Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

Abstract

Background: Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship.

Objective: To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis.

Materials and methods: We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation.

Results: Combining the results from the discovery and replication stages, we identified one causal bacterial genus, Bifidobacterium. A higher relative abundance of the Bifidobacterium genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339-1.922; P_FDR = 4.19 × 10^-7] and CeD (OR: 1.401; 95% CI, 1.139-1.722; P_FDR = 2.03 × 10^-3), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the Bifidobacterium genus.

Conclusion: This study implied a causal relationship between the Bifidobacterium genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.

Keywords: Mendelian randomization; autoimmune disease (AD); celiac disease; gut microbiota; type 1 diabetes.

Figure 1

The flowchart of the study. The whole workflow of MR analysis. MR, Mendelian randomization; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; MS, multiple sclerosis; IBD, inflammatory bowel disease; T1D, type 1 diabetes; CeD, celiac disease.

Figure 2

Leave-one-out analysis of the causal effect of Bifidobacterium on T1D. Red lines represent estimations from the IVW test. T1D, type 1 diabetes; IVW, inverse variance weighted.

Figure 3

Leave-one-out analysis of the causal effect of Bifidobacterium on CeD. Red lines represent estimations from the IVW test. CeD, celiac disease; IVW, inverse variance weighted.