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The Potential Link between Gut Microbiota and Serum TRAb in Chinese Patients with Severe and Active Graves' Orbitopathy.

ABSTRACT: Background and Objective:A previous study reported alterations in the intestinal microbiota in patients with Graves' orbitopathy (GO). Thyrotropin receptor autoantibody (TRAb) stimulates orbital and periorbital tissues and plays a pivotal role in the development of GO. However, the association between gut microbiota and TRAb in GO patients has still remained elusive. In this study, we explored the relationships between gut microbiota and GO-related traits, in which we applied a metabolic-network-driven analysis to identify GO trait-related modules and extracted significant operational taxonomic units (OTUs). Methods:In the present study, we profiled gut microbiota using 16S rRNA gene sequencing in 31 GO patients. We performed metabolic-network-driven analysis to investigate the association between gut microbiota and GO-related traits (e.g., TRAb, TGAb, and TPOAb) in the combination of microbial effects. Results:Applying microbiome network analysis of cooccurrence patterns and analysis of topological properties, we found that s_Prevotella_copri and f_Prevotellaceae showed a significant correlation with TRAb. In particular, we applied the latent class model to explore the association between gut microbiota and GO-related traits in the combination of microbial effects. It was revealed that the subjects involved in the latent class model with the higher abundance of s_Prevotella_copri and g_Bacteroides had a higher TRAb level. Conclusions:Our results revealed the potential relationships between gut microbiota and GO-related traits in the combination of microbial effects. This study may provide a new insight into the interaction between the intestinal microbiota and TRAb-associated immune responses in GO patients.

SUBMITTER: Shi TT

PROVIDER: S-EPMC6942819 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Potential Link between Gut Microbiota and Serum TRAb in Chinese Patients with Severe and Active Graves' Orbitopathy.

Shi Ting-Ting TT Hua Lin L Wang Hua H Xin Zhong Z

International journal of endocrinology 20191218

<h4>Background and objective</h4>A previous study reported alterations in the intestinal microbiota in patients with Graves' orbitopathy (GO). Thyrotropin receptor autoantibody (TRAb) stimulates orbital and periorbital tissues and plays a pivotal role in the development of GO. However, the association between gut microbiota and TRAb in GO patients has still remained elusive. In this study, we explored the relationships between gut microbiota and GO-related traits, in which we applied a metabolic ...[more]

PMID: 31933641

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Project description:BackgroundGraves' disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves' orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (?gal; age ~?6?weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~?22?weeks).ResultsIn ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-?gal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors' microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25+ Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO.ConclusionsThese results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments. Video abstract.

Project description:BackgroundImmunosuppressive therapy of Graves' orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC.Methodsof 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety.ResultsBaseline CAS decreased significantly in all groups (P<0.0001), independently of GO duration or whether patients had newly occurring or relapsing GO after IVGC. Proptosis did not significantly change. There was an inverse correlation between the Gorman score for diplopia and RTX dose (P<0.01). The appearance score of the GO-QoL improved in Group 1 (P=0.015), and the visual function score, in Group 2 (P=0.04). A reduction of serum TRAb was observed in Group 1 (P=0.002) and Group 2 (P<0.0002), but not in Group 3. CD19+ cell decreased in all groups (P<0.01), independently of the dose.ConclusionsWe studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients' quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.

Project description:BACKGROUND: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 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. 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 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 ?gal 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.

Dataset Information

The Potential Link between Gut Microbiota and Serum TRAb in Chinese Patients with Severe and Active Graves' Orbitopathy.

Publications

The Potential Link between Gut Microbiota and Serum TRAb in Chinese Patients with Severe and Active Graves' Orbitopathy.

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