Causal relationship betweengut microbiome andsex hormone-binding globulin: Abidirectional two-sample Mendelian randomization study.

Abstract

Currently, there is a variety of evidence linking the gut microbiota to changes in sex hormones. In contrast, the causal relationship between SHBG, a carrier of sex hormones, and the gut microbiota is unclear. Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between SHBG and the gut microbiome. Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and SHBG were obtained from public datasets. Inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger and simple mode methods were used to operate the MR analysis. F-statistics and sensitivity analyses performed to evaluate bias and reliability. When we set gut microbiome as exposure and SHBG as outcome, we identified nine causal relationships. In males, Coprobacter (PIVW=2.01×10-6 ), Ruminococcus2 (PIVW=3.40×10-5 ), Barnesiella (PIVW=2.79×10-2 ), Actinobacteria (PIVW=3.25×10-2 ) and Eubacterium fissicatena groups (PIVW=3.64×10-2 ) were associated with lower SHBG levels; Alphaproteobacteria (PIVW=1.61×10-2 ) is associated with higher SHBG levels. In females, Lachnoclostridium (PIVW=9.75×10-3 ) and Defluviitaleaceae UCG011 (PIVW=3.67×10-2 ) were associated with higher SHBG levels; Victivallaceae (PIVW=2.23×10-2 ) was associated with lower SHBG levels. According to the results of reverse MR analysis, three significant causal effect of SHBG was found on gut microbiota. In males, Dorea (PIVW=4.17×10-2 ) and Clostridiales (PIVW=4.36×10-2 ) were associated with higher SHBG levels. In females, Lachnoclostridium (PIVW=7.44×10-4 ) was associated with higherr SHBG levels. No signifcant heterogeneity of instrumental variables or horizontal pleiotropy was found in bidirectional two-sample MR analysis. This study may provide new insights into the causal relationship between the gut microbiome and sex hormone-binding protein levels, as well as new treatment and prevention strategies for diseases such as abnormal changes in sex hormones.