Causal relationship between gut microbiota and rheumatoid arthritis: data analysis in European populations based on GWAS data

doi:10.12307/2026.536

Abstract

Abstract: BACKGROUND: Studies have shown that gut microbiota may affect the progression of rheumatoid arthritis. However, the causal relationship between the two is unknown. Mendelian randomization analysis of the two using published Genome Wide Association Study (GWAS) data can explore the causal relationship between gut microbiota and rheumatoid arthritis, helping to develop targeted microbial therapies and provide methods and strategies for the prevention and treatment of rheumatoid arthritis.
OBJECTIVE: To explore the potential causal relationship between gut microbiota and rheumatoid arthritis using two-sample two-way Mendelian randomization method.
METHODS: Gut microbiota GWAS data from the MiBio-Gen consortium and rheumatoid arthritis GWAS data from the IEU Open GWAS database (a large gene-phenotype association database developed at the MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK) were used. Inverse variance weighting was used as the main analysis method, and MR-Egger regression method, weighted median method, weighted model and simple model method were used as supplements to study the causal relationship between gut microbiota and rheumatoid arthritis. Heterogeneity was assessed using Cochran’s Q test, horizontal pleiotropy was assessed using MR-PRESSO and MR-Egger intercept tests, robustness of results was tested using leave-one method, and reverse Mendelian randomization analysis was used to assess the presence or absence of reverse causality.
RESULTS AND CONCLUSION: (1) There was a causal relationship between five kinds of enteric bacteria and rheumatoid arthritis. Ruminococcus gauvreauii group (β=0.262, odds ratio [OR]=1.300, P=0.013) and Butyricimonas (β=0.001, OR=1.001, P=0.014) increased the risk of rheumatoid arthritis, while Anaerostipes (β=-0.225, OR=0.798, P=0.025), Lachnospiraceae-UCG010 (β=-0.177, OR=0.838, P=0.026) and Oxalobacter (β=-0.171, OR=0.843, P=0.001) reduced the risk of rheumatoid arthritis. Sensitivity analyses showed no significant heterogeneity or horizontal pleiotropy (all P > 0.05), and leave-one-out testing confirmed the robustness of the results, while the addition of the remaining four methods other than the inverse variance weighting method further validated the reliability and stability of the results. (2) Reverse Mendelian randomization analysis did not find a causal association between rheumatoid arthritis and the five kinds of enteric bacteria identified by Mendelian randomization analysis. These findings indicate that Ruminococcus gauvreauii group and Butyricimonas may be the risk factors of rheumatoid arthritis, while Anaerostipes, Lachnospiraceae-UCG010 and Oxalobacter may be the protective factors of rheumatoid arthritis. Gut microbiota may play an important role in the pathogenesis of rheumatoid arthritis, and provide new biomarkers for the prevention and treatment of rheumatoid arthritis. In addition, for the field of biomedical research in China, we can learn from international experience and gradually establish and improve a multi-center large-scale genetic database, so as to deeply explore the relationship between gut microbiota and disease risk, and promote the development of precision medicine and personalized treatment in China.

Key words: gut microbiota, rheumatoid arthritis, Mendelian randomization, causality, inverse variance weighting method

CLC Number:

Wang Tao, Wang Shunpu, Min Youjiang, Wang Min, Li Le, Zhang Chen, Xiao Weiping. Causal relationship between gut microbiota and rheumatoid arthritis: data analysis in European populations based on GWAS data[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(35): 7663-7668.

Figures/Tables 4

2.1 正向孟德尔随机化分析结果以逆方差加权法为主要分析法，经过一系列的筛选与检测，最终纳入5类与类风湿关节炎相关的肠道菌群。与“ebi-a-GCST002318”数据库有关的肠道菌群有4类，共43个单核苷酸多态性，其中厌氧斯氏菌属(β=-0.225，OR=0.798，P=0.025)、毛螺菌属-UCG010(β=-0.177，OR=0.838，P=0.026)和草酸杆菌属(β=-0.171，OR=0.843，P= 0.001)是类风湿关节炎的保护菌，瘤胃球菌属(β=0.262，OR=1.300，P=0.013)是类风湿关节炎的危险菌；与“ukb-d-M13_RHEUMA”数据库有关的肠道菌群有1类，共17个单核苷酸多态性，其中丁酸梭菌属(β=0.001，OR=1.001，P=0.014)是类风湿关节炎的危险菌，见表1。另外，文章还运用MR-Egger、加权中位数法、加权模型法和简单模型法对结果进行补充验证，结果显示其他4种方法结果方向与逆方差加权法基本一致，见图2。 2.2 敏感性分析结果使用Cochran’s Q检验评估异质性，MR-PRESSO全局检验和MR-Egger intercept检验评估水平多效性，留一法检验结果的稳健性。Cochran’s Q检验发现，纳入的肠道菌群P均> 0.05，说明所选的工具变量之间未发现显著的异质性；MR-PRESSO全局检验和MR-Egger intercept检验发现，纳入的肠道菌群P均> 0.05，说明纳入的工具变量之间不存在水平多效性，结果可靠，见表2。留一法检验结果发现，在逐一剔除单个单核苷酸多态性之后结果没有发生改变，未见明显离散群，进一步验证了研究结果的稳健性，见图3。 2.3 反向孟德尔随机化分析结果将类风湿关节炎作为暴露因素，正向孟德尔随机化分析中筛选的菌群为结局变量进行孟德尔随机化分析，结果显示P均> 0.05，见表3，说明类风湿关节炎与筛选得到的菌群无反向因果关系，进一步验证了此次研"

