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Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease
journal contribution
posted on 2018-05-20, 10:24 authored by Giulia Masetti, Sajad Moshkelgosha, Hedda-Luise Köhling, Danila Covelli, Jasvinder Paul Banga, Utta Berchner-Pfannschmidt, Mareike Horstmann, Salvador J. Diaz-CanoSalvador J. Diaz-Cano, Gina-Eva Goertz, Sue Plummer, Anja Eckstein, Marian Ludgate, Filippo Biscarini, Julian Marchesi, INDIGO consortiumBackground:
Variation in induced models of autoimmunity has been attributed to the
housing environment and its effect on the gut microbiota. In Graves'
disease (GD), autoantibodies to the thyrotropin receptor (TSHR) cause
autoimmune hyperthyroidism. Many GD patients develop Graves' orbitopathy
(GO) characterized by orbital tissue remodeling including adipogenesis.
Murine models of GD/GO would help delineate pathogenetic mechanisms and
although several have been reported most lack reproducibility. A model
comprising immunization of female BALBc mice with a TSHR expression
plasmid using in vivo electroporation, was reproduced in two independent
laboratories. Similar orbital disease was induced in both centers, but
differences were apparent (e.g., hyperthyroidism in Center 1 but not
Center 2). We hypothesized a role for the gut microbiota influencing the
outcome and reproducibility of induced GO.
Results: We combined metataxonomics (16S rRNA gene sequencing) and
traditional microbial culture of the intestinal contents from the GO
murine model, to analyze the gut microbiota in the two centers. We
observed significant differences in alpha, beta-diversity and in the
taxonomic profiles, e.g. Operational Taxonomic Units (OTUs) from the
genus Lactobacillus were more abundant in Center 2, Bacteroides and
Bifidobacterium counts were more abundant in Center 1 where we also
observed a negative correlation between the OTUs of the genus
Intestinimonas and TSHR autoantibodies. Traditional microbiology largely
confirmed the metataxonomics data and indicated significantly higher
yeast counts in Center 1 TSHR-immunized mice. We also compared the gut
microbiota between immunization groups within the Center 2, comprising
the TSHR or βgal control immunized mice and naïve untreated mice. We
observed a shift of the TSHR immunized mice bacterial communities
described by the beta-diversity weighted Unifrac. Furthermore, we
observed a significant positive correlation between the presence of
Firmicutes and orbital-adipogenesis specifically in TSHR-immunized mice.
Conclusions: The significant differences observed in microbiota
composition from BALBc mice undergoing the same immunization protocol in
comparable specific-pathogen free (SPF) units in different centers
support a role for the gut microbiota in modulating the induced
response. The gut microbiota might also contribute to the heterogeneity
of induced response since we report potential disease-associated
microbial taxonomies and correlation with ocular disease.