Abstract
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women. Accumulating evidence indicates that gut dysbiosis and metabolic disturbances are associated with the pathogenesis of PCOS. However, the mechanisms by which metabolic alterations influence gut homeostasis and contribute to PCOS progression remain poorly understood. Here, we show that N-acetylneuraminic acid (Neu5Ac) exacerbates dehydroepiandrosterone (DHEA)-induced PCOS phenotypes in female mice in a gut microbiota-dependent manner. Specifically, Neu5Ac promotes the expansion of the gut Ligilactobacillus salivarius (L. sa) with bile salt hydrolase (BSH) activity. Administration of L. sa to DHEA-treated mice worsens PCOS symptoms by reducing levels of the conjugated bile acid tauroursodeoxycholic acid (TUDCA) via BSH activity. Reduced TUDCA enhances intestinal farnesoid X receptor (FXR) activation, leading to suppression of IL-22 production. Mechanistically, IL-22 attenuates DHEA-induced ovarian ferroptosis by activating the STAT3 signaling pathway. These findings reveal that sialic acid-mediated bile acid–FXR–IL-22 signaling contributes to PCOS pathogenesis, highlighting a potential therapeutic strategy for PCOS intervention.
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16S rRNA sequencing data for all samples have been deposited in NCBI and are publicly available as of the date of publication (PRJNA1403253). All other data associated with this study are present in the paper or the Supplementary Information. Source data are provided with this paper.
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Acknowledgements
The study was supported by the National Key R&D Program of China (2023YFD1801100 to Y.F), National Natural Science Foundation of China (32473101 to Y.F), Jilin Province Science and Technology Development Project (20240402019GH to C.Y), and Youth Development Program of China-Japan Union Hospital of Jilin University (2025QM03 to C.Y).
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C.Z., C.Y, Y.F., and S.W. designed the study. Y.Z. (Yue Zhang) and K.C. performed all mouse animal experiments and all statistical analysis. Z.L., L.C., X.X., H.G., Y.Z. (Yang Zheng), and Y.Z. (Yun Zhang) assisted with animal experiments and experimental parameter determinations. Y.F. and C.Y obtained funding. C.Z. wrote the manuscript, and all authors revised and approved the manuscript.
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Nature Communications thanks Changtao Jiang and Anna Benrick for their contribution to the peer review of this work. A peer review file is available.
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Zhao, C., Zhang, Y., Chen, K. et al. Sialic acid exacerbates polycystic ovary syndrome in mice by modulating gut microbiota-mediated bile acid metabolism and FXR activation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71365-4
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DOI: https://doi.org/10.1038/s41467-026-71365-4
