Integrated fecal microbiota and metabolomics analysis of the orlistat intervention effect on polycystic ovary syndrome rats induced by letrozole combined with a high-fat diet Original paper

What was studied?

This integrated study of fecal microbiota and metabolomics in orlistat-treated polycystic ovary syndrome (PCOS) rats investigates how orlistat reshapes gut microbial composition and metabolite profiles. The focus keyphrase orlistat PCOS gut microbiome is central because the research explores how gut ecosystem alterations may mediate orlistat’s therapeutic mechanisms. The authors induced PCOS using letrozole plus a high-fat diet, then compared untreated PCOS rats with those receiving graded doses of orlistat. Using 16S rRNA sequencing and untargeted metabolomics, they analysed shifts in bacterial taxa, community structure, and functional metabolites. The study particularly emphasizes microbial signatures relevant to metabolic regulation, steroid hormone biosynthesis, and inflammatory pathways, which are highly pertinent to microbiome signature databases. This dual-omics design allows interpretation of how microbiota–metabolite interactions influence PCOS physiology and how orlistat modulates these networks toward metabolic and endocrine improvement.

Who was studied?

Female rats aged 5–6 weeks were used to model PCOS through chronic letrozole exposure combined with a high-fat diet. Forty animals with successful induction were randomized into PCOS control and three orlistat-treated groups (low, medium, high dose), each containing ten rats. Fecal samples from untreated PCOS rats and high-dose orlistat rats were analysed for microbial and metabolic profiling, while blood samples were collected for hormone and lipid assays. The model replicates key PCOS features including hyperandrogenism, estrous cycle disturbance, metabolic dysregulation, and obesity, enabling mechanistic insight into orlistat’s effects on PCOS-related gut–hormone interactions.

Most important findings

Orlistat PCOS gut microbiome alterations were substantial. Microbial richness and diversity increased modestly, and the Firmicutes/Bacteroidetes ratio—a hallmark often elevated in PCOS and obesity—declined with orlistat treatment. High-dose orlistat shifted taxa away from Ruminococcaceae and Lactobacillaceae, families associated with insulin resistance, inflammation, and hyperandrogenism, toward Muribaculaceae and Bacteroidaceae, which are linked to short-chain fatty acid production, improved metabolic signaling, and anti-inflammatory effects. LEfSe analysis showed PCOS rats enriched in Lactobacillus and Ruminococcaceae_UCG groups, while orlistat-treated rats were enriched in Bacteroides and Muribaculaceae. Metabolomics revealed 216 differential metabolites and strong enrichment of steroid hormone biosynthesis, vitamin digestion pathways, and neuroactive ligand–receptor interactions. Androgenic metabolites such as DHEAS and dihydrotestosterone decreased significantly and correlated negatively with Bacteroides but positively with Ruminococcaceae groups, indicating microbe–hormone interplay. Progesterone increased notably and correlated positively with Bacteroides. These paired shifts reflect a microbiome-mediated reduction in hyperandrogenemia.

Key implications

The findings suggest orlistat’s therapeutic effects in PCOS extend beyond fat absorption inhibition and involve microbiome restructuring. By suppressing obesity-associated Firmicutes groups and increasing Bacteroidetes-linked taxa, orlistat improves endocrine and metabolic parameters through microbial and metabolite pathway modulation. The marked shifts in steroid hormone biosynthesis intermediates highlight the microbiome as an orchestrator of PCOS hormone imbalance. This work underscores the potential of targeting gut microbiota—alone or with pharmacologic therapy—to correct PCOS metabolic and reproductive dysfunction and offers new microbial signatures relevant for clinical microbiome profiling.

Citation

Yang J, Wang E, Jiang M, et al. Integrated fecal microbiota and metabolomics analysis of the orlistat intervention effect on polycystic ovary syndrome rats induced by letrozole combined with a high-fat diet.Journal of Ovarian Research. 2023;16:109. doi:10.1186/s13048-023-01193-3