Genetic liability to gut microbiota and inflammatory cytokines in relation to systemic lupus erythematosus risk: a...

Systemic lupus erythematosus (SLE) has been associated with gut microbiota in some studies. There is no clear evidence that cytokines act as mediators.

We first assessed the differences in gut microbiota between SLE patients and healthy controls using 16S rDNA sequencing. Subsequently, we used the summary statistics of gut microbiota, cytokines, and SLE from large genome-wide association studies. To explore the causal relationships between gut microbiota and SLE and identify potential mediating cytokines, we performed bidirectional Mendelian randomization analyses. Finally, the levels of potentially mediating cytokines were determined by ELISA.

Fecal 16S rDNA sequencing showed that there was gut microbiota disorder in SLE patients. Based on two-sample analysis, seven gut microbiota taxa were causally associated with SLE. SLE influenced the relative abundance of two gut microbiota taxa in our large-scale MR study. Mediation analyses revealed that the causal relationship between genus Lachnospiraceae UCG001 and SLE was exclusively mediated by fibroblast growth factor 19 (FGF19) levels and the causal relationship between order Lactobacillales and SLE was exclusively mediated by tumor necrosis factor receptor superfamily member 9 (TNFRSF9) levels. Elevated levels of FGF19 affected the association between the reduced relative abundance of the genus Coprobacter and SLE, mediating by a proportion of 10.64% (P = 0.030). Furthermore, ELISA showed that circulating TNFRSF9 and FGF19 levels were higher in SLE patients than healthy controls.

Our study demonstrated that there is a causal link between some gut microbiota taxa and SLE. In addition, we revealed possible mediating effects in this relationship. Key Points • We first demonstrate a causal association between gut microbiota, cytokines, and SLE comprehensively. • Our experiments also confirmed that TNFRSF9 and FGF19 may play a role in SLE. These results provide new ideas for microbiome-based investigation of new mechanisms and therapies for SLE.