Alterations in the intestinal microbiota of patients with severe and active Graves’ orbitopathy: a cross-sectional study

  • T.-T. Shi
  • Z. XinEmail author
  • L. HuaEmail author
  • R.-X. Zhao
  • Y.-L. Yang
  • H. Wang
  • S. Zhang
  • W. Liu
  • R.-R. Xie
Original Article



The intestinal microbiota was linked to autoimmune diseases. Graves’ orbitopathy (GO) is an autoimmune disease that is usually associated with Graves’ disease. However, information on the microbiome of GO patients is yet lacking.


To investigate whether GO patients differ from healthy controls in the fecal microbiota.


A cross-sectional study.


33 patients with severe and active GO and 32 healthy controls of Han nationality were enrolled between March 2017 and March 2018.


The Gut microbial communities of the fecal samples of GO patients and healthy controls were analyzed and compared by 16S rRNA gene sequencing.


Community diversity (Simpson and Shannon) was significantly reduced in fecal samples from patients with GO as compared to controls (p < 0.05). The similarity observed while assessing the community diversity (PCoA) proposed that the microbiota of patients with GO differ significantly from those of controls (p < 0.05). At the phyla levels, the proportion of Bacteroidetes increased significantly in patients with GO (p < 0.05), while at the genus and species levels, significant differences were observed in the bacterial profiles between the two groups (p < 0.05).


Single-centered study design and limited fecal samples.


The present study indicated distinctive features of the gut microbiota in GO patients. The study provided evidence for further exploration in the field of intestinal microbiota with respect to the diagnosis and treatment of GO patients by modifying the microbiota profile.


Graves’ orbitopathy (GO) Gut microbiota 16S rRNA gene Thyrotropin receptor antibody (TRAb) 



The authors thank all the participants and staff involved in the study.


This work was supported by the Beijing Municipal Hospital Research and Development Program (PX2016063), the Expert Promotion Program of Beijing Health Systems (2015-3-017) to Zhong Xin, and the Foundation of Beijing Tongren Hospital (2015-YJJ-ZZL-006) to Ting-Ting Shi.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

Ethics approval

The study was approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University. All procedures were performed in the study in accordance with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed written consents were obtained from all participants included in this study.

Supplementary material

40618_2019_1010_MOESM1_ESM.jpg (185 kb)
Supplemental Figure S1. The Venn diagram demonstrates the overlap of OTUs in intestinal microbiota between GO patients and healthy controls. OTUs operational taxonomic units


