Causal relationships between gut microbiota and polycystic ovarian syndrome Original paper

What Was Studied?

This study investigated the causal relationship between gut microbiota and polycystic ovary syndrome (PCOS) using a bidirectional two-sample Mendelian randomization (MR) design. Researchers used genome-wide association study (GWAS) summary statistics from the MiBioGen consortium to represent gut microbiota composition and the FinnGen cohort to define PCOS cases and controls. The goal was to determine whether specific bacterial taxa causally influence the risk of developing PCOS and, conversely, whether PCOS causally alters gut microbial abundance. By leveraging genetic variants as instrumental variables, this study minimized biases commonly seen in observational research, including reverse causation and confounding. The analytical approach included several MR methods and sensitivity analyses to verify the robustness of findings.

Who Was Studied?

The study utilized summary-level genetic data rather than individual-level clinical cohorts. Gut microbiota data were derived from 18,340 individuals across 24 cohorts, primarily of European ancestry, through the MiBioGen meta-analysis, which identified 196 microbial taxa with sufficient abundance. PCOS outcome data came from 118,870 participants in the FinnGen cohort, including 642 clinically diagnosed PCOS cases and 118,228 controls. The PCOS diagnosis was based on ICD codes in hospital registries and aligned with the Rotterdam criteria. Importantly, both datasets involved participants of European descent, ensuring consistency for MR assumptions and reducing potential population stratification biases.

What Were the Most Important Findings?

The most significant finding was that specific gut microbiota taxa demonstrated a clear causal relationship with PCOS. Notably, the taxa Bacilli, Burkholderiales, and Lachnospiraceae showed a positive causal association with PCOS risk. In contrast, taxa such as Blautia, Bilophila, Cyanobacteria, Alphaproteobacteria, Holdemania, and CandidatusSoleaferrea exhibited a protective causal relationship. Among these, Blautia and Cyanobacteria retained their protective associations across all MR methods used, including the robust cML-MA approach. The study also found evidence for bidirectional causality in two taxa: Alphaproteobacteria and Lachnospiraceae. PCOS reduced the abundance of these microbes, while alterations in these microbes also contributed to PCOS risk.

These results are highly relevant to microbiome signatures, as they move beyond correlation to genetic causation. The major microbial associations (MMAs) emerging from this study establish Blautia and Bilophila as potential protective taxa and Burkholderiales and Bacilli as risk enhancers for PCOS. These taxa interact with PCOS through mechanisms related to insulin resistance, chronic inflammation, bile acid metabolism, SCFA production, and hormonal modulation, including the gut–brain axis. The presence of bidirectional effects particularly strengthens the hypothesis that gut microbiota and PCOS are engaged in a feedback loop that can worsen or potentially mitigate the disease course depending on microbial composition.

What Are the Implications of This Study?

This study provides the strongest evidence to date for a genetically mediated, bidirectional causal link between gut microbiota and PCOS. It significantly advances the field by identifying specific microbial taxa that not only influence PCOS risk but are also altered by the disease itself. For clinicians, these findings suggest that targeting certain microbial taxa could represent a therapeutic avenue for PCOS prevention or management. Modulating the abundance of Blautia, Bilophila, and Alphaproteobacteria through diet, prebiotics, probiotics, or even microbiota transplantation could potentially alter disease risk or symptom severity. The study’s use of MR methodology also sets a benchmark for establishing causal inference in microbiome research, paving the way for precision interventions rooted in genetic evidence. This work redefines PCOS not only as an endocrine-metabolic disorder but also as one with a microbial signature that may be clinically actionable.