Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study (original) (raw)

Data availability

The data that support the findings of this study are available upon request. All figures are provided with individual values to have a direct access to the raw data. The 16S sequencing datasets generated during the current study are available from the European Genome-Phenome Archive (https://ega-archive.org/) under accession no. EGAS00001003585.

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Acknowledgements

We thank A. Barrois for the excellent technical assistance. We are very grateful to M. Buysschaert for his continuous support and helpful criticism during the preparation of this project. We also thank the volunteers who participated in this study. P.D.C. is a senior research associate at Fonds de la Recherche Scientifique (FRS-FNRS). A.E. is a research associated at FRS-FNRS. C. Druart was supported by a FIRST Spin-Off grant from the Walloon Region (no. 1410053). Research in the Wageningen laboratory of W.M.d.V. was partially supported by a European Research Council (ERC) Advanced Grant no. 250172 (Microbes Inside), the SIAM Gravity Grant no. 024.002.002 and the Spinoza Award of the Netherlands Organization for Scientific Research. P.D.C. is the recipient of grants from the FNRS (nos. J.0084.15 and 3.4579.11) and Projet de Recherche (no. T.0138.14) and FRFS-WELBIO grants (no. WELBIO-CR-2017C-02). This work was supported by the Funds Baillet Latour (Grant for Medical Research 2015), a prize of the Banque Transatlantique Belgium and a FIRST Spin-Off grant from the Walloon Region (no. 1410053). P.D.C. is a recipient of the PoC ERC grant 2016 (no. Microbes4U_713547) and ERC Starting Grant 2013 (no. 336452-ENIGMO). P.D.C. and J.R. are recipients of a grant from the FNRS and FWO (EOS program no. 30770923).

Author information

Author notes

  1. These authors contributed equally: Clara Depommier, Amandine Everard.
  2. These authors jointly supervised this work: Marie de Barsy, Audrey Loumaye, Michel P. Hermans, Jean-Paul Thissen, Willem M. de Vos.

Authors and Affiliations

  1. Metabolism and Nutrition Research Group, Louvain Drug Research Institute, WELBIO, Walloon Excellence in Life Sciences and BIOtechnology, UCLouvain, Université catholique de Louvain, Brussels, Belgium
    Clara Depommier, Amandine Everard, Céline Druart, Hubert Plovier, Matthias Van Hul & Patrice D. Cani
  2. Laboratory of Molecular Bacteriology—Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    Sara Vieira-Silva, Gwen Falony & Jeroen Raes
  3. Center for Microbiology, VIB, Leuven, Belgium
    Sara Vieira-Silva, Gwen Falony & Jeroen Raes
  4. Pôle EDIN, Institut de Recherches Expérimentales et Cliniques, UCLouvain, Université catholique de Louvain, Louvain-la-Neuve, Belgium
    Dominique Maiter, Marie de Barsy, Audrey Loumaye, Michel P. Hermans & Jean-Paul Thissen
  5. Division of Endocrinology and Nutrition, Cliniques universitaires St-Luc, Brussels, Belgium
    Dominique Maiter, Marie de Barsy, Audrey Loumaye, Michel P. Hermans & Jean-Paul Thissen
  6. Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
    Nathalie M. Delzenne
  7. Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands
    Willem M. de Vos
  8. Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
    Willem M. de Vos

Authors

  1. Clara Depommier
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  2. Amandine Everard
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  3. Céline Druart
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  4. Hubert Plovier
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  5. Matthias Van Hul
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  6. Sara Vieira-Silva
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  7. Gwen Falony
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  8. Jeroen Raes
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  9. Dominique Maiter
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  10. Nathalie M. Delzenne
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  11. Marie de Barsy
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  12. Audrey Loumaye
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  13. Michel P. Hermans
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  14. Jean-Paul Thissen
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  15. Willem M. de Vos
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  16. Patrice D. Cani
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Contributions

P.D.C. conceived the project. J.-P.T., M.P.H., A.L., D.M., A.E., C. Depommier, C. Druart, H.P., M.V.H., W.M.d.V. and P.D.C. designed the clinical study. P.D.C. supervised the clinical part of the study and W.M.d.V. contributed to the microbial culturing of A. muciniphila. P.D.C., A.E., C. Depommier, C. Druart, M.d.B., J.-P.T., A.L., D.M. and M.P.H. performed the clinical part of the study. N.M.D. contributed to interpretation of the results. S.V.-S., G.F. and J.R. performed the fecal microbiome sequencing and analysis. P.D.C., A.E. and C. Depommier performed the experiments and interpreted all the results. P.D.C., A.E. and C. Depommier generated the figures and tables. P.D.C. and C. Depommier wrote the manuscript. All authors discussed the results and approved the manuscript.