  1. 1.
    Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Pearce SH (2018) 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J 7:167–186CrossRefGoogle Scholar
  2. 2.
    Drui D, Du Pasquier Fediaevski L, Vignal Clermont C, Daumerie C (2018) Graves’ orbitopathy: diagnosis and treatment. Ann Endocrinol (Paris) 79:656–664CrossRefGoogle Scholar
  3. 3.
    Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM, European Group on Graves’ Orbitopathy (2016) The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J 5:9–26CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L (2013) Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 36:444–449PubMedGoogle Scholar
  5. 5.
    Perros P, Hegedus L, Bartalena L, Marcocci C, Kahaly GJ, Baldeschi L, Salvi M, Lazarus JH, Eckstein A, Pitz S, Boboridis K, Anagnostis P, Ayvaz G, Boschi A, Brix TH, Curro N, Konuk O, Marino M, Mitchell AL, Stankovic B, Toruner FB, von Arx G, Zarkovic M, Wiersinga WM (2017) Graves’ orbitopathy as a rare disease in Europe: a European Group on Graves’ Orbitopathy (EUGOGO) position statement. Orphanet J Rare Dis 12:72CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Leo M, Menconi F, Rocchi R, Latrofa F, Sisti E, Profilo MA, Mazzi B, Albano E, Nardi M, Vitti P, Marcocci C, Marino M (2015) Role of the underlying thyroid disease on the phenotype of Graves’ orbitopathy in a tertiary referral center. Thyroid 25:347–351CrossRefGoogle Scholar
  7. 7.
    Kugelberg E (2017) Microbiota: diet can protect against type 1 diabetes. Nat Rev Immunol 17:279CrossRefGoogle Scholar
  8. 8.
    Edwards CJ, Costenbader KH (2014) Epigenetics and the microbiome: developing areas in the understanding of the aetiology of lupus. Lupus 23:505–506CrossRefGoogle Scholar
  9. 9.
    Matsuoka K, Kanai T (2015) The gut microbiota and inflammatory bowel disease. Semin Immunopathol 37:47–55CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J (2015) The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 21:895–905CrossRefGoogle Scholar
  11. 11.
    Covelli D, Ludgate M (2017) The thyroid, the eyes and the gut: a possible connection. J Endocrinol Invest 40:567–576CrossRefGoogle Scholar
  12. 12.
    Ponto KA, Schuppan D, Zwiener I, Binder H, Mirshahi A, Diana T, Pitz S, Pfeiffer N, Kahaly GJ (2014) Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity. Clin Exp Immunol 178:57–64CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Zhao F, Feng J, Li J, Zhao L, Liu Y, Chen H, Jin Y, Zhu B, Wei Y (2018) Alterations of the Gut Microbiota in Hashimoto’s thyroiditis patients. Thyroid 28:175–186CrossRefGoogle Scholar
  14. 14.
    Zhou L, Li X, Ahmed A, Wu D, Liu L, Qiu J, Yan Y, Jin M, Xin Y (2014) Gut microbe analysis between hyperthyroid and healthy individuals. Curr Microbiol 69:675–680CrossRefGoogle Scholar
  15. 15.
    Masetti G, Moshkelgosha S, Kohling HL, Covelli D, Banga JP, Berchner-Pfannschmidt U, Horstmann M, Diaz-Cano S, Goertz GE, Plummer S, Eckstein A, Ludgate M, Biscarini F, Marchesi JR, INDIGO consortium (2018) Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease. Microbiome 6:97CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Li Q, Ye H, Ding Y, Chen G, Liu Z, Xu J, Chen R, Yang H (2017) Clinical characteristics of moderate-to-severe thyroid associated ophthalmopathy in 354 Chinese cases. PLoS One 12:e0176064CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Zhou Y, Ou Z, Tang X, Zhou Y, Xu H, Wang X, Li K, He J, Du Y, Wang H, Chen Y, Nie Y (2018) Alterations in the gut microbiota of patients with acquired immune deficiency syndrome. J Cell Mol Med 22:2263–2271CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C (2011) Metagenomic biomarker discovery and explanation. Genome Biol 12:R60CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Chen Z, Liu J, Ng HK, Nadarajah S, Kaufman HL, Yang JY, Deng Y (2011) Statistical methods on detecting differentially expressed genes for RNA-seq data. BMC Syst Biol 5(Suppl 3):S1CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Muegge BD, Kuczynski J, Knights D, Clemente JC, Gonzalez A, Fontana L, Henrissat B, Knight R, Gordon JI (2011) Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332:970–974CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ercolini AM, Miller SD (2009) The role of infections in autoimmune disease. Clin Exp Immunol 155:1–15CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Kohling HL, Plummer SF, Marchesi JR, Davidge KS, Ludgate M (2017) The microbiota and autoimmunity: their role in thyroid autoimmune diseases. Clin Immunol 183:63–74CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Benjamin JL, Hedin CR, Koutsoumpas A, Ng SC, McCarthy NE, Prescott NJ, Pessoa-Lopes P, Mathew CG, Sanderson J, Hart AL, Kamm MA, Knight SC, Forbes A, Stagg AJ, Lindsay JO, Whelan K (2012) Smokers with active Crohn’s disease have a clinically relevant dysbiosis of the gastrointestinal microbiota. Inflamm Bowel Dis 18:1092–1100CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Biedermann L, Brulisauer K, Zeitz J, Frei P, Scharl M, Vavricka SR, Fried M, Loessner MJ, Rogler G, Schuppler M (2014) Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH. Inflamm Bowel Dis 20:1496–1501CrossRefPubMedCentralGoogle Scholar
  25. 25.
    De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 107:14691–14696CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Bassi V, Santinelli C, Iengo A, Romano C (2010) Identification of a correlation between Helicobacter pylori infection and Graves’ disease. Helicobacter 15:558–562CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Corapcioglu D, Tonyukuk V, Kiyan M, Yilmaz AE, Emral R, Kamel N, Erdogan G (2002) Relationship between thyroid autoimmunity and Yersinia enterocolitica antibodies. Thyroid 12:613–617CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Chiuri RM, Matronola MF, Di Giulio C, Comegna L, Chiarelli F, Blasetti A (2013) Bartonella henselae infection associated with autoimmune thyroiditis in a child. Horm Res Paediatr 79:185–188CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Chen S, Cheng H, Wyckoff KN, He Q (2016) Linkages of Firmicutes and Bacteroidetes populations to methanogenic process performance. J Ind Microbiol Biotechnol 43:771–781CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Mariat D, Firmesse O, Levenez F, Guimaraes V, Sokol H, Dore J, Corthier G, Furet JP (2009) The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 9:123CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Lantz M, Planck T, Asman P, Hallengren B (2014) Increased TRAb and/or low anti-TPO titers at diagnosis of Graves’ disease are associated with an increased risk of developing ophthalmopathy after onset. Exp Clin Endocrinol Diabetes 122:113–117CrossRefGoogle Scholar
  32. 32.
    Jarusaitiene D, Verkauskiene R, Jasinskas V, Jankauskiene J (2016) Predictive factors of development of Graves’ ophthalmopathy for patients with juvenile Graves’ disease. Int J Endocrinol 2016:8129497CrossRefPubMedCentralGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.Department of Endocrinology, Beijing Tongren HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of Mathematics, School of Biomedical EngineeringCapital Medical UniversityBeijingChina
  3. 3.Department of Emergency, Beijing Tongren HospitalCapital Medical UniversityBeijingChina
  4. 4.Department of Pharmacy, Beijing Tongren HospitalCapital Medical UniversityBeijingChina

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