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  • Review Article
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The microbiome and HLA-B27-associated acute anterior uveitis

Nature Reviews Rheumatology volume 14, pages 704–713 (2018)Cite this article

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Abstract

Acute anterior uveitis (AAU) and the spondyloarthritis (SpA) subtypes ankylosing spondylitis, reactive arthritis and psoriatic arthritis are among the inflammatory diseases affected by the biology of the intestinal microbiome. In this Review, the relationship between AAU, SpA and the microbiome is discussed, with a focus on the major SpA risk gene HLA-B*27 and how it is associated with both intestinal tolerance and the loss of ocular immune privilege that can accompany AAU. We provide four potential mechanisms to account for how dysbiosis, barrier function and immune response contribute to the development of ocular inflammation and the pathogenesis of AAU. Finally, potential therapeutic avenues to target the microbiota for the clinical management of AAU and SpA are outlined.

Key points

  • Acute anterior uveitis (AAU) is the most common, clinically apparent, extra-articular manifestation of ankylosing spondylitis.

  • Both AAU and ankylosing spondylitis are strongly associated with HLA-B27.

  • HLA-B27 affects the composition of the gut microbiome, which in turn can modify the immune system and thereby affect health and disease.

  • The intestinal microbiome is strongly implicated in the pathogenesis of AAU and ankylosing spondylitis.

  • Although the mechanisms by which the intestinal microbiome cause AAU and ankylosing spondylitis are incompletely understood, a great potential exists to treat or prevent ankylosing spondylitis and AAU by altering the microbiome.

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Fig. 1: Uveitis subtyping by affected site.
Fig. 2: Frequency of uveitis in patients with spondyloarthritis.
Fig. 3: Disease manifestations of spondyloarthritis.
Fig. 4: Potential mechanisms of microbiome-mediated uveitis.
Fig. 5: Therapeutic strategies to target intestinal microbiota.

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References

  1. Lederberg, J. ‘Ome Sweet’ Omics: a geneological treasury of words. Scientist 15, 8 (2001).

    Google Scholar 

  2. Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804–810 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).

    CAS  PubMed  Google Scholar 

  5. Yang, X., Xie, L., Li, Y. & Wei, C. More than 9,000,000 unique genes in human gut bacterial community: estimating gene numbers inside a human body. PLOS One 4, e6074 (2009).

    PubMed  PubMed Central  Google Scholar 

  6. Shreiner, A. B., Kao, J. Y. & Young, V. B. The gut microbiome in health and in disease. Curr. Opin. Gastroenterol. 31, 69–75 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Osokine, I. & Erlebacher, A. Inflammation and autism: from maternal gut to fetal brain. Trends Mol. Med. 23, 1070–1071 (2017).

    PubMed  Google Scholar 

  8. Stevens, B. R. et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut 67, 1555–1557 (2017).

    PubMed  Google Scholar 

  9. Nussenblatt, R. B. The natural history of uveitis. Int. Ophthalmol. 14, 303–308 (1990).

    CAS  PubMed  Google Scholar 

  10. Rothova, A., Suttorp-van Schulten, M. S., Frits Treffers, W. & Kijlstra, A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br. J. Ophthalmol. 80, 332–336 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Suttorp-Schulten, M. S. & Rothova, A. The possible impact of uveitis in blindness: a literature survey. Br. J. Ophthalmol. 80, 844–848 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Gritz, D. C. & Wong, I. G. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis study. Ophthalmology 111, 491–500; discussion 500 (2004).

    PubMed  Google Scholar 

  13. D’Alessandro, L. P., Forster, D. J. & Rao, N. A. Anterior uveitis and hypopyon. Am. J. Ophthalmol. 112, 317–321 (1991).

    PubMed  Google Scholar 

  14. Rosenbaum, J. T. Characterization of uveitis associated with spondyloarthritis. J. Rheumatol 16, 792–796 (1989).

    CAS  PubMed  Google Scholar 

  15. Brewerton, D. A., Caffrey, M., Nicholls, A., Walters, D. & James, D. C. Acute anterior uveitis and HL-A 27. Lancet 302, 994–996 (1973). This seminal paper demonstrates an association between HLA-B*27 and susceptibility to AAU.

    CAS  PubMed  Google Scholar 

  16. Lyons, J. L. & Rosenbaum, J. T. Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy. Arch. Ophthalmol. 115, 61–64 (1997).

