Effect of the ketogenic diet on gut microbiome composition and metabolomics in polycystic ovarian syndrome rats induced by letrozole and a high-fat diet Original paper

What was studied?

This study investigated the ketogenic diet and gut microbiome in PCOS, examining how an eight-week ketogenic diet (KD) alters gut microbial composition, metabolomic profiles, and androgen-related metabolic pathways in a rat model of polycystic ovary syndrome induced by letrozole and a high-fat diet. The research aimed to clarify whether changes in microbial communities and metabolites mediate improvements in insulin resistance and hyperandrogenism. Using 16S rRNA sequencing and untargeted metabolomics, the investigators mapped shifts in bacterial taxa, steroidogenic metabolites, and their intercorrelations to uncover microbial signatures relevant to PCOS pathophysiology.

Who was studied?

The study used thirty-six-week-old female Sprague-Dawley rats divided into control, PCOS-IR (insulin-resistant), and PCOS-IR-KD groups. PCOS was induced through daily oral letrozole plus a high-fat diet for four weeks, producing ovarian cysts, estrous disruption, hyperandrogenism, and elevated HOMA-IR. Ten PCOS-IR rats received the ketogenic diet for eight weeks while controls continued standard chow. Fecal samples from five to six rats per group underwent microbiome and metabolomic profiling, while serum samples and ovarian tissues were collected from eight rats per group for biochemical and histologic analysis.

Most important findings

KD intervention reduced body weight, normalized estrous cycling, lowered testosterone and luteinizing hormone, and improved insulin levels and HOMA-IR. In the gut microbiome, KD reduced alpha diversity but shifted community structure toward increased Bacteroides and Lachnoclostridium, both short-chain fatty acid–producing genera, and decreased Colidextribacter, Ruminococcus, and unclassified Firmicutes known to correlate with dysregulated glucose and lipid metabolism. At the phylum level, KD partially restored the Firmicutes-to-Bacteroidetes ratio disrupted in PCOS. Metabolomics identified significant reductions in steroidogenic intermediates—testosterone, androstenedione, 17α-hydroxyprogesterone, 7α-hydroxytestosterone—and in metabolites linked with insulin resistance such as UDP-N-acetylglucosamine. Correlation analysis showed testosterone and androstenedione positively associated with Ruminococcus, Roseburia, and unclassified clostridiales, but negatively associated with Bacteroides and Lachnoclostridium. These combined findings indicate coordinated remodeling of microbial and metabolic networks central to androgen and insulin signaling.

Key implications

The ketogenic diet modulates gut microbial composition and steroidogenic metabolites in a way that aligns with clinical improvements in PCOS-related insulin resistance and hyperandrogenism. The increased abundance of Bacteroides and Lachnoclostridium suggests enhanced short-chain fatty acid production, potentially improving metabolic inflammation and mucosal barrier integrity. However, the KD’s reduction in microbial diversity and its contradictory effects on Bacteroides abundance—sometimes linked with PCOS pathology—highlight a need for caution when interpreting microbial shifts as strictly beneficial. This work strengthens the mechanistic link between dietary interventions, gut microbiota, and hormone regulation in PCOS, offering microbial signatures that could inform precision nutrition or probiotic-adjunct therapies. Further clinical studies are necessary to determine optimal KD composition and duration and to evaluate long-term effects on microbial diversity and metabolic health.

Citation

Wang R, Zhao Y, Fang X, et al. Effect of the ketogenic diet on gut microbiome composition and metabolomics in polycystic ovarian syndrome rats induced by letrozole and a high-fat diet.Nutrition. 2023;114:112127. doi:10.1016/j.nut.2023.112127