Uncovering the Gut-Immune-Joint Axis: Causal Links Between Gut Microbiota, Immune Cells, and Osteoarthritis

Abstract Gut microbiota have been increasingly implicated in osteoarthritis (OA), but causal pathways remain unclear. Using the Gut-Immune-Joint Axis framework, we analyzed publicly available genome-wide association study (GWAS) summary statistics from one primary and two secondary datasets to evaluate genetically predicted associations between gut microbiota and OA and to test immune cells as potential mediators. Bidirectional Mendelian randomization (MR) identified five bacterial genera genetically associated with OA in the primary dataset, with no evidence of reverse causality. Two-step MR highlighted Bilophila and the immune cell subtype CD45 on CD33dim HLA DR+ CD11b- as being associated with OA (P 0.05), and multivariable MR suggested partial mediation by this immune cell (20.0%, P = 0.003). In secondary analyses, two genera were associated with knee OA (KOA) and five with hip OA (HOA), again without reverse genetic effects. Terrisporobacter, the HLA DR+ CD4+ to T cell ratio, and the HLA DR+ CD4+ to lymphocyte ratio were associated with KOA (all P 0.05), with mediation by the HLA DR+ CD4+ to T cell ratio (-12.0%, P = 0.001). Roseburia and Myeloid DC AC were associated with HOA (all P 0.05). Collectively, these findings support causal links between specific gut microbial genera and OA and implicate immune-cell traits as mediators, strengthening the Gut-Immune-Joint Axis concept and highlighting potential therapeutic targets.