    CAS  PubMed  Google Scholar 

  17. Rosenbaum, J. T. Uveitis. An internist’s view. Arch. Intern. Med. 149, 1173–1176 (1989).

    CAS  PubMed  Google Scholar 

  18. Fanlo, P. et al. Profile of patients with uveitis referred to a multidisciplinary unit in northern Spain. Arch. Soc. Esp. Oftalmol 92, 202–209 (2017).

    CAS  PubMed  Google Scholar 

  19. Zagora, S. L. et al. Etiology and clinical features of ocular inflammatory diseases in a tertiary referral centre in Sydney, Australia. Ocul. Immunol. Inflamm. 25, S107–S114 (2017).

    PubMed  Google Scholar 

  20. Chung, Y. M., Yeh, T. S. & Liu, J. H. Endogenous uveitis in Chinese—an analysis of 240 cases in a uveitis clinic. Jpn J. Ophthalmol. 32, 64–69 (1988).

    CAS  PubMed  Google Scholar 

  21. Yang, P. et al. Clinical features of HLA-B27-positive acute anterior uveitis with or without ankylosing spondylitis in a Chinese cohort. Br. J. Ophthalmol. 102, 215–219 (2018).

    PubMed  Google Scholar 

  22. Juanola, X., Loza Santamaria, E., Cordero-Coma, M. & Group, S. W. Description and prevalence of spondyloarthritis in patients with anterior uveitis: the SENTINEL interdisciplinary collaborative project. Ophthalmology 123, 1632–1636 (2016).

    PubMed  Google Scholar 

  23. Haroon, M., O’Rourke, M., Ramasamy, P., Murphy, C. C. & FitzGerald, O. A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool). Ann. Rheum. Dis. 74, 1990–1995 (2015).

    PubMed  Google Scholar 

  24. Paiva, E. S., Macaluso, D. C., Edwards, A. & Rosenbaum, J. T. Characterisation of uveitis in patients with psoriatic arthritis. Ann. Rheum. Dis. 59, 67–70 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Rosenbaum, J. T. Uveitis: etiology, clinical manifestations, and diagnosis. UpToDate https://www.uptodate.com/contents/uveitis-etiology-clinical-manifestations-and-diagnosis (updated 21 Aug 2018).

  26. Robinson, P. C. et al. Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol 67, 140–151 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rosenbaum, J. & Chandran, V. Management of comorbidities in ankylosing spondylitis. Am. J. Med. Sci. 343, 364–366 (2012).

    PubMed  Google Scholar 

  28. Murray, P. I. & Rauz, S. The eye and inflammatory rheumatic diseases: the eye and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis. Best Pract. Res. Clin. Rheumatol. 30, 802–825 (2016).

    PubMed  Google Scholar 

  29. Billson, F. A., Dombal, F. T. D., Watkinson, G. & Goligher, J. C. Ocular complications of ulcerative colitis. Gut 8, 102–106 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hopkins, D. J. et al. Ocular disorders in a series of 332 patients with Crohn’s disease. Br. J. Ophthalmol. 58, 732–737 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Petty, R. E. et al. Uveitis and arthritis induced by adjuvant: clinical, immunologic and histologic characteristics. J. Rheumatol. 16, 499–505 (1989).

    CAS  PubMed  Google Scholar 

  32. Kezic, J. M., Davey, M. P., Glant, T. T., Rosenbaum, J. T. & Rosenzweig, H. L. Interferon-gamma regulates discordant mechanisms of uveitis versus joint and axial disease in a murine model resembling spondylarthritis. Arthritis Rheum. 64, 762–771 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rehaume, L. M. et al. ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice. Arthritis Rheumatol. 66, 2780–2792 (2014).

    CAS  PubMed  Google Scholar 

  34. Baggia, S. et al. A novel model of bacterially-induced acute anterior uveitis in rats and the lack of effect from HLA B27 expression. J. Invest. Med. 45, 295–301 (1997).

    CAS  Google Scholar 

  35. De Vos, M., Mielants, H., Cuvelier, C., Elewaut, A. & Veys, E. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 110, 1696–1703 (1996). This paper demonstrates the association between SpA and subclinical inflammation of the intestine in >50% of patients with AS.

    PubMed  Google Scholar 

  36. Mielants, H., Veys, E. M., Joos, R., Cuvelier, C. & De Vos, M. Repeat ileocolonoscopy in reactive arthritis. J. Rheumatol 14, 456–458 (1987).

