Causal Associations Between 141 Gut Microbiota Taxa and 14 Rheumatic Diseases: A Mendelian Randomization Study

OBJECTIVE: Gut microbiota has been increasingly recognized as important and novel targets for rheumatic diseases. However, previous studies mainly examined the associations, leaving causality largely unknown. This knowledge gap hinders the application of gut microbiota in preventing and treating rheumatic diseases. METHODS: We performed Mendelian randomization (MR) analysis to evaluate causal associations between gut microbiota and rheumatic diseases. Genetic instruments for 141 gut microbiota taxa were extracted from the published genome-wide association study (GWAS) (N = 18 340). Summary statistics for 14 rheumatic diseases were obtained from publicly available GWASs and the FinnGen database. The primary MR analysis employed the Wald ratio or inverse variance-weighted method, supported by additional MR approaches. Bi-directional MR and colocalization analyses were performed to test the reciprocal causality and investigate shared causal variants. RESULTS: After multiple testing adjustments (FDR < 0.05), six pairs of relations remained statistically significant. Genus FamilyXIIIAD3011 group (odds ratio [OR] = 2.68, 95% CI = 2.35-3.07), class Deltaproteobacteria (OR = 1.37, 95% CI = 1.17-1.59), order Desulfovibrionales (OR = 1.36, 95% CI = 1.17-1.58), and family Desulfovibrionaceae (OR = 1.36, 95% CI = 1.17-1.58) increased the risk of ankylosing spondylitis (AS). Genus Eubacterium brachy group (OR = 0.56, 95% CI = 0.44-0.72) and order Mollicutes RF9 (OR = 0.60, 95% CI = 0.47-0.77) decreased the risk of gout. Additionally, class Deltaproteobacteria, family Desulfovibrionaceae, and order Desulfovibrionales shared the same genetic variants with AS. No evidence of bi-directional causality was observed. CONCLUSION: We identified and provided genetic evidence for six novel causal associations between gut microbiota taxa with AS and gout. These findings open avenues for future research to investigate the impact of modulating these gut microbiota taxa on the prevention and treatment of AS and gout.