Uncovering the gut-immune-joint axis: causal links between gut Microbiota, immune cells, and osteoarthritis.

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 2 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 5 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, 2 genera were associated with knee OA (KOA) and 5 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.