Changes in Metabolites and Microbial Communities in Follicular Fluid Associated With Ovarian Function in Patients With Polycystic Ovary Syndrome

Manfei Si , Sen Yan , Shu Ding , Rui Liu , Xianglei Xiong , Jie Qiao , Xinyu Qi

MedComm ›› 2026, Vol. 7 ›› Issue (2) : e70622

PDF
MedComm ›› 2026, Vol. 7 ›› Issue (2) :e70622 DOI: 10.1002/mco2.70622
ORIGINAL ARTICLE
Changes in Metabolites and Microbial Communities in Follicular Fluid Associated With Ovarian Function in Patients With Polycystic Ovary Syndrome
Author information +
History +
PDF

Abstract

Polycystic ovary syndrome (PCOS) is a well-documented endocrine disorder associated with metabolic abnormalities. Research has indicated potential links between PCOS and the gut microbiome, and the presence of microbial communities in follicular fluid (FF) has been demonstrated; however, their functional interplay with metabolites has not been elucidated. This case–control study involved 40 patients with PCOS and 40 controls matched for age. A comprehensive analysis of FF metabolites and microbial communities by means of metabolomics analysis and 16S rDNA sequencing was performed. Twelve metabolites and 15 microbial communities were significantly different between the PCOS and control groups. AMH and AFC were significantly associated with the majority of the differentially abundant metabolites and bacteria, suggesting a potential association between FF components and ovarian function. In this study, we found that D-glucose and Alicyclobacillus were the most important variables in the metabolite model and microbial model, respectively. Mechanistically, Alicyclobacillus acidoterrestris, Terrimonas ferruginea, or Terrimonas pekingense can efficiently utilize glucose thereby reducing FF glucose levels, which provides insights into the microbiome–metabolite connection. These findings suggest a potential link among bacteria–metabolite–ovarian function, which could have implications for understanding the pathophysiology of PCOS and developing novel diagnostic and therapeutic strategies targeting metabolic and microbial aspects.

Keywords

follicular fluid / metabolite / microbiota / microecology / polycystic ovary syndrome

Cite this article

Download citation ▾
Manfei Si, Sen Yan, Shu Ding, Rui Liu, Xianglei Xiong, Jie Qiao, Xinyu Qi. Changes in Metabolites and Microbial Communities in Follicular Fluid Associated With Ovarian Function in Patients With Polycystic Ovary Syndrome. MedComm, 2026, 7(2): e70622 DOI:10.1002/mco2.70622

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

H. J. Teede, C. T. Tay, J. Laven, et al., “Recommendations From the 2023 International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome,” Fertility and Sterility 120, no. 4 (2023): 767–793.

[2]

A. H. Balen, L. C. Morley, M. Misso, et al., “The Management of Anovulatory Infertility in Women With Polycystic Ovary Syndrome: An Analysis of the Evidence to Support the Development of Global WHO Guidance,” Human Reproduction Update 22, no. 6 (2016): 687–708.

[3]

L. Sterling, J. Liu, N. Okun, A. Sakhuja, S. Sierra, and E. Greenblatt, “Pregnancy Outcomes in Women With Polycystic Ovary Syndrome Undergoing In Vitro Fertilization,” Fertility and Sterility 105, no. 3 (2016): 791–797.

[4]

S. Liu, M. Mo, S. Xiao, et al., “Pregnancy Outcomes of Women with Polycystic Ovary Syndrome for the First In Vitro Fertilization Treatment: A Retrospective Cohort Study with 7678 Patients,” Frontiers in Endocrinology (Lausanne) 11 (2020): 575337.

[5]

L. Jiang, Y. Sun, P. Pan, et al., “Live Birth Rate per Fresh Embryo Transfer and Cumulative Live Birth Rate in Patients With PCOS Under the POSEIDON Classification: A Retrospective Study,” Frontiers in Endocrinology (Lausanne) 15 (2024): 1348771.