Corresponding author

Correspondence toPatrice D. Cani.

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Competing interests

A.E., C. Druart, H.P., P.D.C. and W.M.d.V. are inventors of patent applications (nos. PCT/EP2013/073972, PCT/EP2016/071327 and PCT/EP2016/060033 filed with the European Patent Office, Australia, Brazil, Canada, China, the Eurasian Patent Organization, Israel, India, Hong Kong, Japan, South Korea, Mexico, New Zealand and the United States) dealing with the use of A. muciniphila and its components in the context of obesity and related disorders. P.D.C. and W.M.d.V. are cofounders of A-Mansia Biotech S.A.

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Peer Review Information: Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Flow chart of the interventional study.

Diagram of the participant selection procedure, which includes the following information: number of individuals enrolled at each step of the study progress; number of individuals included in the final analysis; details of the events that led to a reduction in group size.

Extended Data Fig. 2 Changes in inflammatory parameters and GLP-1.

a, Soluble CD40 Ligand. b, Growth-related oncogene (CXCL1). c, MCP1. d, GLP-1. Differential values (mean difference and mean difference from placebo) are expressed as the mean + s.e.m., either as raw data or as percentages. The bars represent the mean change from baseline value per group, with their s.e.m. Mann–Whitney _U_-tests or unpaired _t_-tests were performed to compare the differential values of both treated groups versus the placebo group (intergroup changes), according to the distribution. The respective P values are shown in the table below each plot. The lines represent the raw values before and after 3 months of supplementation. The distribution of values within each group for each timing is illustrated by a box-and-whisker plot. In the box plots, the line in the middle of the box is plotted at the median, and the inferior and superior limits of the box correspond to the 25th and the 75th percentiles respectively. Matched-pairs Wilcoxon signed-rank tests or paired _t_-tests were performed to verify changes from baseline (intragroup changes), according to the distribution; when drawn, the capped line above the group concerned shows the corresponding P value. Changes between 0 and 3 months across the 3 groups were analyzed with Kruskal–Wallis or one-way ANOVA tests according to the distribution; group-wise comparisons were performed using Bonferroni’s and Tukey’s corrections for multiple testing, respectively. Placebo group, n = 11; pasteurized bacteria group, n = 12; live bacteria group, n = 9 for all parameters except for growth-related oncogene: placebo group, n = 7; pasteurized bacteria group, n = 10; live bacteria group, n = 8. All tests were two-tailed.

Extended Data Fig. 3 Changes in fecal microbiome.

a, Akkermansia muciniphila abundance in feces evaluated by quantitative PCR. Differential values (mean difference and mean difference from placebo) are expressed as the mean ± s.e.m. as raw data. The bars represent the mean change from baseline value per group, with their s.e.m. Mann–Whitney _U_-tests were performed to compare the differential values of both treated groups versus the placebo group (intergroup changes) according to the distribution. The respective P values are shown in the table below each plot. The lines represent the raw values before and after 3 months of supplementation. The distribution of values within each group for each timing is illustrated by a box-and-whisker plot. In the box plots, the line in the middle of the box is plotted at the median, and the inferior and superior limits of the box correspond to the 25th and the 75th percentiles, respectively. Matched-pairs Wilcoxon signed-rank tests were performed to verify changes from baseline (intragroup changes) according to the distribution. When the difference is significant, a capped line is marked above the group concerned with the corresponding P value. Kruskal–Wallis analyses were used to compare changes between 0 and 3 months across the 3 groups according to the distribution. Placebo group, n = 11; pasteurized bacteria group, n = 12; live bacteria, n = 9. All tests were two-tailed. *P < 0.05. b, Visualization of participants’ fecal microbiota composition at baseline and end point of the intervention. Fecal microbiota dissimilarity between samples is represented by principal coordinates analysis (genus-level Aitchison distance), with six sample groups corresponding to the three different treatment arms at baseline or at end point represented by confidence ellipses (80% confidence interval). Intervention effects are symbolized by the colored arrows, with direction and length corresponding to the shift in group centroid coordinates from baseline to end point for each treatment arm (rescaled ×4 and re-centered at the baseline global centroid). Placebo group, n = 11; pasteurized bacteria group, n = 12; live bacteria, n = 9.

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Depommier, C., Everard, A., Druart, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.Nat Med 25, 1096–1103 (2019). https://doi.org/10.1038/s41591-019-0495-2

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