Relationships among gut microbiota, plasma metabolites, and juvenile idiopathic arthritis: a mediation Mendelian randomization study

Abstract

Objective: The objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators.

Methods: Using summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization.

Results: In our MR analysis, a positive correlation was observed between Rikenellaceae and the risk of juvenile idiopathic arthritis, while Dorea showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between Dorea and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86-31.03%].

Conclusion: Our study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis.

Keywords: Bayesian weighted Mendelian randomization; Mendelian randomization; gut microbiota; juvenile idiopathic arthritis; mediation analysis; plasma metabolome.

Figure 1

Study workflow. Panel (A): JIA as the outcome variable, with gut microbiota and plasma metabolites as exposures. Panel (B1): JIA as the exposure variable, with gut microbiota as the outcome variable. Panel (B2): Gut microbiota as the exposure variable, with plasma metabolites as the outcome variable. Panel (C): Preliminary mediation analysis obtained after MR screening as described above. Panel (D): Final mediation MR analysis obtained after thorough screening. JIA, Juvenile Idiopathic Arthritis; MR, Mendelian Randomization; SNPs, Single nucleotide polymorphisms; BWMR, Bayesian weighted Mendelian randomization; IVW, Inverse Variance Weighting.

Figure 2

Forest plot to visualize the causal effects of plasma metabolites with gut microbiota and juvenile idiopathic arthritis.

Figure 3

Scatterplots, the horizontal axis represents the SNP effect on exposure, while the vertical axis illustrates the SNP effect on the outcome. (A) Represents the MR between Dorea and JIA. (B) Represents the MR between Rikenellaceae and JIA. (C) Represents the MR between Eubacteriumrectale and JIA. (D) Represents the MR between Catenibacterium and JIA. (E) Represents the MR between Ruminococcus and JIA. (F) Represents the MR between 1-stearoyl-2-oleoyl and JIA. (G) Represents the MR between Furaneol sulfate and JIA. (H) Represents the MR between Dorea and Furaneol sulfate. (I) Represents the MR between Rikenellaceae and 1-stearoyl-2-oleoyl. JIA, Juvenile Idiopathic Arthritis; MR, Mendelian Randomization; SNP, Single nucleotide polymorphism.

Figure 4

Forest plot to visualize the impact of removing a single SNP on the overall effect. (A) Represents the MR between Dorea and JIA. (B) Represents the MR between Rikenellaceae and JIA. (C) Represents the MR between Eubacteriumrectale and JIA. (D) Represents the MR between Catenibacterium and JIA. (E) Represents the MR between Ruminococcus and JIA. (F) Represents the MR between 1-stearoyl-2-oleoyl and JIA. (G) Represents the MR between Furaneol sulfate and JIA. (H) Represents the MR between Dorea and Furaneol sulfate. (I) Represents the MR between Rikenellaceae and 1-stearoyl-2-oleoyl. JIA, Juvenile Idiopathic Arthritis; MR, Mendelian Randomization; SNP, Single nucleotide polymorphism.