title: Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.
abstract: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Department of Transplantation Medicine, Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: S F
authors.initials: SF
authors.lastname: Jørgensen
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Department of Transplantation Medicine, Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Trøseid
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Kummen
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: J A
authors.initials: JA
authors.lastname: Anmarkrud
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: A E
authors.initials: AE
authors.lastname: Michelsen
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: L T
authors.initials: LT
authors.lastname: Osnes
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Holm
authors.affiliation: Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: M L
authors.initials: ML
authors.lastname: Høivik
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Rashidi
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Department of Cardiology, Oslo University Hospital, Oslo, Norway.
authors.forename: C P
authors.initials: CP
authors.lastname: Dahl
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of Medicine, National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Vesterhus
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.|Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: T E
authors.initials: TE
authors.lastname: Mollnes
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
authors.forename: R K
authors.initials: RK
authors.lastname: Berge
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Moum
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: K E A
authors.initials: KE
authors.lastname: Lundin
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Department of Transplantation Medicine, Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Fevang
authors.affiliation: K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K G Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Ueland
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of clinical medicine, University of Bergen, Bergen, Norway.
authors.forename: T H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Department of Transplantation Medicine, Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K G Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: J R
authors.initials: JR
authors.lastname: Hov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044822:Biodiversity; D015415:Biomarkers; D016022:Case-Control Studies; D017074:Common Variable Immunodeficiency / Q000276:immunology* / Q000382:microbiology*; D064806:Dysbiosis / Q000276:immunology*; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000382:microbiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007070:Immunoglobulin A; D053645:Interleukin-2 Receptor alpha Subunit; D008070:Lipopolysaccharides