Article Text

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism
  1. Eugeni Belda1,2,
  2. Lise Voland1,
  3. Valentina Tremaroli3,
  4. Gwen Falony4,5,
  5. Solia Adriouch1,
  6. Karen E Assmann1,
  7. Edi Prifti6,
  8. Judith Aron-Wisnewsky1,7,
  9. Jean Debédat1,
  10. Tiphaine Le Roy1,
  11. Trine Nielsen8,
  12. Chloé Amouyal1,
  13. Sébastien André1,
  14. Fabrizio Andreelli1,
  15. Matthias Blüher9,
  16. Rima Chakaroun9,
  17. Julien Chilloux10,
  18. Luis Pedro Coelho11,12,
  19. Maria Carlota Dao1,
  20. Promi Das13,
  21. Soraya Fellahi14,15,
  22. Sofia Forslund16,
  23. Nathalie Galleron17,
  24. Tue H Hansen8,
  25. Bridget Holmes18,
  26. Boyang Ji13,
  27. Helle Krogh Pedersen8,
  28. Phuong Le1,
  29. Emmanuelle Le Chatelier17,
  30. Christian Lewinter19,
  31. Louise Mannerås-Holm3,
  32. Florian Marquet1,
  33. Antonis Myridakis20,
  34. Veronique Pelloux1,
  35. Nicolas Pons17,
  36. Benoit Quinquis17,
  37. Christine Rouault1,
  38. Hugo Roume17,
  39. Joe-Elie Salem21,
  40. Nataliya Sokolovska1,
  41. Nadja B Søndertoft8,
  42. Sothea Touch1,
  43. Sara Vieira-Silva4,5,
  44. The MetaCardis Consortium,
  45. Pilar Galan22,
  46. Jens Holst8,
  47. Jens Peter Gøtze23,
  48. Lars Køber19,
  49. Henrik Vestergaard8,24,
  50. Torben Hansen8,25,
  51. Serge Hercberg22,
  52. Jean-Michel Oppert7,
  53. Jens Nielsen13,
  54. Ivica Letunic26,
  55. Marc-Emmanuel Dumas27,28,
  56. Michael Stumvoll29,
  57. Oluf Borbye Pedersen8,
  58. Peer Bork11,12,
  59. Stanislav Dusko Ehrlich17,30,
  60. Jean-Daniel Zucker1,6,
  61. Fredrik Bäckhed3,
  62. Jeroen Raes4,5,
  63. Karine Clément1,7
    1. 1Nutrition and Obesities: Systemic Approaches, NutriOmics, Research Unit, Sorbonne Université, INSERM, Paris, France
    2. 2Integrative Phenomics, Paris, France
    3. 3Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Goteborg, Sweden
    4. 4Center for Microbiology, VIB, Leuven, Belgium
    5. 5Vlaams Instituut voor Biotechnologie, VIB-KU Leuven, Heverlee, Flanders, Belgium
    6. 6Unité de Modélisation Mathématique et Informatique des Systèmes Complexes, UMMISCO, Sorbonne Université, IRD, Bondy, France
    7. 7Department of Nutrition, Pitié-Salpêtrière Hospital, Assistance Publique - Hopitaux de Paris, Paris, France
    8. 8Center for Basic Metabolic Research, Novo Nordisk Foundation, University of Copenhagen, Kobenhavn, Denmark
    9. 9Medical Department III - Endocrinology, Nephrology, Rheumatology - Medical Center, Faculty of Medicine, University of Leipzig, Leipzig, Germany
    10. 10Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London Faculty of Medicine, London, UK
    11. 11Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany
    12. 12Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
    13. 13Department of Biology, Chalmers University of Technology, Goteborg, Sweden
    14. 14Functional Unit, Biochemistry and Hormonology Department, enon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
    15. 15Saint-Antoine Research Center, Sorbonne Université, INSERM, Paris, France
    16. 16Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch, Germany
    17. 17MetaGenoPolis, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
    18. 18Centre Daniel Carasso, Global Nutrition Department, Danone Nutricia Research, Palaiseau, France
    19. 19Department of Cardiology, Rigshospitalet, Kobenhavn, Denmark
    20. 20Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
    21. 21Department of Pharmacology and CIC-1421, Assistance Publique-Hôpitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
    22. 22Nutritional Epidemiology Unit, INSERM, INRAE, CNAM, Paris 13 University, Bobigny, France
    23. 23Department of Clinical Biochemistry, Rigshospitalet, Kobenhavn, Denmark
    24. 24Steno Diabetes Center, Copenhagen, Gentofte, Denmark
    25. 25Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
    26. 26Biobyte Solution, GmbH, Heidelberg, Germany
    27. 27Department of Surgery and Cancer, Section of Computational and Systems Medicine, Imperial College London, London, UK
    28. 28National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK
    29. 29Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, University of Leipzig Faculty of Medicine, Leipzig, Germany
    30. 30Center for Host Microbiome Interactions, King's College London Dental Institute, London, UK
    1. Correspondence to Professor Karine Clément, Nutrition and obesities: systemic approaches (NutriOmics), Sorbonne Université, Paris, Île-de-France, France; karine.clement2{at}


    Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.

    Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice.

    Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration.

    Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.

    Trial registration number NCT02059538.

    • obesity
    • micronutrients
    • nutrition
    • intestinal bacteria
    • diabetes mellitus

    Data availability statement

    Data are available in a public, open access repository. Data are available on reasonable request. metacardis,,, mouse experiments; 16S data,, mouse experiments; nanopore data,, Code paper analyses,

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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    Supplementary materials


    • Twitter @jeandbdt, @A_Myridakis, @BackhedLab

    • EB, LV, VT, GF, SA and KEA contributed equally.

    • JR and KC contributed equally.

    • Correction notice This article has been corrected since it published Online First. The author's name, Edi Prifti, has been corrected.

    • Collaborators The MetaCardis consortium Collaborators: Rohia Alili, Renato Alves, Ehm Astrid Andersson Galijatovic, Olivier Barthelemy, Jean-Philippe Bastard, Jean-Paul Batisse, Magalie Berland, Randa Bittar, Hervé Blottière, Frederic Bosquet, Rachid Boubrit, Olivier Bourron, Mickael Camus, Dominique Cassuto, Cecile Ciangura, Jean-Philippe Collet, Arne Dietrich, Morad Djebbar, Angélique Doré, Line Engelbrechtsen, Leopold Fezeu, Sebastien Fromentin, Philippe Giral, Marianne Graine, Caroline Grünemann, Agnes Hartemann, Bolette Hartmann, Gerard Helft, Malene Hornbak, Lesley Hoyles, Jean-Sebastien Hulot, Richard Isnard, Sophie Jaqueminet, Niklas Rye Jørgensen, Hanna Julienne, Johanne Justesen, Judith Kammer, Nikolaj Karup, Mathieu Kerneis, Jean Khemis, Lars Køber, Ruby Kozlowski, Michael Kuhn, Aurelie Lampure, Véronique Lejard, Ivica Letunic, Florence Levenez, Lajos Marko, Lea Lucas-Martini, Laura Martinez-Gili Robin Massey, Nicolas Maziers, Jonathan Medina-Stamminger, Lucas Moitinho-Silva, Gilles Montalescot, Sandrine Moutel, Ana Luisa Neves, Michael Olanipekun, Laetitia Pasero Le Pavin, Luis Pedro Coelho, Christine Poitou, Francoise Pousset, Laurence Pouzoulet, Andrea Rodriguez-Martinez, Sebastien Schmidt, Tatjana Schütz, Lucas Silva, Johanne Silvain, Mathilde Svendstrup, Timothy D Swartz, Thierry Vanduyvenboden, Camille Vatier, Eric O Verger, Stefanie Walther

    • Contributors EB, GF, JR and KC conceived and designed the project. EB and GF provided principal metagenomic analyses linked with patient phenotypes and adjusted for microbial cell loads. VT, LV, JD, TLR, CA and LM-H performed in vivo murine studies, provided murine biological samples, and their analyses. EB provided metagenomic analyses for in vivo murine studies. KEA and SA determined dietary analysis and patterns and associations with patient clinical phenotypes and inflammatory profiles, BH provided interpretations for dietary FFQ data, SA and FM performed analyses for intestinal inflammation and interpreted patient inflammatory data, VP provided molecular analyses for gene expression in human tissues, FA, MB, RC, JE-S, J-MO, JA-W, TN, KC and MS recruited patients and RC, JA-W and TN contributed to patient investigation and data management. SH and PG provided healthy volunteers from the NutriNet-Santé Study, EB, SF, ELC, GF, NP, EP, IL, JN, SV-S, BJ and PD developed databases, analytical pipelines and performed metagenomics and functional analysis. BQ and HR contributed to stool sample processing and sequencing all patient stool samples, CR, SAn and FM performed all measurements of inflammatory cells and systemic markers, and SFe performed the centralised measures of metabolic variables. JC and AM performed metabolomic measurements on patients, NBS provided network analyses to assist in interpreting data, J-DZ, SH, M-ED, JR, J-MO, OBP, PB, MS and SDE contributed to results’ discussion. EB, LV, VT, GF, SA, TLR, KEA, FB, JR and KC wrote the paper. All authors commented and edited the manuscript. KC is the guarantor who accepts full responsibility for the work and/or the conduct of the study, had access to all data, and controlled the decision to publish.

    • Funding This work was supported by European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 (METACARDIS). Funding supports were also obtained from Leducq Foundation(17CVD01), JPI-Microdiet study (2017-01996_3). Part of the work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG): SFB 1052 (project B1), the Fondation pour la Recherche Médicale (FDT201904008276, FDT202106012793), and the French Agency of Research (ANR-CAPTOR, ANR-DeepIntegromics).

    • Competing interests KC is a consultant for Danone Research, Ysopia and CONFO therapeutics for work not associated with this study. KC held a collaborative research contract with Danone Research in the context of MetaCardis project. FB is a shareholder of Implexion pharma AB. MB received lecture and/or consultancy fees from AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis and Sanofi.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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