A cause–effect relationship between Graves’ disease and the gut microbiome contributes to the thyroid–gut axis: A bidirectional two-sample Mendelian randomization study

BACKGROUND: An association between Graves’ disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear. METHODS: Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between GD and the gut microbiome. Gut microbiome data were derived from samples from a range of different ethnicities (18,340 samples) and data on GD were obtained from samples of Asian ethnicity (212,453 samples). Single nucleotide polymorphisms (SNPs) were selected as instrumental variables according to different criteria. They were used to evaluate the causal effect between exposures and outcomes through inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode methods. F-statistics and sensitivity analyses were performed to evaluate bias and reliability. RESULTS: In total, 1,560 instrumental variables were extracted from the gut microbiome data (p< 1 × 10(5)). The classes Deltaproteobacteria [odds ratio (OR) = 3.603] and Mollicutes, as well as the genera Ruminococcus torques group, Oxalobacter, and Ruminococcaceae UCG 011 were identified as risk factors for GD. The family Peptococcaceae and the genus Anaerostipes (OR = 0.489) were protective factors for GD. In addition, 13 instrumental variables were extracted from GD (p< 1 × 10(–8)), causing one family and eight genera to be regulated. The genus Clostridium innocuum group (p = 0.024, OR = 0.918) and Anaerofilum (p = 0.049, OR = 1.584) had the greatest probability of being regulated. Significant bias, heterogeneity, and horizontal pleiotropy were not detected. CONCLUSION: A causal effect relationship exists between GD and the gut microbiome, demonstrating regulatory activity and interactions, and thus providing evidence supporting the involvement of a thyroid–gut axis.