Abstract: Hashimoto's thyroiditis is an organ-specific autoimmune disease in which both genetic predisposition and environmental factors serve as the trigger of the disease. A growing body of evidence suggests involvement of viral infection in the development of Hashimoto's thyroiditis. However, not only pathogenic microorganisms but also non-pathogenic commensal microorganisms induce proinflammatory or regulatory immune responses within the host. In accordance, series of studies indicate a critical role of intestinal commensal microbiota in the development of autoimmune diseases including inflammatory bowel diseases, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. In contrast, the role of the gut and indigenous microorganisms in Hashimoto's thyroiditis has received little attention. Whereas activation of innate pattern recognition receptors such as Toll-like receptors and disturbed intestinal epithelial barrier may contribute to thyroiditis development, only a few studies have addressed a link between the gut and Hashimoto's thyroiditis and provided just indirect and weak evidence for such a link. Despite this unsatisfactory situation, we here focus on the possible interaction between the gut and thyroid autoimmunity. Further studies are clearly needed to test the hypothesis that the gut commensal microflora represents an important environmental factor triggering Hashimoto's thyroiditis.

Introduction

Hashimoto’s thyroiditis is an organ-specific autoimmune disease characterized by intrathyroidal mononuclear cell infiltration and the production of autoantibodies against thyroglobulin and thyroid peroxidase (Dayan and Daniels, 1996). Series of studies have indicated that environmental factors play a critical role in the development of Hashimoto’s thyroiditis in genetically susceptible individuals (Caturegli et al., 2007; Burek and Talor, 2009). The most extensively investigated environmental factor is excessive dietary iodine (Rose et al., 2002). Viral infection is also one of such factors triggering the illness (Desailloud and Hober, 2009; Morohoshi et al., 2011). However, we need to pay attention to not only pathogenic microorganisms but also commensal microorganisms to understand the etiology of Hashimoto’s thyroiditis since the latter is important for the proper development and function of the innate and adaptive immune systems and accumulating evidence implicates the intestinal microbiota in the pathogenesis of autoimmune diseases (Vaarala et al., 2008; Round and Mazmanian, 2009; Scher and Abramson, 2011). We accordingly review the pathogenic significance of the gut microbiota in Hashimoto’s thyroiditis despite only a limited number of studies addressing this issue.

Intestinal Dysbiosis and Hashimoto’s Thyroiditis

The intestinal mucosa continuously encounters a wide variety of antigens derived from food, commensal organisms, and occasional pathogens. The intestinal immune system accordingly has to balance between protective reactions against harmful pathogens and tolerance against commensal bacteria and dietary antigens to maintain intestinal homeostasis. Indigenous bacteria in the mammalian gut can provide benefits to their hosts, including the formation of barrier against invasive pathogens, the provision of nutrients, and the development of gut immune system (Round and Mazmanian, 2009). In addition, products of the bacterial fermentation of undigested fibers in the intestine such as butyrate reportedly inhibit lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines including tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) and nuclear factor-kappa B (NF-κB) activation in peripheral blood mononuclear cells (PBMC) (Segain et al., 2000). These observations implicate that dysbiosis in the gut could disturb the finely tuned immune balance and break tolerance to self antigens and non-pathogenic non-self antigens, leading to the development of autoimmune disorders. Consistently, altered composition of the gut flora has been reported in inflammatory bowel disease (IBD) and type 1 diabetes (Giongo et al., 2011; Sokol et al., 2009). In contrast, however, little information is available on the gut microbial composition in Hashimoto’s thyroiditis patients.

Antibiotic use can interfere with the intestinal microflora. An increased risk of developing allergic disorders by antibiotic use during early childhood has consistently been demonstrated (Droste et al., 2000), probably resulting from perturbed postnatal T helper 1 (Th1) cell maturation (Oyama et al., 2001). On the other hand, oral administration of antibiotics resulted in amelioration of Th1- and/or Th17-mediated autoimmune diseases in mice (Schwartz et al., 2007; Ochoa-Repáraz et al., 2009). Accordingly, antibiotic-induced altered gut microbial composition may result in the promotion or inhibition of autoimmune disorders. Few studies have examined, however, if antibiotics can influence Hashimoto’s thyroiditis development.

