Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The gut–joint axis in rheumatoid arthritis

Nature Reviews Rheumatology volume 17, pages 224–237 (2021)Cite this article

Subjects

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA.

Key points

  • Alterations in the composition of the microbial flora occurs in individuals in the preclinical stages of rheumatoid arthritis (RA) and in those with established RA.

  • DMARDs modify the intestinal microbial composition in patients with RA.

  • Subclinical gut inflammation occurs in some patients with RA and is associated with altered intestinal permeability.

  • Zonulin family peptides are mediators of altered intestinal permeability in RA and their inhibition ameliorates the severity of arthritis in mouse models of disease.

  • Dysbiosis and altered intestinal permeability could induce chronic activation of innate immune cells.

  • Recirculation of innate immune cells from the gut to the peripheral joints has the potential to support the chronic inflammatory process in at least some patients with RA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The gut–joint axis in rheumatoid arthritis.
Fig. 2: Alteration of intestinal permeability in rheumatoid arthritis.
Fig. 3: Interactions between microbiota, intestinal epithelium and immune cells in RA.

Similar content being viewed by others

References

  1. Aletaha, D. & Smolen, J. S. Diagnosis and management of rheumatoid arthritis. JAMA 320, 1360–1372 (2018).

    PubMed  Google Scholar 

  2. Catrina, A. I., Deane, K. D. & Scher, J. U. Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. Rheumatology 55, 391–402 (2016).

    CAS  PubMed  Google Scholar 

  3. Scher, J. U. et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome 4, 60 (2016).

    PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Holers, V. M. et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat. Rev. Rheumatol. 14, 542–557 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Wells, P. M. et al. Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional study. Lancet Rheumatol. 2, e418–e427 (2020).

    PubMed  PubMed Central  Google Scholar 

  7. Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).

    CAS  PubMed  Google Scholar 

  8. Chen, J. et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 8, 43 (2016).

    PubMed  PubMed Central  Google Scholar 

  9. Marietta, E. V. et al. Suppression of inflammatory arthritis by human gut-derived Prevotella histicola in humanized mice. Arthritis Rheumatol. 68, 2878–2888 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Maeda, Y. et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 68, 2646–2661 (2016).

    CAS  PubMed  Google Scholar 

  11. Alpizar-Rodriguez, D. et al. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann. Rheum. Dis. 78, 590–593 (2019).

    CAS  PubMed  Google Scholar 

  12. Inamo, J. Non-causal association of gut microbiome on the risk of rheumatoid arthritis: A Mendelian randomisation study. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2019-216565 (2019).

    Article  PubMed  Google Scholar 

  13. Alpizar Rodriguez, D., Lesker, T. R., Gilbert, B., Strowig, T. & Finckh, A. Intestinal dysbiosis in RA development: difficulty of establishing causality. Response to: ‘Non-causal association of gut microbiome on the risk of rheumatoid arthritis: a Mendelian randomisation study’ by Inamo. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2019-216637 (2019).

    Article  PubMed  Google Scholar 

  14. Jeong, Y. et al. Gut microbial composition and function are altered in patients with early rheumatoid arthritis. J. Clin. Med. 8, 693 (2019).

    CAS  PubMed Central  Google Scholar 

  15. [No authors listed]. News & highlights. Mucosal Immunol. 1, 246–247 (2008).

    Google Scholar 

  16. Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17, 219–232 (2017).

    CAS  PubMed  Google Scholar 

  17. Quirke, A. M. et al. Bronchiectasis is a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis. Arthritis Rheumatol. 67, 2335–2342 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bergot, A.-S., Giri, R. & Thomas, R. The microbiome and rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 33, 101497 (2019).

    PubMed  Google Scholar 

  19. Clarke, A. et al. Heightened autoantibody immune response to citrullinated calreticulin in bronchiectasis: implications for rheumatoid arthritis. Int. J. Biochem. Cell Biol. 89, 199–206 (2017).

