (1) , Paul Igor Costea (1) , Jens Roat Kultima (1) , Junhua Li (13) , Torben Jorgensen (14, 15, 16) , Florence Levenez (6, 7) , Joel Dore (6, 7) , Metahit Consortium , H. Bjorn Nielsen (9) , Soren Brunak (9, 17) , Jeroen Raes (2, 3, 5) , Torben Hansen (4, 18) , Jun Wang (13, 10, 19, 20, 21) , Dusko S Ehrlich (6, 22) , Peer Bork (23, 1, 24, 11) , Oluf Pedersen (4) , Mathieu Almeida (6, 7) , Jean-Michel J.-M. Batto (7, 6) , Hervé H Blottiere (6, 7) , Antonietta Cultrone (6) , Christine Delorme (6) , Rozenn Derwyn (6) , Eric Guédon (6) , Florence Haimet (6, 7) , Alexandre Jamet (6) , Catherine Juste (6) , Sean P. Kennedy (6, 7) , Ghalia G. Kaci (6) , Séverine Layec (25) , Marion Leclerc (6) , Pierre Léonard (6, 7) , Emmanuelle Maguin (26) , Nicolas Pons (7, 6) , Pierre Renault (6) , Nicolas Sanchez (6) , Maarten van de Guchte (6) , Johan van Hylckama Vlieg (6) , Gaetana Vandemeulebrouck (6) , Yohanan Winogradsky (6)

1 Structural and Computational Biology Unit
2 VIB Center for the Biology of Disease
3 Department of Bioscience Engineering
4 CBMR - Novo Nordisk Foundation Center for Basic Metabolic Research
5 Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology
6 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
7 MetaGenoPolis
8 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
9 Department of Systems Biology, Center for Biological Sequence Analysis
10 Department of Biology [Copenhagen]
11 Molecular Medicine Partnership Unit
12 Department of Applied Tumor Biology, Institute of Pathology
13 BGI - Beijing Genomics Institute [Shenzhen]
14 Faculty of Medicine
15 Research Centre for Prevention and Health
16 Department of Public Health [Copenhagen]
17 Disease Systems Biology [Copenhagen]
18 Faculty of Health Sciences
19 MUST - Macau University of Science and Technology
20 Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology
21 Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders
22 Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy’s Hospital
23 MDC - Max Delbrück Center for Molecular Medicine [Berlin]
24 Department of Bioinformatics
25 GMPA - Génie et Microbiologie des Procédés Alimentaires
26 MICA - Département Microbiologie et Chaîne Alimentaire

In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported(1,2). 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(3,4). 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(3,4). 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.

Domaines: Médecine humaine et pathologie

Kristoffer Forslund, Falk Hildebrand, Trine Nielsen, Gwen Falony, Emmanuelle Le Chatelier, et al.. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature, 2015, 528 (7581), pp.266-273. ⟨10.1038/nature15766⟩. ⟨hal-01535324⟩