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Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized Mice

Galipeau HJ, McCarville JL, Huebener S, Litwin O, Meisel M, Jabri B, Sanz Y, Murray JA, Jordana M, Alaedini A, Chirdo FG, Verdu EF.

Am. J. Pathol. 2015. 185: 2969-2982

PMID:26456581

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.

  • Only 2-5% of genetically susceptible individuals develop celiac disease. Whether environmental factors, such as the intestinal microbiota, play a role in disease susceptibility has been suggested based on clinical associations.
  • Using humanized mice, we show that the absence of bacteria leads to exacerbated gluten-induced pathology.
  • A benign microbiota free from any opportunistic pathogens and Proteobacteria protects from gluten-induced pathology in humanized mice.
  • Neonatal antibiotic treatment, leading to expansion of Proteobacteria, exacerbated gluten-induced pathology.
  • Supplementing the benign microbiota with the Proteobacteria member E. coli exacerbated gluten-induced pathology
  • The intestinal microbiota may be a factor that modulates celiac disease risk.

Celiac disease is a chronic inflammatory disease that is triggered by the ingestion of the dietary protein gluten, which is found in wheat, barely and rye. Why only 2-5% of genetically susceptible individuals go on to develop CD is not understood. Based on clinical associations, environmental factors such as changes in gut bacteria have been suggested to play a role. Using groups of genetically susceptible mice that differed in their gut microorganisms, we compared immune responses to gluten and intestinal pathology. Mice that lacked bacteria (germ-free) developed severe pathology following gluten treatment, whereas mice that had a “clean” bacteria composition (limited number of gut microorganisms that was free from any pathogens) were protected from any gluten-induced pathology. On the other hand, the presence of a more complex gut bacterial community that included opportunistic pathogens, such as E. coli and Helicobacter, exacerbated the gluten-induced pathology. The results suggest that gut bacteria may be a factor that contributes to celiac disease development in genetically susceptible individuals

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