References

[1] DI MATTEO A, BATHON JM, EMERY P. Rheumatoid arthritis. Lancet. 2023; 402(10416):2019-2033.
[2] FINCKH A, GILBERT B, HODKINSON B, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022;18(10):591-602.
[3] CAI Y, ZHANG J, LIANG J, et al. The Burden of Rheumatoid Arthritis: Findings from the 2019 Global Burden of Diseases Study and Forecasts for 2030 by Bayesian Age-Period-Cohort Analysis. J Clin Med. 2023;12(4):1291.
[4] BROWN P, PRATT AG, HYRICH KL. Therapeutic advances in rheumatoid arthritis. BMJ. 2024;384:e070856.
[5] FATEMI B, YAGHOUBI N, SHOBEIRI N, et al. Cost-effectiveness analysis of tofacitinib for the treatment of moderate to severe rheumatoid arthritis: a systematic review and meta-analysis. Expert Rev Pharmacoecon Outcomes Res. 2025;25(1): 29-38.
[6] XU Q, NI JJ, HAN BX, et al. Causal relationship between gut microbiota and autoimmune diseases: a two-sample mendelian randomization study. Front Immunol. 2021;12:746998.
[7] ZAISS MM, JOYCE WU HJ, MAURO D, et al. The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol. 2021;17(4):224-237.
[8] HORTA-BAAS G, ROMERO-FIGUEROA MDS, MONTIEL-JARQUÍN AJ, 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] JETHWA H, ABRAHAM S. The evidence for microbiome manipulation in inflammatory arthritis. Rheumatology (Oxford). 2017; 56(9):1452-1460.
[10] ZHANG Y, ZHEN S, XU H, et al. Vitamin C alleviates rheumatoid arthritis by modulating gut microbiota balance. Biosci Trends. 2024;18(2):187-194.
[11] SANDERSON E, GLYMOUR MM, HOLMES MV, et al. Mendelian randomization. Nat Rev Methods Primers. 2022;2:6.
[12] KURILSHIKOV A, MEDINA-GOMEZ C, BACIGALUPE R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet. 2021;53(2):156-165.
[13] OKADA Y, WU D, TRYNKA G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014; 506(7488):376-381.
[14] DAVIES NM, HOLMES MV, DAVEY SMITH G. Reading mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.
[15] LI P, WANG H, GUO L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample mendelian randomization study. BMC Med. 2022; 20(1):443.
[16] PALMER TM, LAWLOR DA, HARBORD RM, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res. 2012; 21(3):223-242.
[17] YUAN S, CHEN J, RUAN X, et al. Smoking, alcohol consumption, and 24 gastrointestinal diseases: mendelian randomization analysis. eLife. 2023;12: e84051.
[18] LI J, BAI H, QIAO H, et al. Causal effects of COVID-19 on cancer risk: a mendelian randomization study. J Med Virol. 2023; 95(4):e28722.
[19] BOWDEN J, DAVEY SMITH G, HAYCOCK PC, et al. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016; 40(4):304-314.
[20] XU X, WANG M, WANG Z, et al. The bridge of the gut-joint axis: gut microbial metabolites in rheumatoid arthritis. Front Immunol. 2022;13:1007610.
[21] ZHAO T, WEI Y, ZHU Y, et al. Gut microbiota and rheumatoid arthritis: from pathogenesis to novel therapeutic opportunities. Front Immunol. 2022;13:1007165.
[22] MARTIN-GALLAUSIAUX C, MARINELLI L, BLOTTIÈRE HM, et al. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37-49.
[23] SCHROEDER BO, BIRCHENOUGH GMH, STÅHLMAN M, et al. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe. 2018;23(1):27-40.e7.
[24] ZHOU D, JIAO W, SHI W, et al. Mendelian randomization identifies causal associations between GWAS-associated bacteria and their metabolites and rheumatoid arthritis. Front Microbiol. 2024;15:1431367.
[25] LI Y, LIU C, LUO J, et al. Ershiwuwei Lvxue Pill alleviates rheumatoid arthritis by different pathways and produces changes in the gut microbiota. Phytomedicine. 2022;107:154462.
[26] WANG T, STERNES PR, GUO XK, et al. Autoimmune diseases exhibit shared alterations in the gut microbiota. Rheumatology (Oxford). 2024;63(3):856-865.
[27] CHRISWELL ME, LEFFERTS AR, CLAY MR, et al. Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of subdoligranulum. Sci Transl Med. 2022; 14(668):eabn5166.
[28] CHEN S, HAN H, SUN X, et al. Causal effects of specific gut microbiota on musculoskeletal diseases: a bidirectional two-sample mendelian randomization study. Front Microbiol. 2023;14:1238800.
[29] NGUYEN NT, SUN WH, CHEN TH, et al. Gut mucosal microbiome is perturbed in rheumatoid arthritis mice and partly restored after TDAG8 deficiency or suppression by salicylanilide derivative. Int J Mol Sci. 2022;23(7):3527.
[30] GOU Y, ZHANG J, LI C, et al. Causal relationship between gut microbiota and rheumatoid arthritis: a two-sample mendelian randomisation study. Clin Exp Rheumatol. 2024;42(1):166-173.
[31] 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.
[32] 阴旭芳,张明星,张升校,等.类风湿关节炎患者肠道菌群分析与外周血细胞因子关系的研究[J]. 中华风湿病学杂志, 2021,25(1):1-7,c1-1,c1-2.