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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  1. 1.

    et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

  2. 2.

    et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

  3. 3.

    et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

  4. 4.

    et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

  5. 5.

    et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

  6. 6.

    et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

  7. 7.

    et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat. Commun. 5, 5648 (2014).

  8. 8.

    et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 110, 9066–9071 (2013).

  9. 9.

    , , & Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54, 1469–1476 (2004).

  10. 10.

    , , , & Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl. Environ. Microbiol. 73, 7767–7770 (2007).

  11. 11.

    , , , & The mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl. Environ. Microbiol. 74, 1646–1648 (2008).

  12. 12.

    et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65, 426–436 (2016).

  13. 13.

    et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).

  14. 14.

    et al. Genetic and environmental control of host-gut microbiota interactions. Genome Res. 25, 1558–1569 (2015).

  15. 15.

    & The efficacy and safety of heat-killed Lactobacillus paracasei for treatment of perennial allergic rhinitis induced by house-dust mite. Pediatr. Allergy Immunol. 16, 433–438 (2005).

  16. 16.

    et al. Lactobacillus plantarum OLL2712 regulates glucose metabolism in C57BL/6 mice fed a high-fat diet. J. Nutr. Sci. Vitaminol. (Tokyo) 59, 144–147 (2013).

  17. 17.

    et al. Gut microbiota orchestrates energy homeostasis during cold. Cell 163, 1360–1374 (2015).

  18. 18.

    et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl. Acad. Sci. USA 103, 12511–12516 (2006).

  19. 19.

    et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

  20. 20.

    et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17, 49–60 (2013).

  21. 21.

    et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat. Commun. 6, 6498 (2015).

  22. 22.

    , , , & Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe−/− mice. Circulation 133, 2434–2446 (2016).

  23. 23.

    et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

  24. 24.

    Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 10, 131–144 (2010).

  25. 25.

    et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

  26. 26.

    et al. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of epithelial cell layer. Appl. Environ. Microbiol. 81, 3655–3662 (2015).

  27. 27.

    et al. Characterization of outer membrane proteome of Akkermansia muciniphila reveals sets of novel proteins exposed to the human intestine. Front. Microbiol. 7, 1157 (2016).

  28. 28.

    , & Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96 (2006).

  29. 29.

    et al. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. PLoS One 10, e0128274 (2015).

  30. 30.

    et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 6, 392 (2010).

  31. 31.

    , & Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).

  32. 32.

    et al. Barrier protection via Toll-like receptor 2 signaling in porcine intestinal epithelial cells damaged by deoxynivalnol. Vet. Res. 47, 25 (2016).

  33. 33.

    et al. Endocannabinoids—at the crossroads between the gut microbiota and host metabolism. Nat. Rev. Endocrinol. 12, 133–143 (2016).

  34. 34.

    et al. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J. 8, 2116–2130 (2014).

  35. 35.

    , , , & Evaluation of clinical safety and tolerance of a Lactobacillus reuteri NCIMB 30242 supplement capsule: a randomized control trial. Requl Toxicol Pharmacol. 63, 313–320 (2012).

  36. 36.

    et al. Evaluation of safety and human tolerance of the oral probiotic Streptococcus salivarius K12: a randomized, placebo-controlled, double-blind study. Food Chem. Toxicol. 49, 2356–2364 (2011).

  37. 37.

    , , , & Tolerance and safety of the potentially probiotic strain Lactobacillus rhamnosus PRSF-L477: a randomised, double-blind placebo-controlled trial in healthy volunteers. Br. J. Nutr. 104, 1806–1816 (2010).

  38. 38.

    et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60, 2775–2786 (2011).

  39. 39.

    et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 6, e25792 (2011).

  40. 40.

    et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am. J. Gastroenterol. 105, 2420–2428 (2010).

  41. 41.

    et al. Precision high-throughput proton NMR spectroscopy of human urine, serum, and plasma for large-scale metabolic phenotyping. Anal. Chem. 86, 9887–9894 (2014).

  42. 42.

    & Isolation of an R M+ mutant of Yersinia enterocolitica serotype O:8 and its application in construction of rough mutants utilizing mini-Tn5 derivatives and lipopolysaccharide-specific phage. J. Bacteriol. 176, 1756–1760 (1994).

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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.


  1. 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
  2. Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.

    • Julien Chilloux
    • , Antonis Myridakis
    •  & Marc-Emmanuel Dumas
  3. Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.

    • Noora Ottman
    • , Kees C H van der Ark
    • , Steven Aalvink
    • , Clara Belzer
    •  & Willem M de Vos
  4. Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.

    • Thibaut Duparc
    • , Laeticia Lichtenstein
    •  & Laurent O Martinez
  5. RPU Immunobiology, Department of Bacteriology & Immunology, University of Helsinki, Helsinki, Finland.

    • Judith Klievink
    • , Arnab Bhattacharjee
    •  & Willem M de Vos
  6. 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


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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.

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.

Corresponding author

Correspondence to Patrice D Cani.

Supplementary information

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    Supplementary Figures and Text

    Supplementary Figures 1–7 and Supplementary Tables 1–4