Gut Microbiota in Rheumatoid Arthritis: Pathogenic Mechanisms and Therapeutic Potential
-
Ali Abedian
,
Siavash Amiri
,
Maryam Nobakht
,
Faezeh Talari
,
Esmat Aghadavood
,
Mohamad Esmaeil Shahabodin
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and systemic complications. Although genetic susceptibility and environmental factors contribute to disease development, the precise mechanisms underlying RA pathogenesis remain incompletely understood. Increasing evidence suggests that the gut microbiota plays a critical role in regulating host immune responses and maintaining immune homeostasis. Alterations in the composition and function of gut microbial communities (dysbiosis) have been associated with immune dysregulation and the development of autoimmune diseases, including RA. Recent studies indicate that modulation of the gut microbiome through probiotics, prebiotics, dietary interventions, and microbiota-targeted therapies may alleviate inflammation and improve clinical outcomes in RA patients. This review summarizes the current understanding of RA pathogenesis, highlights the role of gut microbiota in immune regulation, and discusses the therapeutic potential of microbiome-based interventions in the management of RA.
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8. Razawy W, van Driel M, Lubberts E. The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. Eur J Immunol. 2018;48(2):220-9. https://doi.org/10.1002/eji.201646787.
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16. Gao Y, Yan W, Sun L, Zhang X. PiRNA hsa_piR_019914 Promoted Chondrocyte Anabolic Metabolism By Inhibiting LDHA-Dependent ROS Production. Cartilage. 2024;15(3):303-14. https://doi.org/10.1177/19476035231181094.
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27. Noviello D, Mager R, Roda G, Borroni RG, Fiorino G, Vetrano S. The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges. Front Immunol. 2021;12:611256. https://doi.org/10.3389/fimmu.2021.611256.
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2. Sparks JA, Harrold LR, Simon TA, Wittstock K, Kelly S, Lozenski K, et al. Comparative effectiveness of treatments for rheumatoid arthritis in clinical practice: A systematic review. Semin Arthritis Rheum. 2023;62:152249. https://doi.org/10.1016/j.semarthrit.2023.152249.
3. Ding Q, Hu W, Wang R, Yang Q, Zhu M, Li M, et al. Signaling pathways in rheumatoid arthritis: implications for targeted therapy. Signal Transduct Target Ther. 2023;8(1):68. https://doi.org/10.1038/s41392-023-01331-9.
4. van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, Moore RA. Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis. Arthritis Res Ther. 2015;17(1):66. https://doi.org/10.1186/s13075-015-0554-0.
5. Sparks JA, Karlson EW. The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis. Curr Rheumatol Rep. 2016;18(3):15. https://doi.org/10.1007/s11926-016-0563-2.
6. Abbasi M, Mousavi MJ, Jamalzehi S, Alimohammadi R, Bezvan MH, Mohammadi H, Aslani S. Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol. 2019;234(7):10018-31. https://doi.org/10.1002/jcp.27860.
7. van Delft MAM, Huizinga TWJ. An overview of autoantibodies in rheumatoid arthritis. J Autoimmun. 2020;110:102392. https://doi.org/10.1016/j.jaut.2019.102392.
8. Razawy W, van Driel M, Lubberts E. The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. Eur J Immunol. 2018;48(2):220-9. https://doi.org/10.1002/eji.201646787.
9. Frade-Sosa B, Sanmartí R. Neutrophils, neutrophil extracellular traps, and rheumatoid arthritis: An updated review for clinicians. Reumatol Clin (Engl Ed). 2023;19(9):515-26. https://doi.org/10.1016/j.reumae.2023.10.002.
10. Pulik Ł, Łęgosz P, Motyl G. Matrix metalloproteinases in rheumatoid arthritis and osteoarthritis: a state of the art review. Reumatologia. 2023;61(3):191-201. https://doi.org/10.5114/reum/168503.
11. Jung YK, Kang YM, Han S. Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis. Immune Netw. 2019;19(1):e2. https://doi.org/10.4110/in.2019.19.e2.
12. Heldin CH, Lu B, Evans R, Gutkind JS. Signals and Receptors. Cold Spring Harb Perspect Biol. 2016;8(4):a005900. https://doi.org/10.1101/cshperspect.a005900.
13. Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2018;10(5-6):117-27. https://doi.org/10.1177/1759720x18776224.
14. Dascani P, Ding C, Kong X, Tieri D, Hu X, Zhang HG, et al. Transcription Factor STAT3 Serves as a Negative Regulator Controlling IgE Class Switching in Mice. Immunohorizons. 2018;2(11):349-62. https://doi.org/10.4049/immunohorizons.1800069.