    CAS  PubMed  Google Scholar 

  37. Vaile, J. H., Meddings, J. B., Yacyshyn, B. R., Russell, A. S. & Maksymowych, W. P. Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives. J. Rheumatol 26, 128–135 (1999).

    CAS  PubMed  Google Scholar 

  38. Granfors, K. et al. Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet 335, 685–688 (1990).

    CAS  PubMed  Google Scholar 

  39. Granfors, K. et al. Yersinia antigens in synovial-fluid cells from patients with reactive arthritis. N. Engl. J. Med. 320, 216–221 (1989).

    CAS  PubMed  Google Scholar 

  40. Wang, F. et al. Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am. J. Pathol. 166, 409–419 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Box, S. A. & Pullar, T. Sulphasalazine in the treatment of rheumatoid arthritis. Br. J. Rheumatol 36, 382–386 (1997).

    CAS  PubMed  Google Scholar 

  42. Halfvarson, J. et al. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat. Microbiol. 2, 17004 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kostic, A. D., Xavier, R. J. & Gevers, D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146, 1489–1499 (2014).

    CAS  PubMed  Google Scholar 

  44. Pascal, V. et al. A microbial signature for Crohn’s disease. Gut 66, 813–822 (2017).

    CAS  PubMed  Google Scholar 

  45. Kubinak, J. L. et al. MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nature Commun. 6, 8642 (2015).

    CAS  Google Scholar 

  46. Breban, M. et al. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann. Rheum. Dis. 76, 1614–1622 (2017).

    CAS  PubMed  Google Scholar 

  47. Tito, R. Y. et al. Dialister as microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol 69, 114–121 (2016).

    PubMed  Google Scholar 

  48. Costello, M. E. et al. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 67, 686–691 (2014). This paper demonstrates intestinal dysbiosis in patients with AS relative to healthy individuals.

    Google Scholar 

  49. Scher, J. U. et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 67, 128–139 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Aggarwal, A., Sarangi, A. N., Gaur, P., Shukla, A. & Aggarwal, R. Gut microbiome in children with enthesitis-related arthritis in a developing country and the effect of probiotic administration. Clin. Exp. Immunol. 187, 480–489 (2017).

    CAS  PubMed  Google Scholar 

  51. Di Paola, M. et al. Alteration of fecal microbiota profiles in juvenile idiopathic arthritis. Associations with HLA-B27 allele and disease status. Front. Microbiol. 7, 1703 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Stoll, M. L. et al. Fecal metabolomics in pediatric spondyloarthritis implicate decreased metabolic diversity and altered tryptophan metabolism as pathogenic factors. Genes Immun. 17, 400–405 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shiina, T., Inoko, H. & Kulski, J. K. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 64, 631–649 (2004).

    CAS  PubMed  Google Scholar 

  54. Jin, P. & Wang, E. Polymorphism in clinical immunology - from HLA typing to immunogenetic profiling. J. Transl Med. 1, 8 (2003).

    PubMed  PubMed Central  Google Scholar 

  55. Lin, P. et al. HLA-B27 and human beta2-microglobulin affect the gut microbiota of transgenic rats. PLOS One 9, e105684 (2014). This paper shows that a specific HLA allele, HLA-B*27, can shape the intestinal microbiota in rats.

    PubMed  PubMed Central  Google Scholar 

  56. Gill, T., Asquith, M., Brooks, S. R., Rosenbaum, J. T. & Colbert, R. A. Effects of HLA-B27 on gut microbiota in experimental spondyloarthritis implicate an ecological model of dysbiosis. Arthritis Rheumatol. 70, 555–565 (2017).

    Google Scholar 

  57. Hammer, R. E., Maika, S. D., Richardson, J. A., Tang, J. P. & Taurog, J. D. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 63, 1099–1112 (1990).

    CAS  PubMed  Google Scholar 

  58. Taurog, J. D. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994).

    CAS  PubMed  Google Scholar 

  59. Dieleman, L. A. et al. Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment. Gut 52, 370–376 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Olivares, M. et al. The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease. Gut 64, 406–417 (2015).

