Mendelian randomization analysis of gut microbiota-driven immune modulation in rheumatoid arthritis: New mechanistic insights and therapeutic targets.

ObjectiveTo explore the complex interactions between gut microbiota and immune cell phenotypes in rheumatoid arthritis development and identify potential therapeutic targets within the gut microbiota-immune cell axis.MethodsWe conducted a Mendelian randomization analysis to explore the causal relationship between gut microbiota and rheumatoid arthritis, including the role of immune cell mediators. Sensitivity analyses assessed pleiotropy and heterogeneity, while mediation analysis identified pathways through which immune cells mediate gut microbiota effects on rheumatoid arthritis development. Key microbial taxa and their effects on rheumatoid arthritis were quantified.ResultsOur analysis identified 27 gut microbiota taxa significantly associated with rheumatoid arthritis, with Provencibacterium massiliense showing the strongest protective effect (odds ratio = 0.807, 95% confidence interval: 0.700-0.911, P = 0.003). Additionally, 20 immune cell phenotypes with IgD+ CD38dim AC were significantly linked to rheumatoid arthritis (odds ratio = 1.064, 95% confidence interval: 1.027-1.102). Mediation analysis uncovered 13 significant gut microbiota-immune cell pathways, with the UBA8517-CCR2 monocyte pathway mediating 10.1% of the total effect (beta1 = -0.595, beta12 = 0.027, mediation proportion = 10.1%).ConclusionThis study offers novel insights into the gut microbiota-immune cell axis in rheumatoid arthritis, identifying Provencibacterium massiliense, IgD+ CD38dim AC and the UBA8517-CCR2 monocyte pathway as potential therapeutic targets for rheumatoid arthritis treatment.