title: Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.
abstract: According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Computer Science, Aalto University School of Science, 02150 Espoo, Finland.
authors.forename: Tommi
authors.initials: T
authors.lastname: Vatanen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Aleksandar D
authors.initials: AD
authors.lastname: Kostic
authors.affiliation: Novartis Institutes for Biomedical Research Inc., Cambridge, MA 02139, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: d'Hennezel
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00290 Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Siljander
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Franzosa
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Moran
authors.initials: M
authors.lastname: Yassour
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Raivo
authors.initials: R
authors.lastname: Kolde
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Hera
authors.initials: H
authors.lastname: Vlamakis
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Arthur
authors.affiliation: Department of Pediatrics, Jorvi Hospital, Helsinki University Hospital, 02740 Espoo, Finland.
authors.forename: Anu-Maaria
authors.initials: AM
authors.lastname: Hämäläinen
authors.affiliation: Department of Pediatrics, University of Tartu and Tartu University Hospital, 51014 Tartu, Estonia.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Peet
authors.affiliation: Department of Pediatrics, University of Tartu and Tartu University Hospital, 51014 Tartu, Estonia.
authors.forename: Vallo
authors.initials: V
authors.lastname: Tillmann
authors.affiliation: Department of Immunology, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, 50411 Tartu, Estonia.
authors.forename: Raivo
authors.initials: R
authors.lastname: Uibo
authors.affiliation: Ministry of Health and Social Development, Karelian Republic of the Russian Federation, Lenin Street 6, 185035 Petrozavodsk, Russia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Mokurov
authors.affiliation: Petrozavodsk State University, Department of Family Medicine, Lenin Street 33, 185910 Petrozavodsk, Russia.
authors.forename: Natalya
authors.initials: N
authors.lastname: Dorshakova
authors.affiliation: Immunogenetics Laboratory, University of Turku, 20520 Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Health, National Institute for Health and Welfare, 00271 Helsinki, Finland; School of Health Sciences, University of Tampere, 33014 Tampere, Finland; Science Centre, Pirkanmaa Hospital District and Research Center for Child Health, University Hospital, 33521 Tampere, Finland.
authors.forename: Suvi M
authors.initials: SM
authors.lastname: Virtanen
authors.affiliation: Novartis Institutes for Biomedical Research Inc., Cambridge, MA 02139, USA.
authors.forename: Susanne J
authors.initials: SJ
authors.lastname: Szabo
authors.affiliation: Novartis Institutes for Biomedical Research Inc., Cambridge, MA 02139, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Porter
authors.affiliation: Department of Computer Science, Aalto University School of Science, 02150 Espoo, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Gevers
authors.affiliation: Novartis Institutes for Biomedical Research Inc., Cambridge, MA 02139, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Cullen
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland; Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00290 Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: xavier@molbio.mgh.harvard.edu.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D000818:Animals; D001439:Bacteroides / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004957:Estonia; D005243:Feces / Q000382:microbiology; D005387:Finland; D005516:Food Microbiology; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007223:Infant; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008895:Milk, Human / Q000276:immunology; D012426:Russia
chemical_list: D008070:Lipopolysaccharides