[6]

D. A. Dumesic, D. R. Meldrum, M. G. Katz-Jaffe, R. L. Krisher, and W. B. Schoolcraft, “Oocyte Environment: Follicular Fluid and Cumulus Cells Are Critical for Oocyte Health,” Fertility and Sterility 103, no. 2 (2015): 303–316.

[7]

R. A. Nagy, H. Hollema, D. Andrei, et al., “The Origin of Follicular Bile Acids in the Human Ovary,” American Journal of Pathology 189, no. 10 (2019): 2036–2045.

[8]

M. V. Moreira, E. Vale-Fernandes, I. C. Albergaria, M. G. Alves, and M. P. Monteiro, “Follicular Fluid Composition and Reproductive Outcomes of Women With Polycystic Ovary Syndrome Undergoing In Vitro Fertilization: A Systematic Review,” Reviews in Endocrine & Metabolic Disorders 24, no. 6 (2023): 1045–1073.

[9]

C. Voros, A. Varthaliti, D. Athanasiou, et al., “The Whisper of the Follicle: A Systematic Review of Micro Ribonucleic Acids as Predictors of Oocyte Quality and In Vitro Fertilization Outcomes,” Cells 14, no. 11 (2025): 787.

[10]

T. Artimani, J. Karimi, M. Mehdizadeh, et al., “Evaluation of Pro-Oxidant-Antioxidant Balance (PAB) and Its Association With Inflammatory Cytokines in Polycystic Ovary Syndrome (PCOS),” Gynecological Endocrinology 34, no. 2 (2018): 148–152.

[11]

B. Wang, M. Hao, Q. Yang, J. Li, and Y. Guo, “Follicular Fluid Soluble Receptor for Advanced Glycation Endproducts (sRAGE): A Potential Protective Role in Polycystic Ovary Syndrome,” Journal of Assisted Reproduction and Genetics 33, no. 7 (2016): 959–965.

[12]

H. Zhang, X. Wang, J. Xu, Y. Zhu, X. Chen, and Y. Hu, “IL-18 and IL-18 Binding Protein Concentration in Ovarian Follicular Fluid of Women With Unexplained Infertility to PCOS During In Vitro Fertilization,” Journal of Reproductive Immunology 138 (2020): 103083.

[13]

K. Gongadashetti, P. Gupta, R. Dada, and N. Malhotra, “Follicular Fluid Oxidative Stress Biomarkers and ART Outcomes in PCOS Women Undergoing In Vitro Fertilization: A Cross-Sectional Study,” International Journal of Reproductive BioMedicine 19, no. 5 (2021): 449–456.

[14]

M. Onal and M. Agar, “Follicular Fluid Redox Balance and DNA Damage According to PCOS Phenotype,” European Review for Medical and Pharmacological Sciences 27, no. 12 (2023): 5583–5589.

[15]

W. Wang, Q. Jiang, Y. Niu, et al., “Proteomics and Bioinformatics Analysis of Follicular Fluid From Patients With Polycystic Ovary Syndrome,” Frontiers in Molecular Biosciences 9 (2022): 956406.

[16]

X. Zhang, X. Xu, P. Li, et al., “TMT Based Proteomic Analysis of Human Follicular Fluid From Overweight/Obese and Normal-Weight Patients With Polycystic Ovary Syndrome,” Frontiers in Endocrinology (Lausanne) 10 (2019): 821.

[17]

Y. Yang, P. Lang, X. Zhang, et al., “Molecular Characterization of Extracellular Vesicles Derived From Follicular Fluid of Women With and Without PCOS: Integrating Analysis of Differential miRNAs and Proteins Reveals Vital Molecules Involving in PCOS,” Journal of Assisted Reproduction and Genetics 40, no. 3 (2023): 537–552.

[18]

K. Patil, S. Yelamanchi, M. Kumar, et al., “Quantitative Mass Spectrometric Analysis to Unravel Glycoproteomic Signature of Follicular Fluid in Women With Polycystic Ovary Syndrome,” PLoS ONE 14, no. 4 (2019): e0214742.

