title: Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings.
abstract: OBJECTIVE
  Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups.
  
  
  METHODS
  Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip.
  
  
  RESULTS
  Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ(2)=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables.
  
  
  CONCLUSIONS
  Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.
authors.affiliation: Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Hedin
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK.
authors.forename: Neil E
authors.initials: NE
authors.lastname: McCarthy
authors.affiliation: Microbiology Group, Gut Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Louis
authors.affiliation: Microbiology Group, Gut Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, UK.
authors.forename: Freda M
authors.initials: FM
authors.lastname: Farquharson
authors.affiliation: Department for Gastroenterology and Clinical Nutrition, University College Hospitals NHS Foundation Trust, London, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: McCartney
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Prescott
authors.affiliation: National Nursing Research Unit, Florence Nightingale School of Nursing and Midwifery, King's College London, London, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Murrells
authors.affiliation: Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London, London, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Stagg
authors.affiliation: Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Whelan
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK Gastroenterology Division, Barts Health NHS Trust, London, UK.
authors.forename: James O
authors.initials: JO
authors.lastname: Lindsay
mesh_terms: D000293:Adolescent; D000328:Adult; D003424:Crohn Disease / Q000276:immunology* / Q000382:microbiology*; D064806:Dysbiosis / Q000276:immunology* / Q000382:microbiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005243:Feces / Q000382:microbiology; D005260:Female; D005838:Genotype; D006801:Humans; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000382:microbiology*; D008297:Male; D064307:Microbiota; D035781:Siblings; D013601:T-Lymphocytes / Q000276:immunology*; D006113:United Kingdom; D055815:Young Adult
keywords: BACTERIAL PATHOGENESIS; CROHN'S DISEASE; GENOTYPE; T LYMPHOCYTES