Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease

Abstract

BackgroundVariation 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 or ophthalmopathy (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.ResultsWe 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 and beta diversity and in the taxonomic profiles, e.g., operational taxonomic units (OTUs) from the genus Lactobacillus were more abundant in Center 2, and 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 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0478-4) contains supplementary material, which is available to authorized users.

Alterations in the gut microbiota and metabolite profiles of thyroid carcinoma patients

“…This finding is consistent with previous studies investigating the gut microbiota in HT and hyperthyroidism patients . However, the opposite results were recently found in patients with GD with/without ophthalmopathy and an animal model of hyperthyroidism . In addition, a decrease in the diversity of the microbiota is associated with several diseases, such as liver cancer, diabetes mellitus type 1 (T1D) and ankylosing spondylitis (AS) .…”

“…In our previous study, the gut microbiota alpha diversity (richness and diversity) in HT patients was higher than that in HCs, although the differences were nonsignificant ( p > 0.05) . However, in recent hyperthyroidism studies, the authors noted that the gut microbiota alpha diversity was lower in hyperthyroidism patients or mouse models than in HCs . A Venn diagram showing the overlapping OTU data of the groups was constructed to better evaluate the shared richness.…”

“…However, the gut microbiota can affect thyroid homeostasis. [21][22][23][24][25][26] The effect of the gut microbiota on iodine absorption has been confirmed in antibiotics feeding rats. 21 Glucuronidase from obligate anaerobic bacteria can hydrolyze iodothyronine conjugates, which re-enter the general circulation and contribute to the iodothyronine pool.…”

“…24 However, in recent hyperthyroidism studies, the authors noted that the gut microbiota alpha diversity was lower in hyperthyroidism patients or mouse models than in HCs. 25,28 A Venn diagram showing the overlapping OTU data of the groups was constructed to better evaluate the shared richness. This analysis revealed that 853 of the 2845 OTUs accounting for the total richness were common to all samples; therefore, approximately 620 and 1372 OTUs were identified in HC and TC patient samples, respectively ( Fig.…”

“…Thus far, no study has addressed the relationship between TC and the gut microbiota. However, the gut microbiota can affect thyroid homeostasis . The effect of the gut microbiota on iodine absorption has been confirmed in antibiotics feeding rats .…”