15. Liu S, Ma H, Zhang H, Deng C, Xin P. Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis. Clin Immunol. 2021;230:108793. https://doi.org/10.1016/j.clim.2021.108793.
16. Gao Y, Yan W, Sun L, Zhang X. PiRNA hsa_piR_019914 Promoted Chondrocyte Anabolic Metabolism By Inhibiting LDHA-Dependent ROS Production. Cartilage. 2024;15(3):303-14. https://doi.org/10.1177/19476035231181094.
17. Kanai T, Kondo N, Okada M, Sano H, Okumura G, Kijima Y, et al. The JNK pathway represents a novel target in the treatment of rheumatoid arthritis through the suppression of MMP-3. J Orthop Surg Res. 2020;15(1):87. https://doi.org/10.1186/s13018-020-01595-9.
18. Hot A, Zrioual S, Toh ML, Lenief V, Miossec P. IL-17A- versus IL-17F-induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in rheumatoid synoviocytes. Ann Rheum Dis. 2011;70(2):341-8. https://doi.org/10.1136/ard.2010.132233.
19. Ba X, Huang Y, Shen P, Huang Y, Wang H, Han L, et al. WTD Attenuating Rheumatoid Arthritis via Suppressing Angiogenesis and Modulating the PI3K/AKT/mTOR/HIF-1α Pathway. Front Pharmacol. 2021;12:696802. https://doi.org/10.3389/fphar.2021.696802.
20. Liu YT, Ding HH, Lin ZM, Wang Q, Chen L, Liu SS, et al. A novel tricyclic BTK inhibitor suppresses B cell responses and osteoclastic bone erosion in rheumatoid arthritis. Acta Pharmacol Sin. 2021;42(10):1653-64. https://doi.org/10.1038/s41401-020-00578-0.
21. Wang J, Zhou Y, Zhang H, Hu L, Liu J, Wang L, et al. Pathogenesis of allergic diseases and implications for therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):138. https://doi.org/10.1038/s41392-023-01344-4.
22. Cici D, Corrado A, Rotondo C, Cantatore FP. Wnt Signaling and Biological Therapy in Rheumatoid Arthritis and Spondyloarthritis. Int J Mol Sci. 2019;20(22). https://doi.org/10.3390/ijms20225552.
23. Chen S, Wang J, Wang J, Jia X, Xuan Z, Cheng Z, et al. Wnt/β-catenin signaling pathway promotes abnormal activation of fibroblast-like synoviocytes and angiogenesis in rheumatoid arthritis and the intervention of Er Miao San. Phytomedicine. 2023;120:155064. https://doi.org/10.1016/j.phymed.2023.155064.
24. Amiri S, Aghadavood E, Mirzaei H, Shahabodin ME. Novel biomarkers for hepatocellular carcinoma: Unraveling the role of piwi-interacting RNAs (piRNAs). Basic Clin Biochem Nutr. 2025;1(4):239-54. https://doi.org/10.48307/bcbn.2025.558271.1039.
25. Wu Z, Yu X, Zhang S, He Y, Guo W. Novel roles of PIWI proteins and PIWI-interacting RNAs in human health and diseases. Cell Commun Signal. 2023;21(1):343. https://doi.org/10.1186/s12964-023-01368-x.
26. Ahmadi Asouri S, Aghadavood E, Mirzaei H, Abaspour A, Esmaeil Shahaboddin M. PIWI-interacting RNAs (PiRNAs) as emerging biomarkers and therapeutic targets in biliary tract cancers: A comprehensive review. Heliyon. 2024;10(13):e33767. https://doi.org/10.1016/j.heliyon.2024.e33767.
27. Noviello D, Mager R, Roda G, Borroni RG, Fiorino G, Vetrano S. The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges. Front Immunol. 2021;12:611256. https://doi.org/10.3389/fimmu.2021.611256.
28. Plestilova L, Neidhart M, Russo G, Frank-Bertoncelj M, Ospelt C, Ciurea A, et al. Expression and Regulation of PIWIL-Proteins and PIWI-Interacting RNAs in Rheumatoid Arthritis. PLoS One. 2016;11(11):e0166920. https://doi.org/10.1371/journal.pone.0166920.
29. Zhang X, Wang X, Yu F, Wang C, Peng J, Wang C, Chen X. PiRNA hsa_piR_019949 promotes chondrocyte anabolic metabolism by inhibiting the expression of lncRNA NEAT1. J Orthop Surg Res. 2024;19(1):31. https://doi.org/10.1186/s13018-023-04511-z.
30. Latif A, Shehzad A, Niazi S, Zahid A, Ashraf W, Iqbal MW, et al. Probiotics: mechanism of action, health benefits and their application in food industries. Front Microbiol. 2023;14:1216674. https://doi.org/10.3389/fmicb.2023.1216674.