    CAS  PubMed  Google Scholar 

  20. Potempa, J., Mydel, P. & Koziel, J. The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 606–620 (2017).

    CAS  PubMed  Google Scholar 

  21. Mariette, X. et al. Role of good oral hygiene on clinical evolution of rheumatoid arthritis: a randomized study nested in the ESPOIR cohort. Rheumatology 59, 988–996 (2020).

    CAS  PubMed  Google Scholar 

  22. Horta-Baas, G. et al. Intestinal dysbiosis and rheumatoid arthritis: a link between gut microbiota and the pathogenesis of rheumatoid arthritis. J. Immunol. Res. 2017, 4835189 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. Salem, F. et al. Gut microbiome in chronic rheumatic and inflammatory bowel diseases: similarities and differences. United European Gastroenterol. J. 7, 1008–1032 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Rogier, R. et al. Alteration of the intestinal microbiome characterizes preclinical inflammatory arthritis in mice and its modulation attenuates established arthritis. Sci. Rep. 7, 15613 (2017).

    PubMed  PubMed Central  Google Scholar 

  25. Jubair, W. K. et al. Modulation of inflammatory arthritis in mice by gut microbiota through mucosal inflammation and autoantibody generation. Arthritis Rheumatol. 70, 1220–1233 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Aa, L.-X. et al. Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol. Acta Pharmacol. Sin. 41, 73–81 (2020).

    CAS  PubMed  Google Scholar 

  27. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Eason, R. J. et al. The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ. Sci. Rep. 6, 37276 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Doonan, J. et al. The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis. Nat. Commun. 10, 1554 (2019).

    PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Atarashi, K. et al. ATP drives lamina propria T(H)17 cell differentiation. Nature 455, 808–812 (2008).

    CAS  PubMed  Google Scholar 

  33. Horai, R. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191, 313–320 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Abdollahi-Roodsaz, S. et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J. Clin. Invest. 118, 205–216 (2008).

    CAS  PubMed  Google Scholar 

  35. Rogier, R. et al. Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis. Microbiome 5, 63 (2017).

    PubMed  PubMed Central  Google Scholar 

  36. Zhang, Y., Li, Y., Lv, T.-T., Yin, Z.-J. & Wang, X.-B. Elevated circulating Th17 and follicular helper CD4+ T cells in patients with rheumatoid arthritis. APMIS 123, 659–666 (2015).

    CAS  PubMed  Google Scholar 

  37. Alunno, A. et al. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediators Inflamm. 2015, 751793 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. Pianta, A. et al. Evidence of the immune relevance of Prevotella copri, a gut microbe, in patients with rheumatoid arthritis. Arthritis Rheumatol. 69, 964–975 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chiang, H.-I. et al. An association of gut microbiota with different phenotypes in Chinese patients with rheumatoid arthritis. J. Clin. Med. 8, 1770 (2019).

    CAS  PubMed Central  Google Scholar 

  40. Van Delft, M. A. M., Van Der Woude, D., Toes, R. E. M. & Trouw, L. A. Secretory form of rheumatoid arthritis-associated autoantibodies in serum are mainly of the IgM isotype, suggesting a continuous reactivation of autoantibody responses at mucosal surfaces. Ann. Rheum. Dis. 78, 146–148 (2019).

    PubMed  Google Scholar 

  41. Rios, D. et al. Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria. Mucosal Immunol. 9, 907–916 (2016).

    CAS  PubMed  Google Scholar 

  42. Jubair, W. et al. Intestinal inflammation and netosis associate with the presence of stool IgA ACPA in subjects at-risk for RA [abstract]. Arthritis Rheumatol. 70 (Suppl. 10), 67 (2018).

    Google Scholar 

  43. Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013).

    CAS  PubMed  Google Scholar 

  44. Johnson, B. M. et al. Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice. J. Autoimmun. 108, 102420 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gomez, A., Luckey, D. & Taneja, V. The gut microbiome in autoimmunity: sex matters. Clin. Immunol. 159, 154–162 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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 

  47. Gonçalves dos Santos, G. et al. The neuropathic phenotype of the K/BxN transgenic mouse with spontaneous arthritis: pain, nerve sprouting and joint remodeling. Sci. Rep. 10, 15596 (2020).

