The Gut Microbiota and Its Metabolites and Their Association with the Risk of Autoimmune Thyroid Disease: A Mendelian...

Objectives: Observational research shows associations of the gut microbiota and its metabolites with autoimmune thyroid disease (AITD), but the causality is undetermined. Methods: Two-sample Mendelian randomization (MR) was employed to analyze the association of the gut microbiota and its metabolites with AITD. A total of 119 gut microbiotas and nine fecal/circulating metabolites were the exposures. AITD, Graves' disease (GD), and Hashimoto's thyroiditis (HT) were the outcomes. Inverse-variance weighting (IVW) was primarily used to assess causality; Cochran's Q was used to assess heterogeneity. Sensitivity analyses (weighted median, MRPRESSO regression, MRPRESSO intercept, MRPRESSO global, Steiger filtering, leave-one-out) were conducted to assess causal estimate robustness. Multivariable MR (MVMR) was used to estimate the effects of body mass index (BMI) and alcohol consumption frequency on causality. Results: The outcomes were potentially causally associated with 22 gut microbiotas and three metabolites. After multiple-test correction, 3-indoleglyoxylic acid retained significant causality with AITD (IVW: odds ratio [OR] = 1.09, 95% confidence interval [CI] = 1.05-1.14, p = 2.43 × 10^-5, FDR = 0.009). The sensitivity analyses were confirmatory (weighted median: OR = 1.06, 95% CI = 1.01-1.12, p = 0.025; MRPRESSO: OR = 1.09, 95% CI = 1.15-1.14, p = 0.001). MVMR revealed no confounding effects on this association (BMI: OR = 1.21, 95% CI =1.08-1.35, p = 0.001; drinks/week: OR = 1.22, 95% CI = 1.04-1.43, p = 0.014). Conclusions: MR revealed no significant causal effects of the gut microbiota on the outcomes. However, MR revealed the causal effects of 3-indoleglyoxylic acid on the risk of AITD.