title: Intestinal microbiota modulates gluten-induced immunopathology in humanized mice.
abstract: Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility. Germ-free mice, clean specific-pathogen-free (SPF) mice colonized with a microbiota devoid of opportunistic pathogens and Proteobacteria, and conventional SPF mice that harbor a complex microbiota that includes opportunistic pathogens were used. Clean SPF mice had attenuated responses to gluten compared to germ-free and conventional SPF mice. Germ-free mice developed increased intraepithelial lymphocytes, markers of intraepithelial lymphocyte cytotoxicity, gliadin-specific antibodies, and a proinflammatory gliadin-specific T-cell response. Antibiotic treatment, leading to Proteobacteria expansion, further enhanced gluten-induced immunopathology in conventional SPF mice. Protection against gluten-induced immunopathology in clean SPF mice was reversed after supplementation with a member of the Proteobacteria phylum, an enteroadherent Escherichia coli isolated from a CD patient. The intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice. In subjects with moderate genetic susceptibility, intestinal microbiota changes may be a factor that increases CD risk.
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Galipeau
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Justin L
authors.initials: JL
authors.lastname: McCarville
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Sina
authors.initials: S
authors.lastname: Huebener
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Owen
authors.initials: O
authors.lastname: Litwin
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Marlies
authors.initials: M
authors.lastname: Meisel
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
authors.affiliation: Microbial Ecology, Nutrition & Health Research Group, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanz
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.affiliation: Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Armin
authors.initials: A
authors.lastname: Alaedini
authors.affiliation: Institute of Immunological and Pathophysiological Studies, Department of Biological Sciences, Faculty of Sciences, National University of La Plata, La Plata, Argentina.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Chirdo
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address: verdue@mcmaster.ca.
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000906:Antibodies / Q000097:blood*; D002446:Celiac Disease / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D049109:Cell Proliferation; D016207:Cytokines / Q000032:analysis; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome; D005903:Gliadin / Q000009:adverse effects; D005983:Glutens / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology; D014640:Vancomycin / Q000008:administration & dosage
chemical_list: D000900:Anti-Bacterial Agents; D000906:Antibodies; D016207:Cytokines; D014640:Vancomycin; D005983:Glutens; D005903:Gliadin