    PubMed  PubMed Central  Google Scholar 

  48. Taneja, V. et al. New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. Arthritis Rheum. 56, 69–78 (2007).

    PubMed  Google Scholar 

  49. Behrens, M. et al. Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice. J. Autoimmun. 35, 1–9 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun, Y. et al. Characteristics of gut microbiota in patients with rheumatoid arthritis in Shanghai, China. Front. Cell. Infect. Microbiol. 9, 369 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee, Y. K. & Mazmanian, S. K. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330, 1768–1773 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sommer, F. & Bäckhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

    CAS  PubMed  Google Scholar 

  53. Burrello, C. et al. Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat. Commun. 9, 5184 (2018).

    PubMed  PubMed Central  Google Scholar 

  54. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lleal, M. et al. A single faecal microbiota transplantation modulates the microbiome and improves clinical manifestations in a rat model of colitis. EBioMedicine 48, 630–641 (2019).

    PubMed  PubMed Central  Google Scholar 

  56. Tajik, N. et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat. Commun. 11, 1995 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu, X. et al. Role of the gut microbiome in modulating arthritis progression in mice. Sci. Rep. 6, 30594 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cypers, H. et al. Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis. Ann. Rheum. Dis. 75, 1357–1362 (2016).

    CAS  PubMed  Google Scholar 

  59. Hindryckx, P. et al. Subclinical gut inflammation in spondyloarthritis is associated with a pro-angiogenic intestinal mucosal phenotype. Ann. Rheum. Dis. 70, 2044–2048 (2011).

    CAS  PubMed  Google Scholar 

  60. 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).

    PubMed  Google Scholar 

  61. Mielants, H., Veys, E. M., Cuvelier, C., De Vos, M. & Botelberghe, L. HLA-B27 related arthritis and bowel inflammation. Part 2. Ileocolonoscopy and bowel histology in patients with HLA-B27 related arthritis. J. Rheumatol. 12, 294–298 (1985).

    CAS  PubMed  Google Scholar 

  62. Mielants, H. et al. The evolution of spondyloarthropathies in relation to gut histology. I. Clinical aspects. J. Rheumatol. 22, 2266–2272 (1995).

    CAS  PubMed  Google Scholar 

  63. Schatteman, L. et al. Gut inflammation in psoriatic arthritis: a prospective ileocolonoscopic study. J. Rheumatol. 22, 680–683 (1995).

    CAS  PubMed  Google Scholar 

  64. 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 

  65. Ciccia, F. et al. Proinflammatory CX3CR1+CD59+ tumor necrosis factor-like molecule 1A+interleukin-23+ monocytes are expanded in patients with ankylosing spondylitis and modulate innate lymphoid cell 3 immune functions. Arthritis Rheumatol. 70, 2003–2013 (2018).

    CAS  PubMed  Google Scholar 

  66. Viladomiu, M. et al. IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent inflammation. Sci. Transl Med. 9, eaaf9655 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. Nissinen, R. et al. Immune activation in the small intestine in patients with rheumatoid arthritis. Ann. Rheum. Dis. 63, 1327–1330 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Marcolongo, R., Bayeli, P. F. & Montagnani, M. Gastrointestinal involvement in rheumatoid arthritis: a biopsy study. J. Rheumatol. 6, 163–173 (1979).

    CAS  PubMed  Google Scholar 

  69. Porzio, V. et al. Intestinal histological and ultrastructural inflammatory changes in spondyloarthropathy and rheumatoid arthritis. Scand. J. Rheumatol. 26, 92–98 (1997).

    CAS  PubMed  Google Scholar 

  70. Bae, J. M., Choo, J. Y., Kim, K. J. & Park, K. S. Association of inflammatory bowel disease with ankylosing spondylitis and rheumatoid arthritis: a nationwide population-based study. Mod. Rheumatol. 27, 435–440 (2017).

