Emerging Insights Into the Role of Epigenetics and Gut Microbiome in the Pathogenesis of Graves’ Ophthalmopathy

Abstract

Graves’ Ophthalmopathy (GO) is an organ-specific autoimmune disease that is often characterized by infiltration of orbital tissues and is considered as the most common extra-thyroid manifestation of Graves’ disease (GD). Although genetic susceptibility has been found to be critical for the phenotype of GO, the associated risk alleles in a single gene are generally insufficient to cause the disease. Accruing evidence has shown that epigenetic disorders can act as the potentially missing link between genetic risk and clinically significant disease development. Abnormal epigenetic modifications can lead to pro-inflammatory cascades and activation of orbital fibroblasts (OFs) by promoting the various inflammatory response pathways and regulating the diverse signaling molecules that are involved in the fibrogenesis and adipogenesis, thereby leading to the significant expansion of orbital tissues, fibrosis and inflammation infiltration. Additionally, emerging evidence has shown that the gut microbiome can possibly drive the pathogenesis of GO by influencing the secretion of Thyrotropin receptor antibody (TRAb) and T-helper 17 (Th17)/regulatory T cells (Treg) imbalance. This paper describes the latest epigenetic research evidence and progress made in comprehending the mechanisms of GO development, such as DNA methylation, histone modification, non-coding RNAs, and the gut microbiome.

A cause–effect relationship between Graves’ disease and the gut microbiome contributes to the thyroid–gut axis: A bidirectional two-sample Mendelian randomization study

“…found that higher levels of Bacteroides in GD may alter the intestinal barrier and induce an inflammatory reaction by elevating the concentration of inflammatory factors, which may change the immune status and facilitate the incidence of autoimmune disease ( 46 ). In addition, higher thyroid hormone levels have also been positively related to Lactobacillus ( 47 ). Another study based on a mouse model also reported a causal correlation between the gut microbiome and GD.…”

Current concepts regarding Graves’ orbitopathy

“…Additionally, in twin studies the concordance rate is only about 30%, suggesting a low penetrance of involved genes [63,68]. Epigenetic factorsincluding abnormal DNA methylation, histone modification, and noncoding RNAs-may contribute to GO pathogenesis [69], but their role is not clear. Preliminary studies reporting differences in gut microbiota composition in Graves' patients with or without GO [70]-as well as animal studies suggesting a pivotal role of gut microbiota in TSHR-induced disease [71]-opened an interesting field of research [72].…”

Potential Therapeutic Activity of Berberine in Thyroid-Associated Ophthalmopathy: Inhibitory Effects on Tissue Remodeling in Orbital Fibroblasts

“…The gut microbiota recently surfaced as a novel contributor to TAO pathogenesis. 53 Besides the above effects, BBR also exerts great modulatory effects on the gut microbiota, as shown in patients with Graves’ disease. 54 Regulating the gut microbiota and other in vivo activities of BBR should be conducted in future animal models of TAO.…”