Deciphering the microbiota-immune axis in adult-onset Still’s disease: evidence from Mendelian randomization and experimental evaluation

Abstract

Objectives Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disorder with unclear etiology. Although gut microbiota may influence immune-mediated diseases, their genetically predicted associations with AOSD remain unclear. This study aims to investigate the potential associations between gut microbiota and AOSD susceptibility and to elucidate the potential mediating roles of immune-cell traits. Methods A two-sample Mendelian randomization (MR) framework was employed using genome-wide association study (GWAS) summary statistics from the Dutch Microbiome Project (7,738 individuals), FinnGen cohort (113 AOSD cases and 341,455 controls), and 731 immune-cell traits (3,757 individuals). Potential associations with AOSD susceptibility were assessed using inverse-variance weighted (IVW) and Bayesian weighted MR (BWMR) methods, with Benjamini-Hochberg (BH) false discovery rate (FDR) correction, and were complemented by comprehensive sensitivity analyses to assess robustness. A two-step MR approach was subsequently applied to investigate potential immune-mediated effects. The inflammatory potential of the identified microbial taxa was further examined in collagen-induced arthritis (CIA) mice and microbiota-depleted models treated with Parabacteroides goldsteinii (P. goldsteinii) and Alistipes shahii (A. shahii). Results MR analysis identified 10 microbial taxa and three metabolic pathways significantly associated with AOSD susceptibility. Notably, the taxa Streptococcaceae, Streptococcus, P. goldsteinii, Parabacteroides distasonis, and A. shahii showed positive genetically predicted associations with increased risks of AOSD, whereas Verrucomicrobia and Akkermansia exhibited inverse associations. Mediation analysis revealed that several T-cell-related immune traits, including CD127+CD4+T cells and CD25hiCD4+T cells, partially mediated these associations, with mediation proportions ranging from 3.44% to 26.79%. Importantly, administration of P. goldsteinii and A. shahii significantly increased circulating levels of IL-1β, IL-6, and TNF-α in CIA mice, supporting the biological plausibility of the MR findings. Conclusion This study integrates genetic and experimental evidence to support potential roles of gut microbiota in AOSD susceptibility and immune dysregulation. Specific taxa, including P. goldsteinii and A. shahii, may exhibit pro-inflammatory effects, while Akkermansia may have protective effects. These findings offer novel insights into microbiota-immune interactions in AOSD, and highlight potential microbial and immunological targets for future therapeutic intervention.