Exploring reciprocal causation: bidirectional mendelian randomization study of gut microbiota composition and thyroid cancer.

While an association between gut microbiota composition and thyroid cancer (TC) has been observed, the directionality and causality of this relationship remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal effect between gut microbiota composition and TC. Gut microbiota data were derived from a diverse population encompassing various ethnicities (n = 18,340 samples), while TC data were sourced from an European population (n = 218,792 samples). Instrumental variables, represented by single nucleotide polymorphisms (SNPs), were employed to assess the causal relationship using multiple MR methods, including inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode. F-statistics and sensitivity analyses were performed to evaluate the robustness of the findings. Our investigation identified a comprehensive set of 2934 instrumental variables significantly linked to gut microbiota composition (p < 1 × 10-5). The analysis illuminated notable candidates within the phylum Euryarchaeota, including families Christensenellaceae and Victivallaceae, and genera Methanobrevibacter, Ruminococcus2, and Subdoligranulum, which emerged as potential risk factors for TC. On the other hand, a protective influence against TC was attributed to class Betaproteobacteria, family FamilyXI, and genera Anaerofilum, Odoribacter, and Sutterella, alongside order Burkholderiales. Further enhancing our insights, the integration of 7 instrumental variables from TC data (p < 1 × 10-5) disclosed the regulatory potential of one family and five genera. Notably, the genus Coprobacter innocuum group (p = 0.012, OR = 0.944) exhibited the highest probability of regulation. Our meticulous analyses remained free from significant bias, heterogeneity, or horizontal pleiotropy concerns. Through a bidirectional two-sample Mendelian randomization approach, we elucidated a potential bidirectional causal relationship between gut microbiota composition and TC. Specific microbial taxa were associated with an increased risk or conferred protection against TC. These findings advance our understanding of the complex interplay between the gut microbiota and TC pathogenesis, offering new insights into the therapeutic potential of modulating the gut microbiota for managing TC.

Zhou J ，Zhang X ，Xie Z ，Li Z ... -  《-》

Causal relationship of genetically predicted gut microbiota with thyroid cancer: a bidirectional two-sample mendelian randomization study.

Previous investigations have demonstrated a correlation between the composition of gut microbiota and the development of thyroid cancer (TC). Nonetheless, there was no consensus on the causal effect of gut microbiota composition on TC risk. Therefore, the present study aimed to perform a bidirectional two-sample Mendelian randomization (MR) analysis to explore potential causal associations between gut microbiota and TC risk. Utilizing data from the MiBioGen consortium's genome-wide association studies (GWAS) meta-analysis involving a sample size of 18,340, we identified instrumental variables for 211 gut microbiota taxa. The summary statistics for TC was from relevant large-scale GWAS conducted by the FinnGen consortium. In the first stage, the Inverse-variance weighted (IVW) method was used as the primary estimate method, and the stability of estimations was tested by a battery of sensitivity analyses. In the second stage, a reverse MR analysis was applied to determine whether reverse causality existed. According to the IVW method, we identified 9 genetically predicted gut microbiota that were causally correlated with TC risk. Among them, we observed a positive causal effect of Family Christensenellaceae (OR = 1.664, 95% CI: 1.103-2.511, P = 0.015), Family Victivallaceae (OR = 1.268, 95% CI: 1.009-1.594, P = 0.042), Genus Methanobrevibacter (OR = 1.505, 95% CI: 1.049-2.159, P = 0.027), Genus Ruminococcus2 (OR = 1.846, 95% CI: 1.261-2.704, P = 0.002), Genus Subdoligranulum (OR = 1.907, 95% CI: 1.165-3.121, P = 0.010), Phylum Verrucomicrobia (OR = 1.309, 95% CI: 1.027-1.668, P = 0.029) on TC risk, while Class Betaproteobacteria (OR = 0.522, 95% CI: 0.310-0.879, P = 0.015), Family Family XI (OR = 0.753, 95% CI: 0.577-0.983, P = 0.037), Genus Sutterella (OR = 0.596, 95% CI: 0.381-0.933, P = 0.024) might be correlated with a decreased risk of TC. Subsequently, various sensitivity analyses indicated no heterogeneity, directional pleiotropy or outliers. In addition, reverse analysis demonstrated a negative causal effect of TC risk on the abundance of the gut microbiota (Genus Ruminococcus2, OR = 0.947, 95% CI: 0.907-0.989, P = 0.014). Genetic evidence suggested that bidirectional causal associations of specific bacteria taxa and the risk of TC, highlighting the association of the "gut-thyroid" axis. Further exploration of the potential microbiota-related mechanisms might have profound implications for public health in terms of the early prevention and treatment of TC.

Sun X ，Chen S ，Zhao S ，Wang J ，Cheng H ... -  《Frontiers in Endocrinology》

Mendelian randomization suggests a causal relationship between gut dysbiosis and thyroid cancer.

Zhu F ，Zhang P ，Liu Y ，Bao C ，Qian D ，Ma C ，Li H ，Yu T ... -  《Frontiers in Cellular and Infection Microbiology》

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

An association between Graves' disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear. 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. In total, 1,560 instrumental variables were extracted from the gut microbiome data (p< 1 × 105). 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. 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.

Cao J ，Wang N ，Luo Y ，Ma C ，Chen Z ，Chenzhao C ，Zhang F ，Qi X ，Xiong W ... -  《Frontiers in Immunology》

Causal relationship between gut microbiome and sex hormone-binding globulin: A bidirectional two-sample Mendelian randomization study.

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.

Yan Z ，Zheng Z ，Xia T ，Ni Z ，Dou Y ，Liu X ... -  《-》