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Kouki Mori

Does the Gut Microbiota Trigger Hashimoto’s Thyroiditis?

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.


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.


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.


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.


Abdollahi-Roodsaz S, Joosten LAB, Koenders MI, Devesa I, Roelofs MF, Radstake TRDJ, Heuvelmans-Jacobs M, Akira S, Nicklin MJH, Ribeiro-Dias F, van den Berg WB. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 118(1):205-216, 2008.

Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov Il, Umesaki Y, Itoh K, Honda K. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337-341, 2011.

Bosi E, Molteni L, Radaelli MG, Folini L, Fermo I, Bazzigaluppi E, Piemonti L, Pastore MR, Paroni R. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49(12):2824-2827, 2006.

Bouskra D, Brézillon C, Brard M, Werts C, Varona R, Boneca IG, Eberl G. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456(7221):507-510, 2008.

Burek CL, Talor MV. Environmental triggers and autoimmune thyroiditis. J Autoimmun 33(3-4):183-189, 2009.

Calcinaro F, Dionisi S, Marinaro M, Candeloro P, Bonato V, Marzotti S, Corneli RB, Ferretti E, Gulino A, Grasso F, De Simone, Di Mario U, Falorni A, Boirivant M, Dotta F. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48(8):1565-1575, 2005.

Caturegli P, Kimura H, Rocchi R, Rose NR. Autoimmune thyroid diseases. Curr Opin Rheumatol 19(1):44-48, 2007.

Christensen HR, Frøkiær H, Pestka JJ. Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells. J Immunol 168(1):171-178, 2002.

Cindoruk M, Tuncer C, Dursun A, Yetkin I, Karakan T, Çakir N, Soykan I. Increased colonic intraepithelial lymphocytes in patients with Hashimoto’s thyroiditis. J Clin Gastroenterol 34(3):237-239, 2002.

Coombes JL, Siddiqui KRR, Arancibia-Cárcamo CV, Hall J, Sun C-M, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induced Foxp3+ regulatory T cells via TGF-β- and retinoic acid-dependent mechanism. J Exp Med 204(8):1757-1764, 2007.

Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 335(2):99-107, 1996.

Desailloud R, Hober D. Viruses and thyroiditis: an update. Virology J 6:5-18, 2009.

Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-β-bearing regulatory cells. J Immunol 174(6):3237-3246, 2005.

Droste JHJ, Wieringa MH, Weyler JJ, Nelen VJ, Vermeire PA, van Bever HP. Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease? Clin Exp Allergy 30(11):1547-1553, 2000.

Ezendam J, van Loveren H. Lactobacillus casei Shirota administered during lactation increases the duration of autoimmunity in rats and enhances lung inflammation in mice. Br J Nutr 99(1):83-90, 2008.

Foligne B, Zoumpopoulou G, Dewulf J, Younes AB, Chareyre F, Sirad J-C, Pot B, Grangette C. A key role of dendritic cells in probiotic functionality. PLoS One 2(3):e313, 2007.

Gardine CA, Kouki T, DeGroot L. Characterization of the T lymphocyte subsets and lymphoid populations involved in the induction of low-dose oral tolerance to human thyroglobulin. Cell Immunol 212(1):1-15, 2001.

Gill HS, Rutherfurd KJ, Prasad J, Gopal PK. Enhancement of natural and acquired immunity by Lactobacillus rhamnosus (HN001), Lactobacillus acidophilus (HN017) and Bifidobacterium lactis (HN019). Br J Nutr 83(2):167-176, 2000.

Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 5(1):82-91, 2011.

Gray DHD, Gavenescu I, Benoist C, Mathis D. Danger-free autoimmune disease in Aire-deficient mice. Proc Natl Acad Sci U S A 104(46):18193-18198, 2007.

Hart AL, Lammers K, Brigidi P, Vitali B, Rizzello F, Gionchetti P, Campieri M, Kamm MA, Knight SC, Stagg AJ. Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53(11):1602-1609, 2004

Horie I, Abiru N, Nagayama Y, Kuriya G, Saitoh O, Ichikawa T, Iwakura Y, Eguchi K. T helper type 17 immune response plays an indispensable role for development of iodine-induced autoimmune thyroiditis in nonobese diabetic-H2h4 mice. Endocrinology 150(11):5135-5142, 2009

Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB Sartor RB, Finlay BB, Littman DR. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4(4):337-349, 2008.

Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song S-Y. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21(4):527-538, 2004.

Iwata M, Eshima Y, Kagechika H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int Immunol 15(8):1017-1025, 2003.

Kaisho T, Akira S. Toll-like receptor function and signaling. J Allergy Clin Immunol 117(5):979-987, 2006.

Lee AS, Gibson DL, Zhang Y, Sham HP, Vallence BA, Dutz JP. Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice. Diabetologia 53(4):741-748, 2010.

Loyola-Rodriguez JP, Martinez-Martinez RE, Abud-Mendoza C, Patiño-Marin N, Seymour GJ. Rheumatoid arthritis and the role of oral bacteria. J Oral Microbiol 2:5784, 2010.

MacDonald TT, Monteleone G. Immunity, inflammation and allergy in the gut. Science 307(5717):1920-1925, 2005.

Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL, Kasturi SP, Rosenthal KM, Evavold BD, Pulendran B. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med 15(4):401-409, 2009.

Maurano F, Mazzarella G, Luongo D, Stefanile R, D’Arienzo R, Rossi M, Auricchio S, Troncone R. Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia 48(5):931-937, 2005.

Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122(1):107-118, 2005.

Mileti E, Matteoli G, Iliev ID, Rescingno M. Comparison of the immunomodulatory properties of three probiotic strains of Lactobacilli using complex culture systems: prediction for in vivo efficacy. PLoS One 4(9):e7056, 2009.

Morohoshi K, Yoshida K, Nakagawa Y, Hoshikawa S, Ozaki H, Takahashi Y, Ito S, Mori K. Effects of synthetic retinoid Am80 on iodide-induced autoimmune thyroiditis in nonobese diabetic mice. Cell Immunol 270(1):1-4, 2011.

Moroshoshi K, Takahashi Y, Mori K. Viral infection and innate pattern recognition receptors in induction of Hashimoto’s thyroiditis. Discov Med 12(67):505-511, 2011.

Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835):256-260, 2007.

Ochoa-Repáraz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, Kasper LH. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 183(10):6041-6050, 2009.

Oyama N, Sudo N, Sogawa H, Kubo C. Antibiotic use during infancy promotes a shift in the TH1/TH2 balance toward TH2-dominant immunity in mice. J Allergy Clin Immunol 107(1):153-159, 2001.

Penhale WJ, Young PR. The influence of the normal microbial flora on the susceptibility of rats to experimental autoimmune thyroiditis. Clin Exp Immunol 72(2):288-292, 1988.

Peterson KE, Braley-Mullen H. Suppression of murine experimental autoimmune thyroiditis by oral administration of porcine thyroglobulin. Cell Immunol 166(1):123-130, 1995.

Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118(2):229-241, 2004.

Rakoff-Nahoum S, Hao L, Medzhitov R. Role of Toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25(2):319-329, 2006.

Rose NR, Bonita R, Burek CL. Iodine: an environmental trigger of thyroiditis. Autoimmun Rev 1(1-2):97-103, 2002.

Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9(5):313-323, 2009.

Round JL, O’Connell RM, Mazmanian SK. Coordination of tolerogenic immune responses by the commensal microbiota. J Autoimmunol 34(3):J220-J225, 2010.

Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 107(27):12204-12209, 2010.

Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK. The Toll-like receptor pathway establishes commensal gut colonization. Science 332(6032):974-977, 2011.

Sasso FC, Carbonara O, Torella R, Mezzogiorno A, Esposito V, deMagistris L, Secondulfo M, Carratu R, Iafusco D, Carteni M. Ultrastructural changes in enterocytes in subjects with Hashimoto’s thyroiditis. Gut 53(12):1878-1880, 2004.

Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 7(10):569-578, 2011.

Schmidt EGW, Cleasson MH, Jensen SS, Ravn P, Kristensen NN. Antigen-presenting cells exposed to Lactobacillus acidophilus NCFM, Bifidobacterium bifidum BI-98, and BI-504 reduce regulatory T cell activity. Inflamm Bowel Dis 16(3):390-400, 2010.

Schwartz RF, Neu J, Schatz D, Atkinson MA, Wasserfall C. Comment on: Brugman S et al. (2006) Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia 49:2105-2108. Diabetologia 50(1):220-221, 2007.

Segain J-P, Raingeard de la Blétière D, Bourreille A, Leray V, Gervois N, Rosales C, Ferrier L, Bonnet C, Blottière HM, Galmiche J-P. Butyrate inhibits inflammatory responses through NFkB inhibition: implications for Crohn’s disease. Gut 47(3):397-403, 2000.

Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, Cosnes J, Corthier G, Marteau P, Doré J. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 15(8):1183-1189, 2009.

Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux J-J, Blugon S, Bridonneau, Furet J-P, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottière HM, Doré J, Marteau P, Seksik P, Langella P. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105(43):16731-16736, 2008.

Sun C-M, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J Exp Med 204(8):1775-1785, 2007.

Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 57(10):2555-2562, 2008.

Van Y-H, Lee W-H, Ortiz S, Lee M-H, Qin H-J, Liu C-P. All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-g-producing T-cells without affecting Th17 cells. Diabetes 58(1):146-155, 2009.

Wang SH, Fan Y, Makidon PE, Cao Z, Baker JR. Induction of immune tolerance in mice with a novel mucosal nanoemulsion adjuvant and self-antigen. Nanomedicine 7(6):867-876, 2012.

Weetman AP. Cellular immune responses in autoimmune thyroid disease. Clin Endocrinol 61(4):405-413, 2004.

Wen L, Ley RE, Volchkov PV, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455(7216):1109-1113, 2008.

Worbs T, Bode U, Hoffmann MW, Hintzen G, Bernhardt G, Förster R, Pabst O. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med 203(39):519-527, 2006.

Wu H-J, Ivanov Il, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32(6):815-827, 2010.

Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B, Kuchroo VK. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-b-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 181(4):2277-2284, 2008.

Yu S, Maiti PK, Dyson M, Jain R, Braley-Mullen H. B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis. J Exp Med 203(2):349-358, 2006.

Zhou JS, Gill HS. Immunostimulatory probiotic Lactobacillus rhamnosus HN001 and Bifidobacterium lactis HN019 do not induce pathological inflammation in mouse model of experimental autoimmune thyroiditis. Int J Food Microbiol 103(1):97-104, 2005.

[Discovery Medicine; ISSN: 1539-6509; Discov Med 14(78):321-326, November 2012. Copyright © Discovery Medicine. All rights reserved.]

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