[19]

Q. Wan, Z. Zhang, M. Zhao, et al., “Efficient Diagnosis of Benign and Malignant Pulmonary Nodules Based on Nano-Zero-Valent Iron Enhanced Serum Metabolic Fingerprinting,” Chinese Chemical Letters 36, no. 10 (2025): 110794.

[20]

Y. Ding, Y. Jiang, M. Zhu, et al., “Follicular Fluid Lipidomic Profiling Reveals Potential Biomarkers of Polycystic Ovary Syndrome: A Pilot Study,” Frontiers in Endocrinology (Lausanne) 13 (2022): 960274.

[21]

Z. Yang, W. Zhou, C. Zhou, et al., “Steroid Metabolome Profiling of Follicular Fluid in Normo- and Hyperandrogenic Women With Polycystic Ovary Syndrome,” Journal of Steroid Biochemistry and Molecular Biology 206 (2021): 105806.

[22]

T. Naessen, M. M. Kushnir, A. Chaika, et al., “Steroid Profiles in Ovarian Follicular Fluid in Women With and Without Polycystic Ovary Syndrome, Analyzed by Liquid Chromatography-Tandem Mass Spectrometry,” Fertility and Sterility 94, no. 6 (2010): 2228–2233.

[23]

M. A. Castiglione Morelli, A. Iuliano, S. C. A. Schettini, et al., “NMR Metabolic Profiling of Follicular Fluid for Investigating the Different Causes of Female Infertility: A Pilot Study,” Metabolomics 15, no. 2 (2019): 19.

[24]

Y. R. Wu, Y. H. Dong, C. J. Liu, et al., “Microbiological Composition of Follicular Fluid in Patients Undergoing IVF and Its Association With Infertility,” American Journal of Reproductive Immunology 89, no. 3 (2023): e13652.

[25]

S. Ou, M. Liao, L. Cui, et al., “Associations Between Microbial Presence in Follicular Fluid With IVF Outcomes: A Systematic Review and Meta-Analysis,” Journal of Assisted Reproduction and Genetics 40, no. 11 (2023): 2501–2511.

[26]

S. M. Kim, K. H. Won, Y. H. Hong, et al., “Microbiology of Human Follicular Fluid and the Vagina and Its Impact on In Vitro Fertilization Outcomes,” Yonsei Medical Journal 63, no. 10 (2022): 941–947.

[27]

S. O. Noor, “Bacterial Isolation of Human Follicular Fluid and Potential Impact on In Vitro Fertilization Outcomes Medical Science,” Medical Science 24, no. 105 (2020): 2782–2791.

[28]

N. So, A. Eh, N. Aa, A. Hs, and H. Ha, “Detection of Human Follicular Fluid Microorganisms at the Time of Oocyte Retrieval and Its Impact on In-Vitro Fertilization Outcomes,” Prensa Médica Argentina (2020): 106–109.

[29]

A. A. Najjar, E. H. Alosaimi, H. S. Abduljabbar, et al., “Prevalence of Fungi in Human Follicular Fluid and Its Potential Impact on In Vitro Fertilization Process,” Archives of Pharmacy Practice 11, no. 4 (2020): 75–82.

[30]

E. S. Pelzer, J. A. Allan, K. Cunningham, et al., “Microbial Colonization of Follicular Fluid: Alterations in Cytokine Expression and Adverse Assisted Reproduction Technology Outcomes,” Human reproduction (Oxford, England) 26, no. 7(2011): 1799–1812.

[31]

Y. Wei, Z. Zhang, Y. Zhang, et al., “Nontargeted Metabolomics Analysis of Follicular Fluid in Patients With Endometriosis Provides a New Direction for the Study of Oocyte Quality,” MedComm 4, no. 3 (2023): e302.

[32]

Y. Qian, Y. Tong, Y. Zeng, et al., “Integrated Lipid Metabolomics and Proteomics Analysis Reveal the Pathogenesis of Polycystic Ovary Syndrome,” Journal of Translational Medicine 22, no. 1 (2024): 364.

