title: 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 composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. 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 medicine. 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.
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Hubert
authors.initials: H
authors.lastname: Plovier
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Amandine
authors.initials: A
authors.lastname: Everard
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Druart
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Clara
authors.initials: C
authors.lastname: Depommier
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: Van Hul
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Lucie
authors.initials: L
authors.lastname: Geurts
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Julien
authors.identifier: 0000-0002-0384-7317
authors.initials: J
authors.lastname: Chilloux
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
authors.forename: Noora
authors.initials: N
authors.lastname: Ottman
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Duparc
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Lichtenstein
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Antonis
authors.initials: A
authors.lastname: Myridakis
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.affiliation: RPU Immunobiology, Department of Bacteriology &Immunology, University of Helsinki, Helsinki, Finland.
authors.forename: Judith
authors.initials: J
authors.lastname: Klievink
authors.affiliation: RPU Immunobiology, Department of Bacteriology &Immunology, University of Helsinki, Helsinki, Finland.
authors.forename: Arnab
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
authors.forename: Kees C H
authors.initials: KC
authors.lastname: van der Ark
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: Aalvink
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Martinez
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Marc-Emmanuel
authors.identifier: 0000-0001-9523-7024
authors.initials: ME
authors.lastname: Dumas
authors.affiliation: Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Maiter
authors.affiliation: Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Audrey
authors.initials: A
authors.lastname: Loumaye
authors.affiliation: Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Michel P
authors.initials: MP
authors.lastname: Hermans
authors.affiliation: Pole of Endocrinology, Diabetes and Nutrition, Institut de Recherche Expérimentale et Clinique IREC, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Thissen
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.
authors.forename: Clara
authors.initials: C
authors.lastname: Belzer
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands.|RPU Immunobiology, Department of Bacteriology &Immunology, University of Helsinki, Helsinki, Finland.
authors.forename: Willem M
authors.identifier: 0000-0002-0273-3166
authors.initials: WM
authors.lastname: de Vos
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium.
authors.forename: Patrice D
authors.identifier: 0000-0003-2040-2448
authors.initials: PD
authors.lastname: Cani
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002853:Chromatography, Liquid; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000378:metabolism*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D024821:Metabolic Syndrome / Q000378:metabolism; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000187:drug effects* / Q000378:metabolism; D061327:Verrucomicrobia
chemical_list: D001786:Blood Glucose; D008565:Membrane Proteins; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2