Bridging gut microbiota and polycystic ovary syndrome: the mediating role of metabolites and immune pathways via Mendelian randomization and mediation analysis

Polycystic Ovary Syndrome (PCOS) is a common reproductive metabolic disorder impacting women of reproductive age, with its etiology influenced numerous factors. Recent research indicates that the gut microbiota, along with its metabolites and associated immune-inflammatory responses, may contribute to the pathogenesis of PCOS. However, there is finite understanding of the potential intermediate impacts of circulating metabolites, immune cells, and inflammatory proteins on the linkage between intestinal flora and PCOS. This study seeks to explore the interrelationships among the gut microbiome, immune-inflammatory responses, and the metabolome within the context of PCOS.

Aggregated statistics pertaining to individual traits were derived from genome-wide association studies accessible to general public. To elucidate mediation mechanisms, a two-step MR mediation framework was applied. In the first step, univariable MR was used to identify causal effects of gut microbial taxa on circulating metabolites, immune cells, and inflammatory proteins. In the second step, multivariable MR and mediation analyses were employed to estimate indirect effects of these mediators on PCOS. All analyses were performed using the inverse variance weighted (IVW) method as the primary model, complemented by MR-Egger, weighted median, and MR-PRESSO sensitivity tests.

MR analysis identified the causal impacts of 11 intestinal flora taxa on PCOS, among which 4 taxas (Class Betaproteobacteria, Genus Eubacterium eligens group, Genus Ruminiclostridium6 and Order Burkholderiales) may exert positive effects on PCOS, 7 taxas (Family Bifidobacteriaceae, Genus Bilophila, Genus Holdemania, Genus Hungatella, Genus Ruminococcaceae UCG004, Genus Veillonella, and Order Bifidobacteriales) may act as protective factors on PCOS. Meanwhile, 124 plasma metabolites, 45 circulating immune cell types, and 5 inflammatory proteins exhibited causal effects on PCOS. Notably, the circulating metabolites predominantly involved in PCOS were correlative of androgenic steroids, leucine, isoleucine and valine metabolism, glutathione metabolism, and secondary bile acid metabolism, and other metabolic pathways. Mediation analysis elucidated 34 metabolites-mediated path-ways linking gut microbiota and PCOS, with 13 immune cells/inflammatory proteins-mediated pathways interconnecting gut flora and PCOS.

According to MR analysis, circulating metabolites, immune cells, and inflammatory proteins play a role in the correlation between intestinal flora and PCOS. The findings shed new light on the underlying pathophysiological mechanisms of PCOS.