Gut microbial-derived 3,4-dihydroxyphenylacetic acid ameliorates reproductive phenotype of polycystic ovary syndrome.
Imeta, 2025/10;4(5):e70065.
Li P[1, 2, 3], Xie L[1], Zheng H[1], Feng Y[4], Mai F[5], Tang W[1], Wang J[1], Lan Z[6], Lv S[1], Jayawardana T[3], Koentgen S[3], Xu S[7], Wan Z[8], Chen Y[9], Xu H[2, 10], Shen S[3], Zhang F[3], Yang Y[11], Hold G[3], He F[12], El-Omar EM[3], Yu G[7], Chen X[1, 2]
Affiliations
PMID: 41112053DOI: 10.1002/imt2.70065
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.
Keywords: 3,4‐dihydroxyphenylacetic acid; Streptococcus thermophilus; gut metabolome; gut microbiota; polycystic ovary syndrome; β‐galactosidase
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