Background <p>Rheumatoid arthritis (RA) is a complex autoimmune and inflammatory disease that significantly impacts the quality of life for millions worldwide. In recent years, gut microbiota has garnered extensive attention as a potential health-modulating factor, with associations identified between it and various diseases, including RA. This study aims to investigate the causal relationship between gut microbiota and RA using Mendelian Randomization (MR) analysis, and further examines the mediating role of immune cells in this connection.</p> Method <p>A MR analytical method was employed by us, integrating genome-wide association study (GWAS) data from FinnGen, MiBioGen, and research led by Valeria Orrù and her team to systematically examine the relationships between gut microbiota, immune cells, and RA. Initially, we performed a bidirectional univariable MR analysis to examine the relationship between gut microbiota and RA, consciously avoiding any possible reverse causal influences. Following this, we applied multivariable MR adjustments on gut microbiota that showed positive associations and employed a two-step methodology to examine the overall genetic predictive role of immune cell-mediated gut microbiota in the risk of developing RA.</p> Result <p>Our results demonstrate notable causal connections between different gut microbiota and RA. In particular, Mollicutes, Ruminococcaceae UCG002, and Butyricimonas displayed positive associations with RA, while other microbiota, including Rikenellaceae, Lactobacillaceae, and Veillonella, showed negative associations. Additionally, we identified a reduction in the abundance of certain microbiota, including Lachnospiraceae and Ruminococcus1, which were excluded from our study and validated for analytical accuracy using methods such as "leave-one-out." Immune cells, including CD3 found on activated CD4 regulatory T cells that express CD39, serve a mediating function in the development of RA. To summarize, our research focused on the species Butyricimonas id. 945, recognizing immune cells as crucial contributors to the relationship between genetic predictions of gut microbiota and RA.</p> Conclusion <p>This research clarifies the intricate causal links between gut microbiota and RA, emphasizing the crucial mediating function of immune cells in this mechanism. These findings not only enhance our understanding of the pathogenesis of RA but also provide new perspectives and potential intervention targets for future prevention and treatment strategies. Future research should further investigate the specific mechanisms underlying the interactions among gut microbiota, immune cells, and RA, while considering the validation of these findings across diverse populations.</p>