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

Abstract

Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition1,2,3,4,5,6,7. 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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Figure 1: Pasteurization enhances A. muciniphila–mediated effects on high-fat diet-induced obesity.
Figure 2: Pasteurized A. muciniphila modulates adipose tissue physiology, intestinal energy absorption and urinary metabolome.
Figure 3: A.muciniphila protein Amuc_1100* recapitulates the effects of the pasteurized bacterium on diet-induced obesity.
Figure 4: Effects of A. muciniphila or Amuc_1100* on the intestinal barrier function.

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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).

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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.

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Correspondence to Patrice D Cani.

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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.

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Plovier, H., Everard, A., Druart, C. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 23, 107–113 (2017). https://doi.org/10.1038/nm.4236

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