Immune system regulation is a key indicator of the gut microbiota (GM) influencing disease development. The causal role of the GM in Guillain-Barré syndrome (GBS) and whether it can be mediated by immune cells is unknown. Genome-wide association study (GWAS) summary statistics for the GM were obtained from the Dutch Microbiota Project (n = 7,738) and the FINRISK 2002 (FR02) cohort (n = 5,959). Inverse variance weighting method (IVW) were used as the main method to evaluate the causal relationship between GM and GBS. Subsequently, the mediating effects of 731 immune traits were evaluated. Additionally, we also executed the Bayesian Weighting algorithm for verification. Mendelian randomization (MR) analysis determined the protective effect of the pyrimidine deoxyribonucleoside degradation superpathway on GBS (IVW: P = 0.0019, OR = 0.4508). It is worth noting that in the causal effects of pyrimidine deoxyribonucleoside degradation superpathway on GBS, the mediated proportions of herpesvirus entry mediator (HVEM) ( HVEM on CM CD4 + , HVEM on naive CD4 + , HVEM on CD45RA − CD4 + , HVEM on CM CD8br) in the T cell maturation stage on GBS were -0.0398, -0.0452, -0.0414, -0.0425, accounting for 5.00%, 5.67%, 5.19% and 5.34% of the total effect. 11 types of intestinal bacteria might be involved in the pyrimidine deoxyriboside degradation superpathway, including Staphylococcus A fleurettii, AR31,CAG-274 sp000432155, Photobacterium, Acetobacteraceae, Dysgonomonadaceae, NK4A144,Leptospirae, CAG-81 sp000435795, Leptospirales and CAG-873 sp001701165. This study suggests that there is a causal relationship between pyrimidine deoxyribonucleoside degradation superpathway and GBS, which may be mediated by HVEM on CD4 + and CD8 + T cells. As a bidirectional molecular switch, HVEM plays an important role in T cell regulation. 11 intestinal flora were found to be involved in pyrimidine deoxyribonucleoside degradation superpathway, and their changes may be related to the occurrence of GBS. However, extensive research is still warranted before microbiome sequencing can be used for prevention and targeted treatment of GBS.
