Metformin modifies plasma microbial-derived extracellular vesicles in polycystic ovary syndrome with insulin resistance Original paper

What was studied?

This study investigated metformin plasma microbial EVs by analyzing how metformin treatment alters plasma microbial-derived extracellular vesicles (EVs) in women with polycystic ovary syndrome and insulin resistance (PCOS-IR). Using full-length 16S rRNA sequencing, the researchers characterized microbial composition, diversity, and taxonomic shifts in circulating EVs before and after three months of metformin therapy. The goal was to determine whether specific microbial taxa within plasma EVs could serve as biomarkers of treatment response or illuminate mechanistic connections between microbiota-derived signaling and PCOS-related metabolic dysfunction. By focusing on EV-associated DNA rather than whole-microbiome samples, the authors attempted to capture biologically active microbial signals capable of translocating systemically and influencing host physiology.

Who was studied?

Five women of childbearing age diagnosed with PCOS-IR according to Chinese national guidelines were recruited. All participants exhibited hyperglycemia and insulin resistance (HOMA-IR ≥2.7) and had not used metformin, antibiotics, probiotics, antihistamines, or steroids in the six months prior to enrollment. Plasma samples were collected before treatment and again following three months of metformin therapy (500 mg/day in divided doses). Although the final sample size was small due to dropouts and sequencing failures, paired before-and-after analyses allowed direct comparison of individual microbial EV signatures across treatment.

Most important findings

Metformin significantly improved fasting plasma glucose and insulin resistance, while EV-associated microbial diversity increased after treatment. Alpha diversity (Simpson, Berger-Parker, Shannoneven, Simpsoneven) and beta-diversity analyses showed clear separation between pre- and post-treatment EV communities.

At multiple taxonomic levels, key microbial shifts emerged:

The most clinically relevant microbial change was the dramatic increase in Streptococcus salivarius–derived EVs, rising from 0.03% to 4.33% after metformin treatment. Known for beneficial metabolic effects in prior probiotic trials, S. salivarius may represent a microbiome-linked mechanism through which metformin improves metabolic parameters. Environmental microbial EVs (e.g., Sphingobacterium hotanense, Bradyrhizobium) also shifted, though their biological relevance remains uncertain due to low abundance.

Key implications

These results suggest that metformin’s metabolic benefits in PCOS-IR may be partly mediated through alterations in systemic microbial EV signaling, particularly through increases in potentially probiotic taxa such as Streptococcus salivarius. Plasma EV profiling may provide a sensitive, functionally relevant snapshot of host-microbiome interactions and could serve as a biomarker platform for PCOS-IR treatment monitoring. Larger studies are needed, but the findings support the concept that circulating microbial EVs participate in endocrine-metabolic regulation and may reveal therapeutic targets or diagnostic signatures for metabolic dysfunction in PCOS.

Citation

Hu L, Hong G, Li J, et al. Metformin modifies plasma microbial-derived extracellular vesicles in polycystic ovary syndrome with insulin resistance.Journal of Ovarian Research. 2024;17:136. doi:10.1186/s13048-024-01444-x