Effect of a high-fat high-fructose diet on the composition of the intestinal microbiota and its association with metabolic and anthropometric parameters in a letrozole-induced mouse model of polycystic ovary syndrome Original paper

What was studied?

This study investigated how a high-fat, high-fructose (HF/HFr) diet alters the gut microbiota composition and bacterial metabolites in prepubertal female mice with letrozole-induced polycystic ovary syndrome (PCOS). The work also assessed how specific microbial taxa correlated with PCOS-related metabolic parameters. Because the gut microbiome strongly influences metabolic and endocrine regulation, the authors aimed to determine whether diet or letrozole played a larger role in shaping microbiome signatures relevant to PCOS.

Who was studied?

Researchers used 32 prepubertal female C57BL/6 mice, aged three weeks, divided into four groups (Placebo, Placebo+HF/HFr, LET, LET+HF/HFr; n=8 each). Animals received either a standard diet or the HF/HFr diet, combined with placebo or subcutaneous letrozole implants to induce PCOS. Samples collected included cecal content for microbiome sequencing, feces for short-chain fatty acid (SCFA) quantification, and blood serum for metabolic biomarkers such as testosterone, LPS, and lipid parameters.

Most important findings

Diet exerted a stronger influence on the microbiome than PCOS induction with letrozole. HF/HFr-fed groups showed significantly higher alpha diversity than standard-diet groups, contrary to typical PCOS-associated reductions. Beta-diversity plots revealed distinct clustering for the Placebo+HF/HFr group, indicating major microbial restructuring driven by diet. At the genus level, HF/HFr feeding increased Alloprevotella, Muribaculum, Rikenella, Parasutterella, and several Clostridia-related taxa, while sharply reducing Lactobacillus, a genus often diminished in metabolic dysfunction. Letrozole alone increased Prevotellaceae, but PCOS-specific effects were relatively small, suggesting prepubertal induction limits microbiome shifts. The HF/HFr diet markedly lowered SCFAs, especially acetate, propionate, and butyrate—key metabolites supporting intestinal barrier integrity. Mice receiving both letrozole and HF/HFr displayed the highest serum LPS levels, pointing to compromised gut barrier function and endotoxemia. Figure 5 illustrates strong opposing correlations: Turicibacter abundance was positively associated with total cholesterol and LDL-C, while Lactobacillus was inversely associated with these lipids. Additional positive correlations linked Rikenella, Romboutsia, and Eubacterium_coprostanoligenes_group with LDL-C, suggesting candidate microbial signatures associated with dyslipidemia in PCOS-like physiology.

Key implications

The findings highlight diet—not letrozole-induced PCOS—as the dominant force shaping the gut microbiome in prepubertal mice. Reduced SCFAs and elevated LPS suggest diet-driven intestinal barrier impairment that synergizes with PCOS-like endocrine changes. Several microbial genera, including Turicibacter, Lactobacillus, Rikenella, and Parasutterella, show strong associations with lipid disturbances, positioning them as potential microbial biomarkers for PCOS-related metabolic risk. This supports ongoing efforts to develop targeted microbiome signatures and personalized interventions, including dietary modulation and probiotic strategies, for PCOS management.

Citation

Pieczynska-Zajac JM, Malinowska AM, Pruszynska-Oszmalek E, Kolodziejski PA, Drzymala-Czyz S, Bajerska J. Effect of a high-fat high-fructose diet on the composition of the intestinal microbiota and its association with metabolic and anthropometric parameters in a letrozole-induced mouse model of polycystic ovary syndrome. Nutrition. 2024;124:112450. doi:10.1016/j.nut.2024.112450