Gut microbial-derived 3,4-dihydroxyphenylacetic acid ameliorates reproductive phenotype of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and reproductive disorder affecting women of reproductive age. While the gut microbiota has been implicated in PCOS pathophysiology, the role of microbial-derived metabolites as mediators of host–microbe interactions remains poorly defined. Here, we integrated untargeted gut metabolomics with metagenomic profiling in patients with PCOS and identified a marked depletion of 3,4-dihydroxyphenylacetic acid (DHPAA), a flavonoid-derived microbial catabolite. Oral administration of DHPAA ameliorated PCOS-like phenotypes in two mouse models by suppressing bone morphogenetic protein signaling and reducing anti-Müllerian hormone (AMH) levels. We found that DHPAA production depends on gut microbial degradation of dietary flavonoids. We further identified a bacterial species, Streptococcus thermophilus , consistently depleted in PCOS across two human cohorts and a mouse model, restored DHPAA levels and improved reproductive outcomes in mice. Conversely, a β-galactosidase-deficient mutant of S. thermophilus failed to confer these benefits, highlighting β-galactosidase as a critical enzyme in DHPAA biosynthesis. Our findings establish DHPAA as a key microbial metabolite linking diet, microbiota, and reproductive health, and propose its potential as a novel therapeutic candidate for PCOS. Graphical By integrating multi-level and multi-omics analyses, we identify 3,4-dihydroxyphenylacetic acid (DHPAA), a gut microbiota-derived degradation product of dietary flavonoids, as a key bioactive end-product responsible for the beneficial effects against polycystic ovary syndrome (PCOS). DHPAA exerts direct therapeutic effects on PCOS-like phenotypes independent of the gut microbiota through inhibition of bone morphogenetic protein signaling. We further demonstrate that Streptococcus thermophilus metabolizes flavonoids into DHPAA via β-galactosidase activity, thereby contributing to the improvement of PCOS symptoms. These findings highlight the essential role of the gut microbiota in transforming flavonoids into functionally active metabolites and establish DHPAA as a critical mediator linking microbial metabolism to host reproductive health. This study deepens our understanding of the microbiota-metabolite-host axis in PCOS pathophysiology and provides a promising candidate molecule for therapeutic development. Highlights 3,4-dihydroxyphenylacetic acid (DHPAA) is identified as a key microbial-derived metabolite responsible for the protective effects of flavonoids against polycystic ovary syndrome (PCOS). Streptococcus thermophilus produces DHPAA from flavonoids through β-galactosidase-mediated metabolism. Gut microbiota is essential for transforming flavonoids into bioactive metabolites that confer protection against PCOS.