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.