    CAS  PubMed  Google Scholar 

  71. Nguyen, Y. et al. Chronic diarrhoea and risk of rheumatoid arthritis: findings from the French E3N-EPIC Cohort Study. Rheumatology 59, 3767–3775 (2020).

    PubMed  Google Scholar 

  72. Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018).

    CAS  PubMed  Google Scholar 

  73. Neurath, M. F. Host–microbiota interactions in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 76–77 (2019).

    Google Scholar 

  74. Vrakas, S. et al. Intestinal bacteria composition and translocation of bacteria in inflammatory bowel disease. PLoS ONE 12, e0170034 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. Smith, M. D., Gibson, R. A. & Brooks, P. M. Abnormal bowel permeability in ankylosing spondylitis and rheumatoid arthritis. J. Rheumatol. 12, 299–305 (1985).

    CAS  PubMed  Google Scholar 

  76. Fasano, A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research 9, 69 (2020).

    CAS  Google Scholar 

  77. Fasano, A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin. Gastroenterol. Hepatol. 10, 1096–1100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Thomas, K. E., Sapone, A., Fasano, A. & Vogel, S. N. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in celiac disease. J. Immunol. 176, 2512–2521 (2006).

    CAS  PubMed  Google Scholar 

  79. Clemente, M. G. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 52, 218–223 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Sturgeon, C. & Fasano, A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 4, e1251384 (2016).

    PubMed  PubMed Central  Google Scholar 

  81. Drago, S. et al. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand. J. Gastroenterol. 41, 408–419 (2006).

    CAS  PubMed  Google Scholar 

  82. 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 

  83. El Asmar, R. et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology 123, 1607–1615 (2002).

    CAS  PubMed  Google Scholar 

  84. Evans-Marin, H. et al. Microbiota-dependent involvement of Th17 cells in murine models of inflammatory arthritis. Arthritis Rheumatol. 70, 1971–1983 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sato, K. et al. Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system. Sci. Rep. 7, 6955 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. Flak, M. B. et al. Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis. JCI insight 4, e125191 (2019).

    PubMed Central  Google Scholar 

  87. Arimatsu, K. et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci. Rep. 4, 4828 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Nakajima, M. et al. Oral administration of P. gingivalis induces dysbiosis of gut microbiota and impaired barrier function leading to dissemination of Enterobacteria to the liver. PLoS ONE 10, e0134234 (2015).

    PubMed  PubMed Central  Google Scholar 

  89. Elkan, A.-C. et al. Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study. Arthritis Res. Ther. 10, R34 (2008).

    PubMed  PubMed Central  Google Scholar 

  90. Hafstrom, I. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology 40, 1175–1179 (2001).

    CAS  PubMed  Google Scholar 

  91. Lammers, K. M. et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 135, 194–204.e3 (2008).

    CAS  PubMed  Google Scholar 

  92. Shimada, S. et al. Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage. PLoS ONE 14, e0211436 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Tagesson, C. & Bengtsson, A. Intestinal permeability to different-sized polyethyleneglycols in patients with rheumatoid arthritis. Scand. J. Rheumatol. 12, 124–128 (1983).

    CAS  PubMed  Google Scholar 

  94. Jenkins, R. T., Rooney, P. J., Jones, D. B., Bienenstock, J. & Goodacre, R. L. Increased intestinal permeability in patients with rheumatoid arthritis: a side-effect of oral nonsteroidal anti-inflammatory drug therapy? Rheumatology 26, 103–107 (1987).

    CAS  Google Scholar 

  95. Mielants, H. et al. Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs. J. Rheumatol. 18, 389–393 (1991).

    CAS  PubMed  Google Scholar 

  96. Bjarnason, I. et al. Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet 324, 1171–1174 (1984).

    Google Scholar 

  97. Sigthorsson, G. et al. Intestinal permeability and inflammation in patients on NSAIDs. Gut 43, 506–511 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Mielants, H. et al. Intestinal mucosal permeability in inflammatory rheumatic diseases. II. Role of disease. J. Rheumatol. 18, 394–400 (1991).