    CAS  PubMed  Google Scholar 

  61. Gomez, A. et al. Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice. PLOS One 7, e36095 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Silverman, M. et al. Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny. Proc. Natl Acad. Sci. USA 114, 9671–9676 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Asquith, M. J. et al. Perturbed mucosal immunity and dysbiosis accompany clinical disease in a rat model of spondyloarthritis. Arthritis Rheumatol. 68, 2151–2162 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

    CAS  PubMed  Google Scholar 

  65. Olson, J. A. et al. Calprotectin is raised in endogenous posterior uveitis. Ocul Immunol. Inflamm 4, 91–98 (1996).

    CAS  PubMed  Google Scholar 

  66. Walscheid, K. et al. Elevated S100A8/A9 and S100A12 serum levels reflect intraocular inflammation in juvenile idiopathic arthritis-associated uveitis: results from a pilot study. Invest. Ophthalmol. Vis. Sci. 56, 7653–7660 (2015).

    CAS  PubMed  Google Scholar 

  67. Kim, D. H. et al. Fecal calprotectin as a non-invasive biomarker for intestinal involvement of Behcet’s disease. J. Gastroenterol. Hepatol. 32, 595–601 (2017).

    CAS  PubMed  Google Scholar 

  68. Faure, M. et al. The chronic colitis developed by HLA-B27 transgenic rats is associated with altered in vivo mucin synthesis. Dig. Dis. Sci. 49, 339–346 (2004).

    CAS  PubMed  Google Scholar 

  69. Stoll, M. L. et al. Akkermansia muciniphila is permissive to arthritis in the K/BxN mouse model of arthritis. Genes Immun. https://doi.org/10.1038/s41435-018-0024-1 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Stoll, M. L. et al. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis Res. Ther. 16, 486 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. ELife 2, e01202 (2013).

    PubMed  PubMed Central  Google Scholar 

  72. Macpherson, A. J., Yilmaz, B., Limenitakis, J. P. & Ganal-Vonarburg, S. C. IgA function in relation to the intestinal microbiota. Annu. Rev. Immunol. 36, 359–381 (2018).

    CAS  PubMed  Google Scholar 

  73. Salas-Cuestas, F. et al. Higher levels of secretory IgA are associated with low disease activity index in patients with reactive arthritis and undifferentiated spondyloarthritis. Front. Immunol. 8, 476 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Belkaid, Y. & Harrison, O. J. Homeostatic immunity and the microbiota. Immunity 46, 562–576 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Park, K. et al. ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex. Proc. Natl Acad. Sci. USA 113, E1334–E1342 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Moreau, M. C., Ducluzeau, R., Guy-Grand, D. & Muller, M. C. Increase in the population of duodenal immunoglobulin A plasmocytes in axenic mice associated with different living or dead bacterial strains of intestinal origin. Infect. Immun. 21, 532–539 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lindstedt, G., Lindstedt, S. & Gustafsson, B. E. Mucus in intestinal contents of germfree rats. J. Exp. Med. 121, 201–213 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    CAS  PubMed  Google Scholar 

  80. Qiu, X., Zhang, M., Yang, X., Hong, N. & Yu, C. Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. J. Crohn’ Colitis 7, e558–e568 (2013).

    Google Scholar 

  81. Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358, 359–365 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Nakamura, Y. K. et al. Gut microbial alterations associated with protection from autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 57, 3747–3758 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Cunningham, M. W. Streptococcus and rheumatic fever. Curr. Opin. Rheumatol 24, 408–416 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Shahrizaila, N. & Yuki, N. Guillain-barre syndrome animal model: the first proof of molecular mimicry in human autoimmune disorder. J. Biomed. Biotechnol. 2011, 829129 (2011).

    PubMed  Google Scholar 

  86. Pianta, A. et al. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J. Clin. Invest. 127, 2946–2956 (2017). This paper identifies rheumatoid-arthritis-associated autoantigens with homology to commensal epitopes, consistent with mimicry as a potential disease mechanism that might be shared between rheumatoid arthritis and SpA-associated extraintestinal inflammation.

    PubMed  PubMed Central  Google Scholar 

  87. Yin, Y. & Mariuzza, R. A. The multiple mechanisms of T cell receptor cross-reactivity. Immunity 31, 849–851 (2009).

    CAS  PubMed  Google Scholar 

  88. Horai, R. et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity 43, 343–353 (2015). This study elegantly demonstrates that gut bacteria might prime T cells to drive ocular inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Schwimmbeck, P. L. & Oldstone, M. B. Molecular mimicry between human leukocyte antigen B27 and Klebsiella. Consequences for spondyloarthropathies. Am. J. Med. 85, 51–53 (1988).

