Cross-talk between the gut microbiota and hypothyroidism: a bidirectional two-sample Mendelian randomization study

Abstract

Background: Multiple observational studies suggest a connection between the composition of the gut microbiota and hypothyroidism. However, it has yet to be determined whether the gut microbiota has a causal effect on hypothyroidism.

Methods: To investigate the connection between the gut microbiota and hypothyroidism, two-sample Mendelian randomization was performed using data from a genome-wide association study meta-analysis (n = 18,430) conducted by the MiBioGen consortium. Summary statistics for hypothyroidism (26,342 cases and 59,827 controls) were obtained using the data from the FinnGen consortium R8 release data. To investigate the causal link between the gut microbiota and hypothyroidism, various methods, including MR-Egger, weighted median, weighted model, simple model, MR-PRESSO, and inverse variance weighted (IVW), were employed. The bacteria that were causally linked to hypothyroidism in forward Mendelian randomization analysis were subjected to reverse Mendelian randomization analysis. Cochran's Q statistics were utilized to gauge the heterogeneity of the instrumental variables.

Results: The results indicated that Akkermansia had a positive impact on hypothyroidism, with an odds ratio of 0.84 (95% CI 0.74-0.95, p = 0.01) based on the inverse variance-weighted estimates. Additionally, Anaerostipes (OR = 1.17, 95% CI 1.01-1.36, p = 0.04), Butyrivibrio (OR = 0.93, 95% CI 0.88-0.99, p = 0.02), Holdemania (OR = 0.89, 95% CI 0.81-0.99, p = 0.03), Intestinimonas (OR = 1.13, 95% CI 1.02-1.26, p = 0.03), Ruminiclostridium5 (OR = 1.19, 95% CI 1.01-1.41, p = 0.04), and Ruminococcaceae UCG-011 (OR = 0.91, 95% CI 0.84-0.99, p = 0.03) were identified. The gut microbiota was not significantly affected by hypothyroidism, as indicated by the results of the reverse MR analysis. There was no significant variation in the instrumental variables or horizontal pleiotropy.

Conclusion: The findings of this study using two-sample Mendelian randomization indicate a causal relationship between Akkermansia and hypothyroidism. Increased Akkermansia inhibits the onset and progression of hypothyroidism. Additional randomized controlled experiments are necessary to elucidate the beneficial impact of probiotics on hypothyroidism and their distinct protective mechanisms.

Keywords: Mendelian randomization; causal effect; gut microbiome; hypothyroidism; probiotics.

Figure 1

Schematic of the three core assumptions of Mendelian randomization research. SNP, single nucleotide polymorphism. Created by Figdraw.com.

Figure 2

Schematic diagram of Mendelian randomization (MR) analysis process. The workflow was performed twice for gut microbiome and hypothyroidism (HY). GWAS, genome-wide association study; IVs, instrumental variables; IVW, inverse variance weighting; MR, Mendelian randomization.

Figure 3

Mendelian randomization results of causal effects between the gut microbiome and Hypothyroidism. MR, Mendelian randomization; SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Figure 4

Scatterplot (A-G) of the effect of the gut microbiome on Hypothyroidism. In each plot, individual single nucleotide polymorphisms (SNPs) from the summary dataset of the gut microbiome genome-wide association study (GWAS) are represented by dots. The x-axis denotes the impact of these SNPs on the gut microbiome, while the y-axis signifies their influence on Hypothyroidism. Distinct colors of lines correspond to various Mendelian randomization (MR) methods. A positive slope indicates that exposure is a risk factor, whereas a negative slope signifies the contrary.

Figure 5

Leave-one-out analysis for gut microbiome on Hypothyroidism. The sensitivity of the causal effect was assessed across different components (A–G) using the method of inverse-variance weighting (IVW), with the error bar indicating the 95% confidence interval.