A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice | Nature Medicine

qianfengnh 2018-07-19

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Abstract

Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition^{1,2,3,4,5,6,7}. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications⁸. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine⁹. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.

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Acknowledgements

We wish to thank A. Barrois, H. Danthinne, M. De Barsy, R.-M. Goebbels and T. Pringels for excellent technical assistance; S. Matamoros for helpful discussion and aid during tissue sampling; and the individuals who participated in this study. C. Druart's researcher position is supported by a FIRST Spin-Off grant from the Walloon Region (convention 1410053). Research in the Wageningen and Helsinki labs of W.M.d.V. was partially supported by ERC Advanced Grant 250172 (Microbes Inside), the SIAM Gravity Grant 024.002.002 and Spinoza Award of the Netherlands Organization for Scientific Research, and Grants 137389, 141140 and 1272870 of the Academy of Finland. P.D.C. is the recipient of grants from FNRS (convention J.0084.15, convention 3.4579.11), PDR (Projet de Recherche, convention: T.0138.14) and ARC (Action de Recherche Concertée–Communauté française de Belgique convention: 12/17-047). This work was supported by the FRFS-WELBIO under grant WELBIO-CR-2012S-02R. This work is supported in part by the Funds Baillet Latour (Grant for Medical Research 2015), a FIRST Spin-Off grant (FSO) from the Walloon Region, Belgium (convention 1410053) and FP7 METACARDIS (HEALTH-F4-2012-305312). P.D.C. is a recipient of POC ERC grant 2016 (European Research Council, Microbes4U_713547) and ERC Starting Grant 2013 (Starting grant 336452-ENIGMO).

Author information

Author notes

- Noora Ottman
Present address: Metapopulation Research Centre, University of Helsinki, Helsinki, Finland.
- Amandine Everard
- , Céline Druart
- & Clara Depommier
These authors contributed equally to this work.

Affiliations

Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
- Hubert Plovier
- , Amandine Everard
- , Céline Druart
- , Clara Depommier
- , Matthias Van Hul
- , Lucie Geurts
- , Nathalie M Delzenne
- & Patrice D Cani
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
- Julien Chilloux
- , Antonis Myridakis
- & Marc-Emmanuel Dumas
Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
- Noora Ottman
- , Kees C H van der Ark
- , Steven Aalvink
- , Clara Belzer
- & Willem M de Vos
Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.
- Thibaut Duparc
- , Laeticia Lichtenstein
- & Laurent O Martinez
RPU Immunobiology, Department of Bacteriology & Immunology, University of Helsinki, Helsinki, Finland.
- Judith Klievink
- , Arnab Bhattacharjee
- & Willem M de Vos
Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
- Dominique Maiter
- , Audrey Loumaye
- , Michel P Hermans
- & Jean-Paul Thissen

Contributions

P.D.C. and W.M.d.V. conceived the project. P.D.C. supervised the preclinical and clinical aspects, and W.M.d.V. the microbial culturing and expression. P.D.C. and H.P. designed the mouse experiments, performed experiments and interpreted all the results, generated figures and tables and wrote the manuscript; A.E., C. Druart, M.V.H., L.G. and C. Depommier performed experiments. J.C., A.M. and M.-E.D. performed ¹H-NMR and UPLC-MS metabolomic analyses. N.M.D. provided reagents and analytic tools. T.D., L.L. and L.O.M. analyzed plasma lipoprotein profiles. C.B., K.C.H.v.d.A., H.P., C. Druart and S.A. performed the culturing and pasteurization of A. muciniphila. J.K. produced and purified Amuc_1100*, which was structurally analyzed by A.B. In vitro analysis of A. muciniphila and Amuc_1100* signaling was carried out by N.O. and C.B. J.-P.T., M.P.H., A.L., D.M., A.E., C. Druart, C. Depommier, W.M.d.V. and P.D.C. designed the clinical study. D.M., A.L., M.P.H. and J.-P.T., screened the subjects and contributed to follow-up. A.E., C. Druart, C. Depommier and P.D.C. followed subjects during the study. All authors discussed results and approved the manuscript.

Competing interests

A.E., C. Druart, P.D.C., C.B. and W.M.d.V. are inventors on patent applications dealing with the use of A. muciniphila and its components in the treatment of obesity and related disorders.