    CAS  PubMed  Google Scholar 

  90. van Bohemen, C. G., Grumet, F. C. & Zanen, H. C. Identification of HLA-B27M1 and -M2 cross-reactive antigens in Klebsiella, Shigella and Yersinia. Immunology 52, 607–610 (1984).

    PubMed  PubMed Central  Google Scholar 

  91. Mielants, H., Veys, E. M., De Vos, M. & Cuvelier, C. Increased intestinal permeability in ankylosing spondylitis. Gut 33, 1150 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ciccia, F. et al. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann. Rheum. Dis. 76, 1123–1132 (2017).

    CAS  PubMed  Google Scholar 

  93. Pacheco-Tena, C. et al. Bacterial DNA in synovial fluid cells of patients with juvenile onset spondyloarthropathies. Rheumatology (Oxford) 40, 920–927 (2001).

    CAS  Google Scholar 

  94. Nikkari, S. et al. Salmonella-triggered reactive arthritis: use of polymerase chain reaction, immunocytochemical staining, and gas chromatography-mass spectrometry in the detection of bacterial components from synovial fluid. Arthritis Rheum. 42, 84–89 (1999).

    CAS  PubMed  Google Scholar 

  95. Siala, M. et al. Analysis of bacterial DNA in synovial tissue of Tunisian patients with reactive and undifferentiated arthritis by broad-range PCR, cloning and sequencing. Arthritis Res. Ther. 10, R40 (2008).

    PubMed  PubMed Central  Google Scholar 

  96. Gutierrez, A. et al. Gut Bacterial DNA translocation is an independent risk factor of flare at short term in patients with Crohn’s disease. Am. J. Gastroenterol. 111, 529–540 (2016).

    CAS  PubMed  Google Scholar 

  97. Muralidhar, B., Rumore, P. M. & Steinman, C. R. Use of the polymerase chain reaction to study arthritis due to Neisseria gonorrhoeae. Arthritis Rheum. 37, 710–717 (1994).

    CAS  PubMed  Google Scholar 

  98. Schrijver, I. A., Melief, M. J., Tak, P. P., Hazenberg, M. P. & Laman, J. D. Antigen-presenting cells containing bacterial peptidoglycan in synovial tissues of rheumatoid arthritis patients coexpress costimulatory molecules and cytokines. Arthritis Rheum. 43, 2160–2168 (2000).

    CAS  PubMed  Google Scholar 

  99. Camus, G. et al. Mild endotoxaemia and the inflammatory response induced by a marathon race. Clin. Sci. (Lond.) 92, 415–422 (1997).

    CAS  Google Scholar 

  100. Bhanji, S., Williams, B., Sheller, B., Elwood, T. & Mancl, L. Transient bacteremia induced by toothbrushing a comparison of the Sonicare toothbrush with a conventional toothbrush. Pediatr. Dent. 24, 295–299 (2002).

    PubMed  Google Scholar 

  101. Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018). This paper demonstrates that translocation of gut commensal microorganisms to the liver might contribute to the pathogenesis of systemic lupus erythematosus and that targeted vaccination against the pathobiont E. gallinarum delays mortality in an animal model of the disease.

    CAS  PubMed  Google Scholar 

  102. Spadoni, I. et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 350, 830–834 (2015).

    CAS  PubMed  Google Scholar 

  103. Bouziat, R. et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356, 44–50 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Rosenbaum, J. T., McDevitt, H. O., Guss, R. B. & Egbert, P. R. Endotoxin-induced uveitis in rats as a model for human disease. Nature 286, 611–613 (1980).

    CAS  PubMed  Google Scholar 

  105. Allensworth, J. J., Planck, S. R., Rosenbaum, J. T. & Rosenzweig, H. L. Investigation of the differential potentials of TLR agonists to elicit uveitis in mice. J. Leukoc. Biol. 90, 1159–1166 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Chang, J. H. et al. Changes in Toll-like receptor (TLR)-2 and TLR4 expression and function but not polymorphisms are associated with acute anterior uveitis. Invest. Ophthalmol. Vis. Sci. 48, 1711–1717 (2007).

    PubMed  Google Scholar 

  107. Morton, A. M. et al. Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut. Proc. Natl Acad. Sci. USA 111, 6696–6701 (2014). This study uses a photoconvertible reporter mouse to provide evidence of migration of leukocytes from the intestine to the periphery.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Nakamura, Y. K. et al. Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine. Sci. Rep. 7, 11745 (2017).