[33]

M. Dai, L. Hong, T. Yin, and S. Liu, “Disturbed Follicular Microenvironment in Polycystic Ovary Syndrome: Relationship to Oocyte Quality and Infertility,” Endocrinology 165, no. 4 (2024): bqae023.

[34]

X. Yang, R. Wu, D. Qi, et al., “Profile of Bile Acid Metabolomics in the Follicular Fluid of PCOS Patients,” Metabolites 11, no. 12 (2021): 845.

[35]

C. Yun, S. Yan, B. Liao, et al., “The Microbial Metabolite Agmatine Acts as an FXR Agonist to Promote Polycystic Ovary Syndrome in Female Mice,” Nature Metabolism 6, no. 5 (2024): 947–962.

[36]

A. Gkantzos, S. Kalogiannis, and O. Deda, “The Role of Aromatic Amino Acids in Polycystic Ovary Syndrome Through Patients' Blood Metabolic Profiling: A Systematic Review of the Past Five Years,” Journal of Proteome Research 24, no. 5 (2025): 2208–2221.

[37]

T. Zeng, Y. Liu, X. Tang, et al., “BCAA Metabolism: The Achilles' heel of Ovarian Cancer, Polycystic Ovary Syndrome, and Premature Ovarian Failure,” Frontiers in Endocrinology (Lausanne) 16 (2025): 1579477.

[38]

K. Y. Wang, T. Yang, Y. F. Ding, A. R. Zeng, Y. Li, and J. W. Qiang, “Ovarian Lipid Metabolic Alterations in Polycystic Ovary Syndrome: Insights From Proton Magnetic Resonance Spectroscopy,” Frontiers in Medicine 12 (2025): 1652954.

[39]

Y. Chen, M. Xie, S. Wu, et al., “Multi-Omics Approach to Reveal Follicular Metabolic Changes and Their Effects on Oocyte Competence in PCOS Patients,” Frontiers in Endocrinology (Lausanne) 15 (2024): 1426517.

[40]

A. T. Brinca, A. C. Ramalhinho, A. Sousa, et al., “Follicular Fluid: A Powerful Tool for the Understanding and Diagnosis of Polycystic Ovary Syndrome,” Biomedicines 10, no. 6 (2022): 1254.

[41]

M. F. Mohd Shukri, M. N. Norhayati, S. Badrin, and A. Abdul Kadir, “Effects of L-Carnitine Supplementation for Women With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis,” PeerJ 10 (2022): e13992.

[42]

S. Tauqir, M. Israr, B. Rauf, et al., “Acetyl-L-Carnitine Ameliorates Metabolic and Endocrine Alterations in Women With PCOS: A Double-Blind Randomized Clinical Trial,” Advances in Therapy 38, no. 7 (2021): 3842–3856.

[43]

G. Di Emidio, F. Rea, M. Placidi, et al., “Regulatory Functions of L-Carnitine, Acetyl, and Propionyl L-Carnitine in a PCOS Mouse Model: Focus on Antioxidant/Antiglycative Molecular Pathways in the Ovarian Microenvironment,” Antioxidants (Basel) 9, no. 9 (2020): 867.

[44]

P. Ghimire and A. S. Dhamoon, Ketoacidosis (StatPearls, 2025).

[45]

K. S. Olaniyi and S. E. Areloegbe, “Acetate Ameliorates Ovarian Mitochondrial Dysfunction in Letrozole-Induced Polycystic Ovarian Syndrome Rat Model by Improving Mitofusin-2,” Journal of Physiological Sciences 74, no. 1 (2024): 22.

[46]

H. Chen and N. Souayah, “Immunoglobulins Reduced Oxidative Stress in Human Microglial Cells Induced by High Dose of Acetoacetate,” Brain Research 1748 (2020): 147054.

[47]

X. Shi, D. Li, Q. Deng, et al., “Acetoacetic Acid Induces Oxidative Stress to Inhibit the Assembly of Very Low Density Lipoprotein in Bovine Hepatocytes,” Journal of Dairy Research 83, no. 4 (2016): 442–446.

