Vol 8, No 4 (2022)
Review paper
Published online: 2022-12-29

open access

Page views 3250
Article views/downloads 506
Get Citation

Connect on Social Media

Connect on Social Media

Intestinal dysbiosis and increased intestinal permeability as a potential risk factor for the development and progression of rheumatoid arthritis

Karolina Zofia Wąż1, Eugeniusz Józef Kucharz1, Magdalena Kopeć-Mędrek1, Robert Pieczyrak1, Przemysław Kotyla1
Rheumatology Forum 2022;8(4):169-177.


Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Factors affecting the development of the disease result from a coincidence of environmental factors, including so-called trigger factors and genetic predisposition which lead to impaired immune tolerance and autoimmune phenomena. The detailed etiopathogenesis of the disease is unclear. Evidence indicates the potential role of the gut microbiome, increased intestinal permeability and disturbed immune response faciliate the development of autoimmune diseases including RA.
The paper is reviewing scientific data on the role of the gut microbiota and increased intestinal permeability in the development and progression of RA. Attention is also focused on factors disrupting the physiological microbial colonization and other factors related to the modern lifestyle in industrialized countries affecting the gut microbiota.
All reported data suggested the role of the gut microbiota in the pathogenesis of RA and further work is necessary to determine whether modulation of the microbiota can serve as a clinical tool to regulate intestinal permeability and influence the development and clinical course of RA.

