(1) Background: Recent studies suggest a potential link between gut microbiomes (GMs) and inflammatory diseases, but the role of GMs in lichen sclerosus (LS) remains unclear. This study aims to investigate the causal relationship between GMs and LS, focusing on key GM taxa. (2) Methods: We utilized GWAS summary statistics for 211 GM taxa and their association with 2,445 LS patients and 353,088 healthy controls, employing Mendelian randomization (MR). GWAS data for GM taxa came from the MiBioGen consortium, and for LS from the FinnGen consortium. The primary analytical tools included the inverse-variance weighted (IVW) method, weighted MR, simple mode, weighted median, and MR-Egger methods. Sensitivity analyses included leave-one-out analysis, MR-Egger intercept test, MR-PRESSO global test, and Cochrane’s Q-test. A reverse MR analysis was conducted on bacteria identified in the forward MR study. (3) Results: We identified one strong causal relationship: order Burkholderiales [odds ratio (OR) = 0.420, 95% confidence interval (CI): 0.230 - 0.765, p = 0.005], and three nominally significant relationships: phylum Cyanobacteria (OR = 0.585, 95% CI: 0.373 - 0.919, p = 0.020), class Betaproteobacteria (OR = 0.403, 95% CI: 0.189 - 0.857, p = 0.018), and genus Butyrivibrio (OR = 0.678, 95% CI: 0.507 - 0.907, p = 0.009). Moreover, this MR analysis was not impacted by horizontal pleiotropy, according to the MR-Egger intercept test and MR-PRESSO global test (p > 0.05). Remarkably, the reliability of our results was confirmed by leave-one-out analysis. Reverse MR analysis showed no significant causal relationship between LS and GM. (4) Conclusions: This MR study identifies specific gut flora linked to a lower risk of LS, offering new insights for disease treatment and prevention. Future research should incorporate metagenomics sequencing of extensive microbiome GWAS datasets.

Objective Recent investigations have proposed a link between gut microbiomes (GMs) and various cancers, yet the involvement of GMs in vulvar cancer (VC) remains unclear. The objective of this study was to discover the causal association between GMs and VC and identify the GM taxa with potential effect. Methods Utilizing Mendelian randomization (MR) with genome-wide association study (GWAS) summary statistics, we analyzed 211 GM taxa and 190 VC cases with 167,189 healthy controls. GWAS data for GM taxa were sourced from the MiBioGen consortium, and VC data were acquired from the FinnGen consortium. The main analysis used the inverse-variance weighted (IVW) approach, complemented by weighted median, MR-Egger, weighted mode, and simple mode approaches. Sensitivity analyses included Cochrane’s Q-test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results Four nominally significant causal relationships were identified between GM taxa and VC. Class Betaproteobacteria [odds ratio (OR)=0.064, 95% confidence interval (CI):0.004-0.946, p=0.045], order Burkholderiales [OR=0.074, 95% CI:0.009-0.630, p=0.017], genus Intestinibacter [OR=0.073, 95% CI:0.009-0.617, p=0.016], and genus RuminococcaceaeUCG003 [OR=0.162, 95% CI:0.028-0.938, p=0.042] were linked to a lower chance of VC. The MR-Egger intercept test and MR-PRESSO global test confirmed the lack of horizontal pleiotropy (p>0.05), and leave-one-out analysis indicated result robustness. Conclusion Our findings highlight four potential causal relationships and specific intestinal flora associated with decreased VC risk, offering insights for VC prevention and treatment.