    CAS  PubMed  Google Scholar 

  99. Rodríguez-Lagunas, M. J., Martín-Venegas, R., Moreno, J. J. & Ferrer, R. PGE2 promotes Ca2+-mediated epithelial barrier disruption through EP1 and EP4 receptors in Caco-2 cell monolayers. Am. J. Physiol. Physiol. 299, C324–C334 (2010).

    Google Scholar 

  100. Teng, F. et al. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer’s patch T follicular helper cells. Immunity 44, 875–888 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nielen, M. M. J. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).

    PubMed  Google Scholar 

  102. Rantapää-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).

    PubMed  Google Scholar 

  103. Shi, J. et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann. Rheum. Dis. 73, 780–783 (2013).

    PubMed  Google Scholar 

  104. Demoruelle, M. K. et al. Brief report: Airways abnormalities and rheumatoid arthritis–related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 64, 1756–1761 (2011).

    PubMed  PubMed Central  Google Scholar 

  105. Gizinski, A. M. et al. Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA. Clin. Rheumatol. 28, 611–613 (2009).

    PubMed  PubMed Central  Google Scholar 

  106. Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA–DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006).

    CAS  PubMed  Google Scholar 

  107. Botton, E., Saraux, A., Laselve, H., Jousse, S. & Le Goff, P. Musculoskeletal manifestations in cystic fibrosis. Joint Bone Spine 70, 327–335 (2003).

    PubMed  Google Scholar 

  108. Elkayam, O., Segal, R., Lidgi, M. & Caspi, D. Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis. Ann. Rheum. Dis. 65, 1110–1112 (2006).

    CAS  PubMed  Google Scholar 

  109. Thé, J. & Ebersole, J. L. Rheumatoid factor (RF) distribution in periodontal disease. J. Clin. Immunol. 11, 132–142 (1991).

    PubMed  Google Scholar 

  110. Kelmenson, L. B. et al. Timing of elevations of autoantibody isotypes prior to diagnosis of rheumatoid arthritis. Arthritis Rheumatol. 72, 251–261 (2020).

    CAS  PubMed  Google Scholar 

  111. Hvatum, M., Kanerud, L., Hällgren, R. & Brandtzaeg, P. The gut-joint axis: cross reactive food antibodies in rheumatoid arthritis. Gut 55, 1240–1247 (2006).

    CAS  PubMed  Google Scholar 

  112. Salmi, M., Andrew, D. P., Butcher, E. C. & Jalkanen, S. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J. Exp. Med. 181, 137–149 (1995).

    CAS  PubMed  Google Scholar 

  113. May, E. et al. Identical T-cell expansions in the colon mucosa and the synovium of a patient with enterogenic spondyloarthropathy. Gastroenterology 119, 1745–1755 (2000).

    CAS  PubMed  Google Scholar 

  114. Trollmo, C., Verdrengh, M. & Tarkowski, A. Fasting enhances mucosal antigen specific B cell responses in rheumatoid arthritis. Ann. Rheum. Dis. 56, 130–134 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Mauro, D., Macaluso, F., Fasano, S., Alessandro, R. & Ciccia, F. ILC3 in axial spondyloarthritis: the gut angle. Curr. Rheumatol. Rep. 21, 37 (2019).

    PubMed  Google Scholar 

  116. Simoni, Y. et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 46, 148–161 (2017).

    CAS  PubMed  Google Scholar 

  117. Mebius, R. E., Rennert, P. & Weissman, I. L. Developing lymph nodes collect CD4+CD3− LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).

    CAS  PubMed  Google Scholar 

  118. Longman, R. S. et al. CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J. Exp. Med. 211, 1571–1583 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Mauro, D. & Ciccia, F. Gut dysbiosis in spondyloarthritis: cause or effect? Best Pract. Res. Clin. Rheumatol. 33, 101493 (2020).

    Google Scholar 

  120. Li, S., Bostick, J. W. & Zhou, L. Regulation of innate lymphoid cells by aryl hydrocarbon receptor. Front. Immunol. 8, 1909 (2017).