Multiple lines of evidence have demonstrated that probiotic organisms such as Bifidobacterium and Lactobacillus confer health benefits on the host. For instance, oral administration of probiotics to mice induced IL-10 production and prevented the development of autoimmune diseases including type 1 diabetes and colitis (Calcinaro et al., 2005; Di Giacinto et al., 2005; Sokol H et al., 2008). This probiotic-induced anti-inflammatory effect is reportedly mediated by dendritic cells (Hart et al., 2004; Foligne et al., 2007). However, series of in vivo and in vitro studies have demonstrated that certain probiotic strains exacerbated colitis and encephalomyelitis (Ezendam and van Loveren, 2008; Mileti et al., 2009), enhanced interferon-γ (IFNγ) production (Gill et al., 2000) and reduced regulatory T cell (Treg) activity (Schmidt et al., 2010), indicating that attention should be paid when choosing a probiotic strain to treat autoimmune disorders. In experimental autoimmune thyroiditis (EAT), a murine model of Hashimoto’s thyroiditis, probiotic strains Lactobacillus rhamnosus HN001 and Bifidobacterium lactis HN019, which had been shown to enhance splenocyte IFNγ production in mice (Gill et al., 2000), exhibited neither stimulatory nor inhibitory effect on the disease development (Zhou and Gill, 2005). Taken collectively, the presence and the role of intestinal dysbiosis and the effect of alteration in the gut microbial composition remain to be investigated in Hashimoto’s thyroiditis.

Role of Gut Microbiota in Regulating the Immune System

Series of studies have clearly demonstrated the critical role of gut commensal microbiota in the normal immune system development (Round et al., 2010). Rodents raised under germ-free conditions exhibit a variety of immune defects including reduced CD4+ T cell number and Th2 predominance in the spleen and altered Th17 cell and Treg cell differentiation in the lamina propria and these defects are reportedly restored by colonization of some commensal bacteria such as Bacteroides fragilis and segmented filamentous bacteria (Mazmanian et al., 2005; Ivanov et al., 2008; Round and Mazmanian, 2010; Atarashi et al., 2011). These observations indicate that the mucosal effector T cell balance can be skewed by dysbiosis in the gut, resulting in acceleration or suppression of autoimmunity. In accordance, increased or decreased frequency of autoimmune diseases has been demonstrated in germ-free mice (Wen et al., 2008; Ochoa-Repáraz et al., 2009; Wu et al., 2010). In animal models of Hashimoto’s thyroiditis, rodents raised under conventional conditions develop thyroiditis at a greater incidence over those housed under specific pathogen free conditions (Penhale and Young, 1988; Burek and Talor, 2009). Whereas it remains undefined whether thyroiditis development is enhanced or prevented in germ-free rodents, these findings suggest that commensal microorganisms may affect thyroiditis development by skewing balance between Th1 and/or Th17 cells (Weetman, 2004; Horie et al., 2009) and Treg cells (Yu et al., 2006).

Both pathogenic and non-pathogenic bacteria are sensed by pattern recognition receptors such as Toll-like receptors (TLRs) expressed on antigen presenting cells such as dendritic cells and macrophages (Kaisho and Akira, 2006). Among TLRs, TLR2, TLR4, and TLR9 recognize bacteria-derived molecules including lipoproteins, LPS, and DNA, respectively. A growing body of evidence indicates that recognition of commensal microorganisms by TLRs is required for the protection from colonic injury (Rakoff-Nahoum et al., 2004) and for the establishment of host-microbial symbiosis (Round et al., 2011). In addition, Gram-negative bacteria-derived peptidoglycan induces the genesis of intestinal lymphoid tissues through an innate receptor nucleotide-binding oligomerization domain-containing protein 1 (Bouskra et al., 2008). Collectively, these observations suggest that the gut commensal microflora communicates with the intestinal immune system through innate receptors including TLRs and that such a communication may be involved in the development of autoimmune diseases. In fact, spontaneous onset of arthritis, colitis, and type 1 diabetes in mice is reportedly dependent on TLR activation by intestinal microflora (Rakoff-Nahoum et al., 2006; Abdollahi-Roodsaz et al., 2008; Wen et al., 2008). In contrast, it remains largely unknown whether gut microbiota-induced activation of TLRs affects thyroiditis development. There are only a few studies suggesting an association of TLR activation with thyroiditis development in mice (Burek and Talor, 2009; Morohoshi et al., 2011). For instance, TLR4 activation by LPS triggered thyroiditis development in nonobese diabetic (NOD).H2h4 mice (Burek and Talor, 2009). Stimulation of TLR4, TLR7, or TLR2 and dectin-1 in combination induced the production of anti-thyroglobulin antibody in NOD mice whereas it presented little effects on thyroiditis development (Morohoshi et al., 2011). However, TLRs were stimulated by intraperitoneally injected-TLR ligands in those studies and accordingly the effect of TLR activation by the intestinal microflora on thyroiditis development remains to be examined.

Gut Microflora and Tolerance Induction

Food antigens and commensal bacteria constantly exposed to the intestinal mucosa elicit systemic unresponsiveness to themselves, called oral tolerance. Dendritic cells in gut-associated lymphoid tissues (GALT) play a critical role in the establishment of oral tolerance by inducing the gut-homing receptors, integrin α4β7 and chemokine receptor CCR9, on naïve T cells and the peripheral conversion of these naïve T cells to Treg cells (Iwata et al., 2004; Coombs et al., 2007; Sun et al., 2007). In addition, antigen transport into mesenteric lymph nodes is prerequisite to oral tolerance induction (Worbs et al., 2006). Microbiota can modulate dendritic cell function (Christensen et al., 2002; Foligne et al., 2007) and dysbiosis may therefore result in the imbalance between immune activation and tolerance.

