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.
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Forslund
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.|Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Bioscience Engineering, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Falk
authors.initials: F
authors.lastname: Hildebrand
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Nielsen
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Leuven, Belgium.
authors.forename: Gwen
authors.initials: G
authors.lastname: Falony
authors.affiliation: MICALIS, Institut National de la Recherche Agronomique, Jouy en Josas, France.|Metagenopolis, Institut National de la Recherche Agronomique, Jouy en Josas, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Le Chatelier
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sunagawa
authors.affiliation: MICALIS, Institut National de la Recherche Agronomique, Jouy en Josas, France.|Metagenopolis, Institut National de la Recherche Agronomique, Jouy en Josas, France.|Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Edi
authors.initials: E
authors.lastname: Prifti
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Leuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Vieira-Silva
authors.affiliation: Center for Biological Sequence Analysis, Dept. of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Valborg
authors.initials: V
authors.lastname: Gudmundsdottir
authors.affiliation: Center for Biological Sequence Analysis, Dept. of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Helle K
authors.initials: HK
authors.lastname: Pedersen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Manimozhiyan
authors.initials: M
authors.lastname: Arumugam
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.|Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit , University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Anita Yvonne
authors.initials: AY
authors.lastname: Voigt
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Vestergaard
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Rajna
authors.initials: R
authors.lastname: Hercog
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Paul Igor
authors.initials: PI
authors.lastname: Costea
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Jens Roat
authors.initials: JR
authors.lastname: Kultima
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Li
authors.affiliation: Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.|Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.affiliation: MICALIS, Institut National de la Recherche Agronomique, Jouy en Josas, France.|Metagenopolis, Institut National de la Recherche Agronomique, Jouy en Josas, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Levenez
authors.affiliation: MICALIS, Institut National de la Recherche Agronomique, Jouy en Josas, France.|Metagenopolis, Institut National de la Recherche Agronomique, Jouy en Josas, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Dore
authors.affiliation: Center for Biological Sequence Analysis, Dept. of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: H Bjørn
authors.initials: HB
authors.lastname: Nielsen
authors.affiliation: Center for Biological Sequence Analysis, Dept. of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark.|Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.|Department of Bioscience Engineering, Vrije Universiteit Brussel, Brussels, Belgium.|KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Raes
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.|BGI-Shenzhen, Shenzhen, China.|Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.|Macau University of Science and Technology, Avenida Wai long, Taipa, Macau, China.|Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: MICALIS, Institut National de la Recherche Agronomique, Jouy en Josas, France.|Metagenopolis, Institut National de la Recherche Agronomique, Jouy en Josas, France.|King's College London, Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy's Hospital, United Kingdom.
authors.forename: S Dusko
authors.initials: SD
authors.lastname: Ehrlich
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D044822:Biodiversity; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000382:microbiology*; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D054892:Metagenome / Q000187:drug effects / Q000502:physiology; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D012336:RNA, Ribosomal, 16S / Q000235:genetics
chemical_list: D007004:Hypoglycemic Agents; D012336:RNA, Ribosomal, 16S; D008687:Metformin