    PubMed  Google Scholar 

  121. Kim, S.-H., Cho, B.-H., Kiyono, H. & Jang, Y.-S. Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer’s patches. Sci. Rep. 7, 3980 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. Chun, E. et al. Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity. Immunity 51, 871–884.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Soare, A. et al. Cutting edge: Homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis. J. Immunol. 200, 1249–1254 (2018).

    CAS  PubMed  Google Scholar 

  124. Cuthbert, R. J. et al. Brief report: Group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 69, 1816–1822 (2017).

    CAS  PubMed  Google Scholar 

  125. Rodríguez-Carrio, J. et al. Brief report: Altered innate lymphoid cell subsets in human lymph node biopsy specimens obtained during the at-risk and earliest phases of rheumatoid arthritis. Arthritis Rheumatol. 69, 70–76 (2017).

    PubMed  Google Scholar 

  126. Fang, W., Zhang, Y. & Chen, Z. Innate lymphoid cells in inflammatory arthritis. Arthritis Res. Ther. 22, 25 (2020).

    PubMed  PubMed Central  Google Scholar 

  127. Takaki-Kuwahara, A. et al. CCR6+ group 3 innate lymphoid cells accumulate in inflamed joints in rheumatoid arthritis and produce Th17 cytokines. Arthritis Res. Ther. 21, 198 (2019).

    PubMed  PubMed Central  Google Scholar 

  128. Ren, J., Feng, Z., Lv, Z., Chen, X. & Li, J. Natural killer-22 cells in the synovial fluid of patients with rheumatoid arthritis are an innate source of interleukin 22 and tumor necrosis factor-α. J. Rheumatol. 38, 2112–2118 (2011).

    CAS  PubMed  Google Scholar 

  129. Toubal, A., Nel, I., Lotersztajn, S. & Lehuen, A. Mucosal-associated invariant T cells and disease. Nat. Rev. Immunol. 19, 643–657 (2019).

    CAS  PubMed  Google Scholar 

  130. Toussirot, E. & Saas, P. MAIT cells: potent major cellular players in the IL-17 pathway of spondyloarthritis? RMD Open 4, e000821 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. 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 

  132. Treiner, E. Mucosal-associated invariant T cells in inflammatory bowel diseases: bystanders, defenders, or offenders? Front. Immunol. 6, 27 (2015).

    PubMed  PubMed Central  Google Scholar 

  133. Koppejan, H. et al. Altered composition and phenotype of mucosal-associated invariant T cells in early untreated rheumatoid arthritis. Arthritis Res. Ther. 21, 3 (2019).

    PubMed  PubMed Central  Google Scholar 

  134. Leeansyah, E. et al. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood 121, 1124–1135 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Cho, Y.-N. et al. Mucosal-associated invariant T cell deficiency in systemic lupus erythematosus. J. Immunol. 193, 3891–3901 (2014).

    CAS  PubMed  Google Scholar 

  136. Kim, M. et al. TNFα and IL-1β in the synovial fluid facilitate mucosal-associated invariant T (MAIT) cell migration. Cytokine 99, 91–98 (2017).

    CAS  PubMed  Google Scholar 

  137. Kurioka, A., Walker, L. J., Klenerman, P. & Willberg, C. B. MAIT cells: new guardians of the liver. Clin. Transl Immunol. 5, e98 (2016).

    Google Scholar 

  138. Nowotschin, S. & Hadjantonakis, A.-K. Use of KikGR a photoconvertible green-to-red fluorescent protein for cell labeling and lineage analysis in ES cells and mouse embryos. BMC Dev. Biol. 9, 49 (2009).

    PubMed  PubMed Central  Google Scholar 

  139. Tsutsui, H., Karasawa, S., Shimizu, H., Nukina, N. & Miyawaki, A. Semi-rational engineering of a coral fluorescent protein into an efficient highlighter. EMBO Rep. 6, 233–238 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Proietti, M. et al. ATP-gated ionotropic P2X7 receptor controls follicular T helper cell numbers in Peyer’s patches to promote host-microbiota mutualism. Immunity 41, 789–801 (2014).

