Microbiome and Graves' Orbitopathy

Abstract

Background: Studies from animal models of autoimmunity have highlighted the potential importance of microorganisms and their metabolic products in shaping the immune system.

Summary: This review provides an introduction to the current state-of-the-art in microbiome research both from the perspective of "what is known" and of methodologies for its investigation. It then summarises the evidence for a role for the microbiome in the pathogenesis of Graves' disease and Graves' orbitopathy with reference to animal models and studies in human cohorts, from both published and ongoing sources.

Key message: Microbiome research is in its infancy but has already provided novel insights into disease pathogenesis across the spectrum from cancer to mental health and autoimmunity.

Keywords: Autoimmunity; Graves' disease; Graves' orbitopathy; Microbiome.

Fig. 1

The gut microbiota and its effects on the immune system. The interaction between gut epithelium, antigen-presenting cells such as dendritic cells, and the “healthy” gut microbiota produces cytokines and other metabolites which preserve the balance between regulatory T cells (Treg) and proinflammatory Th17 and Th1 cells. When the microbiota is suboptimal, the cytokines produced favour generation of proinflammatory Th17 cells, which may lead to loss of tolerance. In an individual with a particular genetic predisposition the result of this so-called “dysbiosis” or “dysbacteriosis” could lead to GD and, in extreme cases, GO. Transforming growth factor beta (TGFβ) is secreted by gut dendritic cells and is a differentiation factor for both Th17 and Treg cells, the latter characterised by expression of the FoxP3 forkhead transcription factor. Another product of dendritic cells, retinoic acid, enhances Treg development whilst inhibiting Th17 cells, which in turn are maintained by IL–23. IL-10 and IL–2 are secreted by gut macrophages; the latter inhibits Th17 development while the former inhibits secretion of Th17 cytokines, e.g., the IL-17 family (including IL–25 or IL-17E) which recruit neutrophils, a crucial component of innate immunity. Treg cells inhibit the development of proinflammatory Th17 and Th1 cells, the latter secrete interferon gamma (IFN-γ), which exacerbates autoimmune responses by upregulating major histocompatibility complex II expression. B. fragilis, Bacteroides fragilis; S. typhimurium, Salmonella typhimurium; SFB, segmented filamentous bacteria.