The gut-joint axis: Genetic evidence for a causal association between gut microbiota and seropositive rheumatoid arthritis and seronegative rheumatoid arthritis

Abstract

This study aimed to assess the causal relationship between GM and RA (seropositive RA and seronegative RA). A two-sample Mendelian randomization (MR) analysis was performed to assess the causality of GM on seropositive RA and seronegative RA. GM’s genome-wide association study (GWAS) was used as the exposure, whereas the GWAS datasets of seropositive RA and seronegative RA were the outcomes. The primary analysis approach was used as inverse-variance weighted (IVW), followed by 3 additional MR methods (MR-Egger, weighted median, and weighted mode). Cochran’s Q test was used to identify heterogeneity. The MR-Egger intercept test and leave-one-out analyses were used to assess horizontal pleiotropy. All statistical analyses were performed in R software. We discovered that Alloprevotella (IVW OR 0.84, 95% CI 0.71–0.99, P = .04) and Christensenellaceae R 7 group (IVW OR 0.71, 95% CI 0.52–0.99, P = .04) were negatively correlated with seropositive RA, Ruminococcaceae UCG002 (IVW OR 1.30, 95% CI 1.10–1.54, P = .002) was positively associated with seropositive RA. Actinomyces (IVW OR 0.73, 95% CI 0.54–0.99, P = .04), Christensenellaceae R 7 group (IVW OR 0.62, 95% CI 0.39–0.97, P = .04), Terrisporobacter (IVW OR 0.64, 95% CI 0.44–0.93, P = .02), Lactobacillales (IVW OR 0.65, 95% CI 0.47–0.90, P = .01) were negatively correlated with seronegative RA. The present MR analysis showed a protective effect of Alloprevotella and Christensenellaceae R 7 group and a potentially anti-protective effect of Ruminococcaceae UCG002 on seropositive RA; and a protective effect of Actinomyces, Christensenellaceae R 7 group, Terrisporobacter, and Lactobacillales on seronegative RA. Further experimental studies and randomized controlled trials are needed to validate these findings.