The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome Original paper

What was studied?

The study investigated the gut microbiome in a letrozole-induced PCOS mouse model, examining how hyperandrogenemia alters microbial diversity and composition over time. This work explored whether the gut microbiome shifts commonly observed in metabolic disease also occur in PCOS, with an emphasis on identifying microbial signatures—particularly within Bacteroidetes and Firmicutes—that could inform a microbiome signatures database. Using 16S rRNA sequencing, the authors evaluated alpha diversity (species richness and phylogenetic diversity), beta diversity (community similarity), and time-dependent taxonomic changes. The core question was whether raising endogenous testosterone with letrozole, independent of diet, disrupts gut microbial ecology in ways biologically relevant to PCOS metabolic dysfunction.

Who was studied?

Researchers used C57BL/6N peripubertal female mice, implanted with either a placebo or a slow-release letrozole pellet delivering 50 μg/day. The study followed animals for five weeks, collecting 120 fecal samples over time for microbiome profiling. Letrozole reliably induced PCOS-like features—hyperandrogenemia, acyclicity, polycystic ovarian morphology, increased adiposity, impaired glucose tolerance, and elevated fasting glucose. These mice provided a controlled in vivo framework to determine how androgen excess during puberty alters the gut microbiome, without dietary confounders typical of metabolic disease models.

Most important findings

Letrozole produced marked microbiome disruption. Alpha diversity decreased significantly by week five, evidenced by lower Chao1 richness and reduced Faith’s Phylogenetic Diversity. Testosterone levels inversely correlated with diversity metrics, linking hyperandrogenemia to microbial depletion. Beta diversity analyses (UniFrac) revealed a clear shift in community composition detectable as early as week one. Time-series PCoA plots showed baseline (week 0) samples segregating from post-treatment samples, especially in letrozole mice. Taxonomically, letrozole caused broad declines in Bacteroidales, including S24-7 family members and one Alistipes OTU, while expanding multiple Firmicutes groups, particularly Lachnospiraceae (e.g., Blautia), Allobaculum, and Ruminococcaceae. Forty-eight OTUs showed significant abundance differences, most within Bacteroidetes and Firmicutes. Page-based visuals reinforce these findings: the stacked bar chart highlights increased Clostridiales and reduced Bacteroidales after letrozole.

Key implications

This study demonstrates that hyperandrogenemia alone—not diet—can drive gut microbiome dysbiosis relevant to metabolic disease. The altered abundance of S24-7, Alistipes, Ruminococcaceae, and Lachnospiraceae links PCOS-related hormonal imbalance to microbial ecosystems known to influence energy harvest, adiposity, and glucose regulation. These findings support the hypothesis that PCOS metabolic phenotypes may involve a gut microbial component. The microbial signatures identified here offer targets for mechanistic exploration via metagenomics, metabolomics, and fecal transplant studies, and may eventually inform microbiome-based diagnostics or therapies for PCOS.

Citation

Kelley ST, Skarra DV, Rivera AJ, Thackray VG. The gut microbiome is altered in a letrozole-induced mouse model of polycystic ovary syndrome.PLOS ONE. 2016;11(1):e0146509. doi:10.1371/journal.pone.0146509. pone.0146509