    CAS  PubMed  Google Scholar 

  141. Felix, K. M. et al. P2RX7 deletion in T cells promotes autoimmune arthritis by unleashing the Tfh cell response. Front. Immunol. 10, 411 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Di Virgilio, F., Dal Ben, D., Sarti, A. C., Giuliani, A. L. & Falzoni, S. The P2X7 receptor in infection and inflammation. Immunity 47, 15–31 (2017).

    PubMed  Google Scholar 

  143. Gattorno, M. et al. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 58, 1505–1515 (2008).

    CAS  PubMed  Google Scholar 

  144. Lucas, C., Perdriger, A. & Amé, P. Definition of B cell helper T cells in rheumatoid arthritis and their behavior during treatment. Semin. Arthritis Rheum. 50, 867–872 (2020).

    CAS  PubMed  Google Scholar 

  145. Cao, G. et al. An imbalance between blood CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells may contribute to the immunopathogenesis of rheumatoid arthritis. Mol. Immunol. 125, 1–8 (2020).

    CAS  PubMed  Google Scholar 

  146. Bates, N. A. et al. Gut commensal segmented filamentous bacteria fine-tune T follicular regulatory cells to modify the severity of systemic autoimmune arthritis. J. Immunol. https://doi.org/10.4049/jimmunol.2000663 (2021).

    Article  PubMed  Google Scholar 

  147. Stone, M., Fortin, P. R., Pacheco-Tena, C. & Inman, R. D. Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J. Rheumatol. 30, 2112–2122 (2003).

    CAS  PubMed  Google Scholar 

  148. Amin, A. R. et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc. Natl Acad. Sci. USA 93, 14014–14019 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Zaura, E. et al. Same exposure but two radically different responses to antibiotics: Resilience of the salivary microbiome versus long-term microbial shifts in feces. mBio 6, e01693-15 (2015).

    PubMed  PubMed Central  Google Scholar 

  150. Toivanen, P. et al. Intestinal anaerobic bacteria in early rheumatoid arthritis (RA) [abstract]. Arthritis Res. 4 (Suppl. 1), 5 (2002).

    PubMed Central  Google Scholar 

  151. Picchianti-Diamanti, A. et al. Analysis of gut microbiota in rheumatoid arthritis patients: disease-related dysbiosis and modifications induced by etanercept. Int. J. Mol. Sci. 19, 2938 (2018).

    PubMed Central  Google Scholar 

  152. Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Bolin, J. T., Filman, D. J., Matthews, D. A., Hamlin, R. C. & Kraut, J. Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 Aθ resolution. I. General features and binding of methotrexate. J. Biol. Chem. 257, 13650–13662 (1982).

    CAS  PubMed  Google Scholar 

  154. Scher, J. U., Nayak, R. R., Ubeda, C., Turnbaugh, P. J. & Abramson, S. B. Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response. Nat. Rev. Rheumatol. 16, 282–292 (2020).

    PubMed  Google Scholar 

  155. Krook, A. Effect of metronidazole and sulfasalazine on the normal human faecal flora. Scand. J. Gastroenterol. 16, 587–592 (1981).

    CAS  PubMed  Google Scholar 

  156. Abdollahi-Roodsaz, S., Abramson, S. B. & Scher, J. U. The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat. Rev. Rheumatol. 12, 446–455 (2016).

    CAS  PubMed  Google Scholar 

  157. Neumann, V. C., Shinebaum, R., Cooke, E. M. & Wright, V. Effects of sulphasalazine on faecal flora in patients with rheumatoid arthritis: a comparison with penicillamine. Rheumatology 26, 334–337 (1987).

    CAS  Google Scholar 

  158. Kanerud, L., Scheynius, A., Nord, C. E. & Hafström, I. Effect of sulphasalazine on gastrointestinal microflora and on mucosal heat shock protein expression in patients with rheumatoid arthritis. Rheumatology 33, 1039–1048 (1994).

    CAS  Google Scholar 

  159. Wang, B., He, Y., Tang, J., Ou, Q. & Lin, J. Alteration of the gut microbiota in tumor necrosis factor-α antagonist-treated collagen-induced arthritis mice. Int. J. Rheum. Dis. 23, 472–479 (2020).