[48]

X. Du, Z. Shi, Z. Peng, et al., “Acetoacetate Induces Hepatocytes Apoptosis by the ROS-Mediated MAPKs Pathway in Ketotic Cows,” Journal of Cellular Physiology 232, no. 12 (2017): 3296–3308.

[49]

M. L. Sutton-McDowall, R. B. Gilchrist, and J. G. Thompson, “The Pivotal Role of Glucose Metabolism in Determining Oocyte Developmental Competence,” Reproduction (Cambridge, England) 139, no. 4 (2010): 685–695.

[50]

C. H. Zhang, X. Y. Liu, and J. Wang, “Essential Role of Granulosa Cell Glucose and Lipid Metabolism on Oocytes and the Potential Metabolic Imbalance in Polycystic Ovary Syndrome,” International Journal of Molecular Sciences 24, no. 22 (2023): 16247.

[51]

Y. Tu, G. Zheng, G. Ding, et al., “Comparative Analysis of Lower Genital Tract Microbiome Between PCOS and Healthy Women,” Frontiers in Physiology 11 (2020): 1108.

[52]

P. Giampaolino, V. Foreste, C. Di Filippo, et al., “Microbiome and PCOS: State-of-Art and Future Aspects,” International Journal of Molecular Sciences 22, no. 4 (2021): 2048.

[53]

S. Lee, O. Aasmets, R. K. Arffman, et al., “The Reproductive Tract Microbiome in Women With Polycystic Ovary Syndrome and Across Different Menstrual Cycle Phases,” Human Reproduction 40, no. 3 (2025): 518–528.

[54]

J. H. Shin, Y. H. Park, M. Sim, S. A. Kim, H. Joung, and D. M. Shin, “Serum Level of Sex Steroid Hormone Is Associated With Diversity and Profiles of Human Gut Microbiome,” Research in Microbiology 170, no. 4–5 (2019): 192–201.

[55]

G. Yin, F. Chen, G. Chen, et al., “Alterations of Bacteriome, Mycobiome and Metabolome Characteristics in PCOS Patients With Normal/Overweight Individuals,” Journal of Ovarian Research 15, no. 1 (2022): 117.

[56]

V. G. Thackray, “Sex, Microbes, and Polycystic Ovary Syndrome,” Trends in Endocrinology and Metabolism 30, no. 1 (2019): 54–65.

[57]

X. Qi, C. Yun, L. Sun, et al., “Gut Microbiota-Bile Acid-Interleukin-22 Axis Orchestrates Polycystic Ovary Syndrome,” Nature Medicine 25, no. 8 (2019): 1225–1233.

[58]

J. M. Baker, L. Al-Nakkash, and M. M. Herbst-Kralovetz, “Estrogen-Gut Microbiome Axis: Physiological and Clinical Implications,” Maturitas 103 (2017): 45–53.

[59]

S. Cotton, C. A. Clayton, and C. Tropini, “Microbial Endocrinology: The Mechanisms by Which the Microbiota Influences Host Sex Steroids,” Trends in Microbiology 31, no. 11 (2023): 1131–1142.

[60]

M. Kwa, C. S. Plottel, M. J. Blaser, and S. Adams, “The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer,” JNCI: Journal of the National Cancer Institute 108, no. 8 (2016): djw029.

[61]

G. Xiang, Y. Wang, K. Ni, et al., “Nasal Staphylococcus aureus Carriage Promotes Depressive Behaviour in Mice via Sex Hormone Degradation,” Nature Microbiology 10, no. 10 (2025): 2425–2440.

[62]

M. Horinouchi, “Identification of Dehydrogenase, Hydratase, and Aldolase Responsible for the Propionyl Residue Removal in Degradation of Cholic Acid C-17 Side Chain in Comamonas testosteroni TA441,” Microbiology Spectrum 13, no. 10 (2025): e0030825.