Oral tolerance can be induced in murine EAT (Peterson and Braley-Mullen, 1995; Gardine et al., 2001). A previous study demonstrated involvement of Peyer’s patches in the oral tolerance induction in EAT by using CD120a-deficient mice (Gardine et al., 2001), suggesting a contribution of GALT to tolerance induction to thyroglobulin. In addition to orally administered thyroid antigens, nasally delivered thyroglobulin was shown to prevent thyroiditis development in a murine EAT model (Wang et al., 2012). Nasally immunized animals exhibited increased numbers of Treg cells in cervical lymph nodes (Wang et al., 2012). These observations strengthen the essential role of the mucosal immune system in tolerance induction to thyroid antigens. However, the contribution of indigenous microbiota to maintaining immune tolerance toward thyroid antigens remains largely unknown.

CD103+ dendritic cells in the GALT induce Foxp3+ Treg cells in a retinoic acid-dependent manner (Iwata et al., 2004; Coombs et al., 2007; Sun et al., 2007). In addition, the former expresses retinoic acid-producing enzyme retinal dehydrogenase (Iwata et al., 2004), indicating a central role of retinoic acid in oral tolerance induction. Microbiota may promote T regulatory responses via TLR2-dependent induction of the enzyme in dendritic cells (Manicassamy et al., 2009). Further, retinoic acid induces Th1 to Th2 shift (Iwata et al., 2003) and inhibits Th17 differentiation (Mucida et al., 2007). Consistently, series of studies have demonstrated beneficial effects of retinoids in animal models of type 1 diabetes (Van et al., 2009) and multiple sclerosis (Xiao et al., 2008). Based on those observations, we recently tested whether administration of a synthetic retinoid Am80 could interfere with the development of iodide-induced autoimmune thyroiditis in NOD mice (Morohoshi et al., 2011). In contrast to previous studies (Xiao et al., 2008; Van et al., 2009), thyroiditis development was not prevented by oral administration of the retinoid. However, our study did not evaluate the mucosal immune system at all in the retinoid-treated mice, and thus the retinoic acid-dependent tolerogenic immune responses in the gut remain to be determined in animal models of Hashimoto’s thyroiditis.

Enteropathy in Hashimoto’s Thyroiditis

The gut epithelial barrier prevents both pathogenic and non-pathogenic bacteria from entering into highly immunoreactive submucosa. Disrupted mucosal barrier therefore allows exposure of submucosal immune cells to bacterial and dietary antigens, leading to unfavorable immune activation and thus development of autoimmune diseases (MacDonald and Monteleone, 2005; Vaarala et al., 2008). In accordance, morphological changes in gut epithelial cells, increased intestinal permeability, and intraepithelial lymphocyte infiltration have been demonstrated in patients with type 1 diabetes and animal models of the illness (Maurano et al., 2005; Bosi et al., 2006; Lee et al., 2010). Similar changes have interestingly been detected in patients with Hashimoto’s thyroiditis (Cindoruk et al., 2002; Sasso et al., 2004), suggesting a pathogenic role of the leaky gut barrier in the development of Hashimoto’s thyroiditis.

Conclusion

A growing body of evidence has demonstrated that environmental factors including infection are critical in triggering Hashimoto’s thyroiditis in genetically predisposed individuals. Not only pathogens but also intestinal symbiotic microorganisms can influence extra-intestinal immune responses, and thus dysbiosis in the gut might lead to the loss of tolerance to self-antigens including thyroglobulin and the autoimmunity that underlies Hashimoto’s thyroiditis. In addition, enteropathy with increased intestinal permeability and intraepithelial lymphocyte infiltration may increase the risk for developing thyroid autoimmunity. However, there are only a limited number of studies investigating the possible link between the gut and Hashimoto’s thyroiditis. Recent studies have revealed that not only the gut commensals but also oral microorganisms such as periodontal bacteria may participate in autoimmune diseases including rheumatoid arthritis (Loyola-Rodriguez et al., 2010). In contrast to many studies showing the microbial contribution to the development of autoimmunity, however, some studies demonstrated that activation of autoreactive T cells might be independent of microbial stimulation by using Aire-deficient mice (Gray et al., 2007). Taken together, further studies are clearly required to determine the role of commensal microorganisms in the gut and the oral cavity in triggering Hashimoto’s thyroiditis and to develop new strategies for the prevention and treatment of the illness.

Disclosure

The authors report no conflicts of interest.

Corresponding Author

Kouki Mori, M.D., Ph.D., Center for Health Promotion, JR Sendai Hospital, 1-1-5 Itsutsubashi, Aoba-ku, Sendai 980-8508, Japan.

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