    PubMed  PubMed Central  Google Scholar 

  109. Hegazy, A. N. et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology 153, 1320–1337.e16 (2017).

    CAS  PubMed  Google Scholar 

  110. Kugadas, A., Wright, Q., Geddes-McAlister, J. & Gadjeva, M. Role of microbiota in strengthening ocular mucosal barrier function through secretory IgA. Invest. Ophthalmol. Vis. Sci. 58, 4593–4600 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Ciccia, F. et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann. Rheum. Dis. 74, 1739–1747 (2015).

    CAS  PubMed  Google Scholar 

  112. Gracey, E. et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann. Rheum. Dis. 75, 2124–2132 (2016).

    CAS  PubMed  Google Scholar 

  113. Grajewski, R. S. et al. Activation of invariant NKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-gamma production and dampening of the adaptive Th1 and Th17 responses. J. Immunol. 181, 4791–4797 (2008).

    CAS  PubMed  Google Scholar 

  114. Cui, Y. et al. Major role of gamma delta T cells in the generation of IL-17+ uveitogenic T cells. J. Immunol. 183, 560–567 (2009).

    CAS  PubMed  Google Scholar 

  115. van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). This study demonstrates the efficacy of faecal microbiota transplant in the treatment of Clostridium difficile-associated colitis and offers the promise that this therapeutic intervention could be used in other diseases.

    PubMed  Google Scholar 

  116. Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

    PubMed  Google Scholar 

  117. Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109.e6 (2015).

    PubMed  Google Scholar 

  118. Hohmann, E. L., Ananthakrishnan, A. N. & Deshpande, V. Case records of the Massachusetts general hospital. Case 25–2014. A 37-year-old man with ulcerative colitis and bloody diarrhea. N. Engl. J. Med. 371, (668–675 (2014).

    Google Scholar 

  119. Asquith, M. et al. Intestinal metabolites are profoundly altered in the context of HLA-B27 expression and functionally modulate disease in a rat model of spondyloarthritis. Arthritis Rheumatol. 69, 1984–1995 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Monteleone, G. et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N. Engl. J. Med. 372, 1104–1113 (2015).

    CAS  PubMed  Google Scholar 

  121. Hansen, C. H. et al. Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice. J. Immunol. 193, 1213–1222 (2014).

    CAS  PubMed  Google Scholar 

  122. Montoya, J. et al. Patients with ankylosing spondylitis have been breast fed less often than healthy controls: a case-control retrospective study. Ann. Rheum. Dis. 75, 879–882 (2016).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work of the authors was supported by NIH Grants EY026572 to J.T.R., and EY029266 to M.A. and J.T.R., the Spondylitis Association of America to M.A., the William and Mary Bauman Foundation to J.T.R., the Stan and Madelle Family Trust to J.T.R., the Rheumatology Research Foundation to J.T.R. and M.A. and Research to Prevent Blindness to J.T.R. The authors wish to acknowledge many valuable contributions made by the research community that were omitted owing to space to constraints.

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Nature Reviews Rheumatology thanks J. Scher and J. Forrester for their contribution to the peer review of this work.

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  1. Departments of Ophthalmology, Medicine and Cell Biology, Oregon Health and Science University, Portland, OR, USA

    James T. Rosenbaum

  2. Legacy Devers Eye Institute, Portland, OR, USA

    James T. Rosenbaum

  3. Department of Medicine, Oregon Health and Science University, Portland, OR, USA

    Mark Asquith

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Both authors contributed to researching data for the article; substantial discussion of content; and writing, reviewing and editing the manuscript before submission.

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Glossary

Masquerade syndromes

Forms of uveitis that clinically mimic inflammation although inflammation is not the primary cause. Examples include a malignancy such as lymphoma or retinoblastoma, retinal degeneration or retinal detachment.

Molecular mimicry

The induction of autoimmunity caused by a non-self-antigen, such as one derived from a bacteria or virus, that resembles a self-antigen sufficiently such that an autoimmune response is induced.

Tachyphylaxis

In pharmacology, the reduced response to a chemical, such as an opioid, resulting from repeated exposure. Continuous or repetitive exposure to bacterial products such as LPS or peptidoglycan results in tachyphylaxis or reduced inflammation.

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Rosenbaum, J.T., Asquith, M. The microbiome and HLA-B27-associated acute anterior uveitis. Nat Rev Rheumatol 14, 704–713 (2018). https://doi.org/10.1038/s41584-018-0097-2

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