[63]

L. Leao, G. A. Esmail, S. Miri, W. Mottawea, and R. Hammami, “In Vitro Modeling of the Female Gut Microbiome: Effects of Sex Hormones and Psychotropic Drugs,” Microbiology Spectrum 13, no. 12 (2025): e0235025.

[64]

G. Marano, M. B. Anesini, M. Milintenda, et al., “Discovering a New Paradigm: Gut Microbiota as a Central Modulator of Sexual Health,” World Journal of Gastrointestinal Pathophysiology 16, no. 3 (2025): 107823.

[65]

G. M. Anifandis, K. Dafopoulos, C. I. Messini, et al., “Prognostic Value of Follicular Fluid 25-OH Vitamin D and Glucose Levels in the IVF Outcome,” Reproductive Biology and Endocrinology [Electronic Resource]: RB&E 8 (2010): 91.

[66]

H. Kobayashi and S. Imanaka, “Recent Progress in Metabolomics for Analyzing Common Infertility Conditions That Affect Ovarian Function,” Reproductive Medicine and Biology 23, no. 1 (2024): e12609.

[67]

W. Wang, M. Shu, J. Li, et al., “The Microbial Communities and Metabolic Profiles of Follicular Fluid in Patients With Premature Ovarian Insufficiency,” Frontiers in Endocrinology (Lausanne) 15 (2024): 1447397.

[68]

W. Wei, Y. Zhou, H. Zuo, et al., “Characterization of the Follicular Fluid Microbiota Based on Culturomics and Sequencing Analysis,” Journal of Medical Microbiology 72, no. 8 (2023): 11–20.

[69]

S. Jalili-Firoozinezhad, F. S. Gazzaniga, E. L. Calamari, et al., “A Complex Human Gut Microbiome Cultured in an Anaerobic Intestine-on-a-Chip,” Nature Biomedical Engineering 3, no. 7 (2019): 520–531.

[70]

A. Lev-Sagie, D. Goldman-Wohl, and Y. Cohen, “Vaginal Microbiome Transplantation in Women With Intractable Bacterial Vaginosis,” Nature Medicine 25, no. 10 (2019): 1500–1504.

[71]

M. P. Pereira, S. Jones, and J. M. Costin, “Association of Polycystic Ovarian Syndrome (PCOS) With Vaginal Microbiome Dysbiosis: A Scoping Review,” Cureus 16, no. 6 (2024): e62611.

[72]

V. Singh, K. Mahra, D. Jung, and J. H. Shin, “Gut Microbes in Polycystic Ovary Syndrome and Associated Comorbidities; Type 2 Diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), Cardiovascular Disease (CVD), and the Potential of Microbial Therapeutics,” Probiotics and Antimicrobial Proteins 16, no. 5 (2024): 1744–1761.

[73]

Y. Dong, S. Yang, S. Zhang, et al., “Modulatory Impact of Bifidobacterium Longum Subsp. Longum BL21 on the Gut-Brain-Ovary Axis in Polycystic Ovary Syndrome: Insights Into Metabolic Regulation, Inflammation Mitigation, and Neuroprotection,” mSphere 10, no. 2 (2025): e0088724.

[74]

C. Jin, L. Qin, Z. Liu, et al., “Comparative Analysis of the Vaginal Microbiome of Healthy and Polycystic Ovary Syndrome Women: A Large Cross-Sectional Study,” Reproductive Biomedicine Online 46, no. 6 (2023): 1005–1016.

[75]

P. Filippou and R. Homburg, “Is Foetal Hyperexposure to Androgens a Cause of PCOS?,” Human Reproduction Update 23, no. 4 (2017): 421–432.

[76]

Rotterdam EA-SPcwg. “Revised 2003 Consensus on Diagnostic Criteria and Long-Term Health Risks Related to Polycystic Ovary Syndrome (PCOS),” Human Reproduction 19, no. 1 (2004): 41–47.

RIGHTS & PERMISSIONS

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

PDF

3

Accesses

0

Citation

Detail

Sections
Recommended

/