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

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Abstract 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.

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