Article available in PDF format

View PDF Download PDF file


  1. Renz H, Skevaki C. Early life microbial exposures and allergy risks: opportunities for prevention. Nat Rev Immunol. 2021; 21(3): 177–191.
  2. Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020; 9.
  3. Berg G, Rybakova D, Fischer D, et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome. 2020; 8(1): 103.
  4. Mu Q, Kirby J, Reilly CM, et al. Leaky gut as a danger signal for autoimmune diseases. Front Immunol. 2017; 8: 598.
  5. Bergot AS, Giri R, Thomas R. The microbiome and rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019; 33(6): 101497.
  6. Skrzydło-Radomańska B, Wronecki J. [Czy mikrobiotę jelitową można skutecznie modyfikować?]. Gastroenterol Klin. 2018; 10(4): 123–134.
  7. Lee N, Kim WU. Microbiota in T-cell homeostasis and inflammatory diseases. Exp Mol Med. 2017; 49(5): e340.
  8. Horta-Baas G, Romero-Figueroa M, Montiel-Jarquín A, et al. Intestinal dysbiosis and rheumatoid arthritis: a link between gut microbiota and the pathogenesis of rheumatoid arthritis. J Immunol Res. 2017; 2017: 4835189.
  9. Li M, Wang F. Role of intestinal microbiota on gut homeostasis and rheumatoid arthritis. J Immunol Res. 2021; 2021: 8167283.
  10. Shekar C, Kaul G. Butyrate: a simple gut microbiota metabolite in the modulation of epigenetic mechanism. Curr Sci. 2019; 117(3): 362–363.
  11. Cuevas-Sierra A, Ramos-Lopez O, Riezu-Boj JI, et al. Diet, gut microbiota, and obesity: links with host genetics and epigenetics and potential applications. Adv Nutr. 2019; 10(Suppl 1): S17–S30.
  12. Celiker C, Kalkan R. Genetic and epigenetic perspective of microbiota. Appl Microbiol Biotechnol. 2020; 104(19): 8221–8229.
  13. Duar RM, Henrick BM, Casaburi G, et al. Integrating the ecosystem services framework to define dysbiosis of the breastfed infant gut: the role of B. infantis and human milk oligosaccharides. Front Nutr. 2020; 7: 33.
  14. Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016; 6: 23129.
  15. Wopereis H, Oozeer R, Knipping K, et al. The first thousand days — intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014; 25(5): 428–438.
  16. Gomez de Agüero M, Ganal-Vonarburg SC, Fuhrer T, et al. The maternal microbiota drives early postnatal innate immune development. Science. 2016; 351(6279): 1296–1302.
  17. Cukrowska B, Bierła JB, Zakrzewska M, et al. The relationship between the infant gut microbiota and allergy. The role of and prebiotic oligosaccharides in the activation of anti-allergic mechanisms in early life. Nutrients. 2020; 12(4): 946.
  18. Moore RE, Townsend SD. Temporal development of the infant gut microbiome. Open Biol. 2019; 9(9): 190128.
  19. Kaczmarczyk M, Löber U, Adamek K, et al. The gut microbiota is associated with the small intestinal paracellular permeability and the development of the immune system in healthy children during the first two years of life. J Transl Med. 2021; 19(1): 177.
  20. Henrick BM, Hutton AA, Palumbo MC, et al. Elevated fecal pH indicates a profound change in the breastfed infant gut microbiome due to reduction of over the past century. mSphere. 2018; 3(2): e00041-18.
  21. Andersen V, Möller S, Jensen PB, et al. Caesarean delivery and risk of chronic inflammatory diseases (inflammatory bowel disease, rheumatoid arthritis, coeliac disease, and diabetes mellitus): a population based registry study of 2,699,479 births in Denmark during 1973–2016. Clin Epidemiol. 2020; 12: 287–293.
  22. Uusitalo U, Liu X, Yang J, et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. JAMA Pediatr. 2016; 170(1): 20–28.
  23. Pärtty A, Kalliomäki M, Wacklin P, et al. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res. 2015; 77(6): 823–828.
  24. Codella R, Luzi L, Terruzzi I. Exercise has the guts: How physical activity may positively modulate gut microbiota in chronic and immune-based diseases. Dig Liver Dis. 2018; 50(4): 331–341.
  25. Summa KC, Voigt RM, Forsyth CB, et al. Disruption of the circadian clock in mice increases intestinal permeability and promotes alcohol-induced hepatic pathology and inflammation. PLoS One. 2013; 8(6): e67102.
  26. Kong J, Zhang Z, Musch MW, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol. 2008; 294(1): G208–G216.
  27. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019; 68(8): 1516–1526.
  28. Beam A, Clinger E, Hao L. Effect of diet and dietary components on the composition of the gut microbiota. Nutrients. 2021; 13(8): 2795.
  29. Turnbaugh PJ, Ridaura VK, Faith JJ, et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009; 1(6): 6ra14.
  30. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505(7484): 559–563.
  31. Kopf JC, Suhr MJ, Clarke J, et al. Role of whole grains versus fruits and vegetables in reducing subclinical inflammation and promoting gastrointestinal health in individuals affected by overweight and obesity: a randomized controlled trial. Nutr J. 2018; 17(1): 72.
  32. Ríos-Covián D, Ruas-Madiedo P, Margolles A, et al. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016; 7: 185.
  33. Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009; 58(7): 1509–1517.
  34. Donohoe DR, Holley D, Collins LB, et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 2014; 4(12): 1387–1397.
  35. Weiss GA, Hennet T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci. 2017; 74(16): 2959–2977.
  36. Korpela K, Salonen A, Virta LJ, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016; 7: 10410.
  37. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011; 108(Suppl 1): 4554–4561.
