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Associations of gut microbiome with endogenous estrogen levels in healthy postmenopausal women

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Abstract

Purpose

The gut microbiome is a potentially important contributor to endogenous estrogen levels after menopause. In healthy postmenopausal women, we examined associations of fecal microbiome composition with levels of urinary estrogens, their metabolites, and relevant metabolic pathway ratios implicated in breast cancer risk.

Methods

Eligible postmenopausal women (n = 164) had a body mass index (BMI) ≤ 35 kg/m2 and no history of hormone use (previous 6 months) or cancer/metabolic disorders. Estrogens were quantified in spot urine samples with liquid chromatography-high resolution mass spectrometry (corrected for creatinine). Bacterial DNA was isolated from fecal samples and the V1–V2 hypervariable regions of 16S rRNA were sequenced on the Illumina MiSeq platform. We examined associations of gut microbiome’s indices of within-sample (alpha) diversity (i.e., Shannon, Chao1, and Inverse Simpson), phylogenetic diversity, and the ratio of the two main phyla (Firmicutes and Bacteroidetes; F/B ratio) with individual estrogens and metabolic ratios, adjusted for age and BMI.

Results

In this sample of 164 healthy postmenopausal women, the mean age was 62.9 years (range 47.0–86.0). We found significant inverse associations of observed species with 4-pathway:total estrogens (p = 0.04) and 4-pathway:2-pathway (p = 0.01). Shannon index was positively associated with 2-catechols: methylated 2-catechols (p = 0.04). Chao1 was inversely associated with E1:total estrogens (p = 0.04), and 4-pathway:2-pathway (p = 0.02) and positively associated with 2-pathway:parent estrogens (p = 0.01). Phylogenetic diversity was inversely associated with 4-pathway:total estrogens (p = 0.02), 4-pathway:parent estrogens (p = 0.03), 4-pathway:2-pathway (p = 0.01), and 4-pathway:16-pathway (p = 0.03) and positively associated with 2-pathway:parent estrogens (p = 0.01). F/B ratio was not associated with any of the estrogen measures.

Conclusion

Microbial diversity was associated with several estrogen metabolism ratios implicated in breast cancer risk. Further studies are warranted to confirm these findings in a larger and more representative sample of postmenopausal women, particularly with enrichment of minority participants.

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Data availability

The microbial RNA sequence data generated and analyzed during the current study are available in the NCBI repository, https://dataview.ncbi.nlm.nih.gov/object/PRJNA905714?reviewer=idghjm9id1npj51bnc8g0bj1pe. The estrogen metabolite data generated during and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This research was supported by pilot funding from the Florida Academic Cancer Center Alliance (FACCA) and the UF Health Cancer Center Bridge Funding. This work has been supported in part by the Tissue Core and the Proteomics & Metabolomics Core facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). The authors would like to thank Martin Abrams at Moffitt Cancer Center Clinical Laboratory for performing the creatinine assays.

Funding

This research was supported by pilot funding from the Florida Academic Cancer Center Alliance (FACCA) and the UF Health Cancer Center Bridge Funding. This work has been supported in part by the Tissue Core and the Proteomics & Metabolomics Core facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292).

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Authors and Affiliations

  1. Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, 2004 Mowry Rd, Gainesville, FL, 32610, USA

    Lusine Yaghjyan, Volker Mai & Shannan N. Rich

  2. Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA

    Volker Mai, Maria Ukhanova & Massimiliano S. Tagliamonte

  3. H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Lancia N. F. Darville, Jayden Cline, Xuefeng Wang, Yessica C. Martinez, John M. Koomen & Kathleen M. Egan

  4. Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA

    Massimiliano S. Tagliamonte

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  1. Lusine Yaghjyan
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Contributions

LY and KE conceived of and designed the study, obtained funding, directed statistical analyses, interpreted results, substantially revised initial drafts of the paper and provided final review and approval. LD, JC and JK analyzed urinary samples to quantify estrogens. MU, VM, ad MT analyzed stool samples for GM. YM and SR recruited participants and collected data and samples. XW performed statistical analyses. LY wrote the first draft of the manuscript which was revised with contribution from all co-authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lusine Yaghjyan.

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Competing interests

The authors declare no competing interests.

Ethical approval

The study was approved by the Moffitt Cancer Center and UF Institutional Review Boards (UF: IRB 201500572 and IRB 201600709; Moffitt Cancer Center Advarra IRB# Pro00014574). Women were offered a $25 gift card for their participation. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

All participants provided written informed consent.

Research involving human and/or animals participants

The study was approved by the Moffitt Cancer Center and UF Institutional Review Boards (UF: IRB 201500572 and IRB 201600709; Moffitt Cancer Center Advarra IRB# Pro00014574). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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All participants provided written informed consent.

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Yaghjyan, L., Mai, V., Darville, L.N.F. et al. Associations of gut microbiome with endogenous estrogen levels in healthy postmenopausal women. Cancer Causes Control 34, 873–881 (2023). https://doi.org/10.1007/s10552-023-01728-5

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