31. Cristofori F, Dargenio VN, Dargenio C, Miniello VL, Barone M, Francavilla R. Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to the Body. Front Immunol. 2021;12:578386. https://doi.org/10.3389/fimmu.2021.578386.
32. Lemme-Dumit JM, Cazorla SI, Perdigón GDV, Maldonado-Galdeano C. Probiotic Bacteria and Their Cell Walls Induce Th1-Type Immunity Against Salmonella Typhimurium Challenge. Front Immunol. 2021;12:660854. https://doi.org/10.3389/fimmu.2021.660854.
33. Darma A, Athiyyah AF, Ranuh RG, Endaryanto A, Budiono B, Sudarmo SM. Effects of probiotics on the enhancement of the innate mucosal immune response against pathogenic bacteria. Iran J Microbiol. 2020;12(5):445-50. https://doi.org/10.18502/ijm.v12i5.4606.
34. Oliviero F, Spinella P. Benefits of Probiotics in Rheumatic Diseases. Front Nutr. 2020;7:157. https://doi.org/10.3389/fnut.2020.00157.
35. Mann ER, Lam YK, Uhlig HH. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol. 2024;24(8):577-95. https://doi.org/10.1038/s41577-024-01014-8.
36. Fan Z, Yang B, Ross RP, Stanton C, Shi G, Zhao J, et al. Protective effects of Bifidobacterium adolescentis on collagen-induced arthritis in rats depend on timing of administration. Food Funct. 2020;11(5):4499-511. https://doi.org/10.1039/d0fo00077a.
37. Kato I, Endo-Tanaka K, Yokokura T. Suppressive effects of the oral administration of Lactobacillus casei on type II collagen-induced arthritis in DBA/1 mice. Life Sci. 1998;63(8):635-44. https://doi.org/10.1016/s0024-3205(98)00315-4.
38. Yamashita M, Matsumoto K, Endo T, Ukibe K, Hosoya T, Matsubara Y, et al. Preventive Effect of Lactobacillus helveticus SBT2171 on Collagen-Induced Arthritis in Mice. Front Microbiol. 2017;8:1159. https://doi.org/10.3389/fmicb.2017.01159.
39. Amdekar S, Singh V, Singh R, Sharma P, Keshav P, Kumar A. Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor. J Clin Immunol. 2011;31(2):147-54. https://doi.org/10.1007/s10875-010-9457-7.
40. Amdekar S, Singh V, Kumar A, Sharma P, Singh R. Lactobacillus casei and Lactobacillus acidophilus regulate inflammatory pathway and improve antioxidant status in collagen-induced arthritic rats. J Interferon Cytokine Res. 2013;33(1):1-8. https://doi.org/10.1089/jir.2012.0034.
41. Pan H, Guo R, Ju Y, Wang Q, Zhu J, Xie 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. https://doi.org/10.1186/s40168-019-0719-1.
42. Achi SC, Talahalli RR, Halami PM. Prophylactic effects of probiotic Bifidobacterium spp. in the resolution of inflammation in arthritic rats. Appl Microbiol Biotechnol. 2019;103(15):6287-96. https://doi.org/10.1007/s00253-019-09864-2.
43. Rovenský J, Stancíková M, Svík K, Utesený J, Bauerová K, Jurcovicová J. Treatment of adjuvant-induced arthritis with the combination of methotrexate and probiotic bacteria Escherichia coli O83 (Colinfant). Folia Microbiol (Praha). 2009;54(4):359-63. https://doi.org/10.1007/s12223-009-0045-2.
44. Abhari K, Shekarforoush SS, Hosseinzadeh S, Nazifi S, Sajedianfard J, Eskandari MH. The effects of orally administered Bacillus coagulans and inulin on prevention and progression of rheumatoid arthritis in rats. Food Nutr Res. 2016;60:30876. https://doi.org/10.3402/fnr.v60.30876.
45. Hatakka K, Martio J, Korpela M, Herranen M, Poussa T, Laasanen T, et al. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis--a pilot study. Scand J Rheumatol. 2003;32(4):211-5. https://doi.org/10.1080/03009740310003695.
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| Files | ||
| Issue | Vol 2026 No 4 (2) | |
| Section | Review Article(s) | |
| Keywords | ||
| Rheumatoid arthritis Gut microbiota Dysbiosis Probiotics Immune regulation Inflammation | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Abedian A, Amiri S, Nobakht M, Talari F, Aghadavood E, Shahabodin ME. Gut Microbiota in Rheumatoid Arthritis: Pathogenic Mechanisms and Therapeutic Potential. ABI. 2026;2026(4):53-62.
