title: Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function.
abstract: Gut barrier function is key in maintaining a balanced response between the host and its microbiome. The microbiota can modulate changes in gut barrier as well as metabolic and inflammatory responses. This highly complex system involves numerous microbiota-derived factors. The gut symbiont Akkermansia muciniphila is positively correlated with a lean phenotype, reduced body weight gain, amelioration of metabolic responses and restoration of gut barrier function by modulation of mucus layer thickness. However, the molecular mechanisms behind its metabolic and immunological regulatory properties are unexplored. Herein, we identify a highly abundant outer membrane pili-like protein of A. muciniphila MucT that is directly involved in immune regulation and enhancement of trans-epithelial resistance. The purified Amuc_1100 protein and enrichments containing all its associated proteins induced production of specific cytokines through activation of Toll-like receptor (TLR) 2 and TLR4. This mainly leads to high levels of IL-10 similar to those induced by the other beneficial immune suppressive microorganisms such as Faecalibacterium prausnitzii A2-165 and Lactobacillus plantarum WCFS1. Together these results indicate that outer membrane protein composition and particularly the newly identified highly abundant pili-like protein Amuc_1100 of A. muciniphila are involved in host immunological homeostasis at the gut mucosa, and improvement of gut barrier function.
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.|Department of Biosciences, University of Helsinki, Helsinki, Finland.|Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Noora
authors.identifier: http://orcid.org/0000-0001-5011-9294
authors.initials: N
authors.lastname: Ottman
authors.affiliation: Cancer and Translational Medicine Research Unit, Biocenter Oulu and Faculty of Medicine, University of Oulu, Oulu, Finland.
authors.forename: Justus
authors.initials: J
authors.lastname: Reunanen
authors.affiliation: Host-Microbe Interactomics, Animal Sciences, Wageningen University, Wageningen, The Netherlands.|Department Risk Analysis for Products in Development, TNO, Zeist, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Meijerink
authors.affiliation: Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Taija E
authors.initials: TE
authors.lastname: Pietilä
authors.affiliation: Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Veera
authors.initials: V
authors.lastname: Kainulainen
authors.affiliation: Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.|Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Judith
authors.initials: J
authors.lastname: Klievink
authors.affiliation: Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Huuskonen
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: Aalvink
authors.affiliation: Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.|Helsinki University Central Hospital Laboratory Diagnostics, Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Skurnik
authors.affiliation: Laboratory of Biochemistry, Wageningen University, Wageningen, The Netherlands.
authors.forename: Sjef
authors.initials: S
authors.lastname: Boeren
authors.affiliation: Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Satokari
authors.affiliation: Host-Microbe Interactomics, Animal Sciences, Wageningen University, Wageningen, The Netherlands.
authors.forename: Annick
authors.initials: A
authors.lastname: Mercenier
authors.affiliation: Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Airi
authors.initials: A
authors.lastname: Palva
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Hauke
authors.initials: H
authors.lastname: Smidt
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.|Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.|Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.
authors.forename: Willem M
authors.initials: WM
authors.lastname: de Vos
authors.affiliation: Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Clara
authors.initials: C
authors.lastname: Belzer
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D061327:Verrucomicrobia / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4