  38. Guslandi M. Rifaximin in the treatment of inflammatory bowel disease. World J Gastroenterol. 2011; 17(42): 4643–4646.
  39. Bruno G, Zaccari P, Rocco G, et al. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J Gastroenterol. 2019; 25(22): 2706–2719.
  40. Kohashi O, Kuwata J, Umehara K, et al. Susceptibility to adjuvant-induced arthritis among germfree, specific-pathogen-free, and conventional rats. Infect Immun. 1979; 26(3): 791–794.
  41. De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. 2019; 195(1): 74–85.
  42. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J Autoimmun. 2020; 110: 102400.
  43. Lourido L, Blanco FJ, Ruiz-Romero C. Defining the proteomic landscape of rheumatoid arthritis: progress and prospective clinical applications. Expert Rev Proteomics. 2017; 14(5): 431–444.
  44. Vassallo R, Luckey D, Behrens M, et al. Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin Immunol. 2014; 152(1-2): 25–35.
  45. Hensvold AH, Magnusson PKE, Joshua V, et al. Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann Rheum Dis. 2015; 74(2): 375–380.
  46. Catrina AI, Joshua V, Klareskog L, et al. Mechanisms involved in triggering rheumatoid arthritis. Immunol Rev. 2016; 269(1): 162–174.
  47. Kelmenson LB, Wagner BD, McNair BK, et al. Timing of elevations of autoantibody isotypes prior to diagnosis of rheumatoid arthritis. Arthritis Rheumatol. 2020; 72(2): 251–261.
  48. Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013; 2: e01202.
  49. Maeda Y, Kurakawa T, Umemoto E, et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016; 68(11): 2646–2661.
  50. Kishikawa T, Maeda Y, Nii T, et al. Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population. Ann Rheum Dis. 2020; 79(1): 103–111.
  51. Alpizar-Rodriguez D, Lesker TR, Gronow A, et al. in individuals at risk for rheumatoid arthritis. Ann Rheum Dis. 2019; 78(5): 590–593.
  52. Marietta EV, Murray JA, Luckey DH, et al. Suppression of inflammatory arthritis by human gut-derived prevotella histicola in humanized mice. Arthritis Rheumatol. 2016; 68(12): 2878–2888.
  53. Chen J, Wright K, Davis JM, et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016; 8(1): 43.
  54. Zhang X, Zhang D, Jia H, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015; 21(8): 895–905.
  55. Forbes JD, Chen CY, Knox NC, et al. A comparative study of the gut microbiota in immune-mediated inflammatory diseases-does a common dysbiosis exist? Microbiome. 2018; 6(1): 221.
  56. Manfredo Vieira S, Hiltensperger M, Kumar V, et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018; 359(6380): 1156–1161.
  57. Zhao Y, Chen B, Li S, et al. Detection and characterization of bacterial nucleic acids in culture-negative synovial tissue and fluid samples from rheumatoid arthritis or osteoarthritis patients. Sci Rep. 2018; 8(1): 14305.
  58. Hammad DBM, Hider SL, Liyanapathirana VC, et al. Molecular characterization of circulating microbiome signatures in rheumatoid arthritis. Front Cell Infect Microbiol. 2019; 9: 440.
  59. Xu H, Yin J. HLA risk alleles and gut microbiome in ankylosing spondylitis and rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019; 33(6): 101499.
  60. Asquith M, Sternes PR, Costello ME, et al. HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome. Arthritis Rheumatol. 2019; 71(10): 1642–1650.
  61. Pianta A, Arvikar SL, Strle K, et al. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest. 2017; 127(8): 2946–2956.
  62. Wang X, Gibson GR, Sailer M, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017; 14(8): 491–502.
  63. Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014; 11(8): 506–514.
  64. Bodkhe R, Balakrishnan B, Taneja V. The role of microbiome in rheumatoid arthritis treatment. Ther Adv Musculoskelet Dis. 2019; 11: 1759720X19844632.
  65. Picchianti-Diamanti A, Panebianco C, Salemi S, et al. Analysis of gut microbiota in rheumatoid arthritis patients: disease-related dysbiosis and modifications induced by etanercept. Int J Mol Sci. 2018; 19(10): 2938.
  66. Kussmann M, Obermueller M, Spettel K, et al. In vitro evaluation of disease-modifying antirheumatic drugs against rheumatoid arthritis associated pathogens of the oral microflora. RMD Open. 2021; 7(3): e001737.
  67. Häger J, Bang H, Hagen M, et al. The role of dietary fiber in rheumatoid arthritis patients: a feasibility study. Nutrients. 2019; 11(10): 2392.
  68. Matsumoto Y, Sugioka Y, Tada M, et al. Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study. Clin Nutr. 2018; 37(2): 675–680.
  69. Zamani B, Golkar HR, Farshbaf S, et al. Clinical and metabolic response to probiotic supplementation in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Int J Rheum Dis. 2016; 19(9): 869–879.
  70. Pan H, Guo R, Ju Y, et al. A single bacterium restores the microbiome dysbiosis to protect bones from destruction in a rat model of rheumatoid arthritis. Microbiome. 2019; 7(1): 107.
  71. Ramezani Ahmadi A, Sadeghian M, Alipour M, et al. The effects of probiotic/synbiotic on serum level of zonulin as a biomarker of intestinal permeability: a systematic review and meta-analysis. Iran J Public Health. 2020; 49(7): 1222–1231.
  72. Janczy A, Aleksandrowicz-Wrona E, Kochan Z, et al. Impact of diet and synbiotics on selected gut bacteria and intestinal permeability in individuals with excess body weight — a prospective, randomized study. Acta Biochim Pol. 2020; 67(4): 571–578.
  73. Zmora N, Zeevi D, Korem T, et al. Taking it personally: personalized utilization of the human microbiome in health and disease. Cell Host Microbe. 2016; 19(1): 12–20.