    CAS  PubMed  Google Scholar 

  160. Forbes, J. D. et al. A comparative study of the gut microbiota in immune-mediated inflammatory diseases – does a common dysbiosis exist? Microbiome 6, 221 (2018).

    PubMed  PubMed Central  Google Scholar 

  161. Aqaeinezhad Rudbane, S. M. et al. The efficacy of probiotic supplementation in rheumatoid arthritis: a meta-analysis of randomized, controlled trials. Inflammopharmacology 26, 67–76 (2018).

    CAS  PubMed  Google Scholar 

  162. Sköldstam, L., Hagfors, L. & Johansson, G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann. Rheum. Dis. 62, 208–214 (2003).

    PubMed  PubMed Central  Google Scholar 

  163. Kjeldsen-Kragh, J. et al. Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. Lancet 338, 899–902 (1991).

    CAS  PubMed  Google Scholar 

  164. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  PubMed  Google Scholar 

  165. Häger, J. et al. The role of dietary fiber in rheumatoid arthritis patients: a feasibility study. Nutrients 11, 2392 (2019).

    PubMed Central  Google Scholar 

  166. Zhang, J. et al. Autophagy and mitochondrial dysfunction in adjuvant-arthritis rats treatment with resveratrol. Sci. Rep. 6, 32928 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Khojah, H. M., Ahmed, S., Abdel-Rahman, M. S. & Elhakeim, E. H. Resveratrol as an effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study. Clin. Rheumatol. 37, 2035–2042 (2018).

    PubMed  Google Scholar 

  168. Alrafas, H. R., Busbee, P. B., Nagarkatti, M. & Nagarkatti, P. S. Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells. J. Leukoc. Biol. 106, 467–480 (2019).

    CAS  PubMed  Google Scholar 

  169. Naskar, D., Teng, F., Felix, K. M., Bradley, C. P. & Wu, H.-J. J. Synthetic retinoid AM80 ameliorates lung and arthritic autoimmune responses by inhibiting T follicular helper and Th17 cell responses. J. Immunol. 198, 1855–1864 (2017).

    CAS  PubMed  Google Scholar 

  170. Ruane, D. T. & Lavelle, E. C. The role of CD103+ dendritic cells in the intestinal mucosal immune system. Front. Immunol. 2, 25 (2011).

    PubMed  PubMed Central  Google Scholar 

  171. Collins, J., Auchtung, J. M., Schaefer, L., Eaton, K. A. & Britton, R. A. Humanized microbiota mice as a model of recurrent Clostridium difficile disease. Microbiome 3, 35 (2015).

    PubMed  PubMed Central  Google Scholar 

  172. Tan, T. G. et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc. Natl Acad. Sci. USA 113, E8141–E8150 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Vaahtovuo, J., Munukka, E., Korkeamäki, M., Luukkainen, R. & Toivanen, P. Fecal microbiota in early rheumatoid arthritis. J. Rheumatol. 35, 1500–1505 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  176. Kishikawa, T. et al. Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population. Ann. Rheum. Dis. 79, 103–111 (2020).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Mario M. Zaiss & Georg Schett

  2. Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Mario M. Zaiss & Georg Schett

  3. Department of Immunobiology, Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, AZ, USA

    Hsin-Jung Joyce Wu

  4. Dipartimento di Medicina di Precisione, University della Campania L. Vanvitelli, Naples, Italy

    Daniele Mauro & Francesco Ciccia

Authors
  1. Mario M. Zaiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hsin-Jung Joyce Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniele Mauro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Georg Schett
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Ciccia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of this article.

Corresponding author

Correspondence to Francesco Ciccia.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Rheumatology thanks V. Taneja, A. Finckh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zaiss, M.M., Joyce Wu, HJ., Mauro, D. et al. The gut–joint axis in rheumatoid arthritis. Nat Rev Rheumatol 17, 224–237 (2021). https://doi.org/10.1038/s41584-021-00585-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-021-00585-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing