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Am J Pathol. 2015 Nov;185(11):2969-82. doi: 10.1016/j.ajpath.2015.07.018. Epub 2015 Oct 9.

Intestinal microbiota modulates gluten-induced immunopathology in humanized mice.

Author information

1
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
2
Department of Medicine, Columbia University Medical Center, New York, New York.
3
Department of Medicine, University of Chicago, Chicago, Illinois.
4
Microbial Ecology, Nutrition & Health Research Group, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain.
5
Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota.
6
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
7
Institute of Immunological and Pathophysiological Studies, Department of Biological Sciences, Faculty of Sciences, National University of La Plata, La Plata, Argentina.
8
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address: verdue@mcmaster.ca.

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.

PMID:
26456581
PMCID:
PMC4630176
DOI:
10.1016/j.ajpath.2015.07.018
[Indexed for MEDLINE]
Free PMC Article

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