Menopause causes a marked decline in circulating estrogen, and the gut microbiota is increasingly proposed as both a target and a mediator of this hormonal shift. Wang et al. (2025) describe this relationship as bidirectional: declining estrogen levels alter the gut microbiota, while microbial activity may, in turn, influence estrogen metabolism and postmenopausal health. Although the underlying mechanisms are biologically plausible and increasingly well characterized, the available human evidence remains considerably weaker than this framework might suggest.
Microbial estrogen metabolism
Estrogens are metabolized in the liver, where they are conjugated and subsequently excreted into the intestine via bile. Gut microbial enzymes, particularly β-glucuronidases, can remove these conjugates and potentially enable the reabsorption of estrogens into the circulation. However, this process appears to be more complex than a single “estrobolome” pathway. In vitro studies indicate that only specific classes of microbial β-glucuronidases can efficiently deconjugate estrogen glucuronides, suggesting that the composition and functional capacity of the microbiota may be more relevant than the mere presence of β-glucuronidase activity (Ervin et al., 2019).
Human evidence provides some support for an association between the gut microbiota and estrogen exposure. In a small study of premenopausal women, circulating estrogens were associated with fecal microbial richness and with specific bacterial groups, including members of the Clostridia and Ruminococcaceae (Flores et al., 2012). Similarly, fecal microbiome composition was associated with estrogen and estrogen-metabolite concentrations in postmenopausal women from Ghana, suggesting that these relationships may persist after the menopausal decline in ovarian estrogen production (Fuhrman et al., 2014). Together, these findings support a potential role for the gut microbiota in estrogen metabolism, but they do not establish the direction of the relationship. Importantly, these studies were small and largely cross-sectional, making it difficult to determine whether differences in the microbiota alter estrogen metabolism, whether hormonal exposure shapes the microbiota, or whether both are influenced by shared factors such as diet, adiposity, age, or medication use. Thus, while the estrobolome provides a plausible mechanistic link between the gut microbiota and systemic estrogen exposure, its contribution to human estrogen physiology remains incompletely established.
Does menopause change the gut microbiota?
The evidence for menopause-related changes in gut microbiota composition remains inconsistent. In a metagenomic study of approximately 2300 adults, postmenopausal women showed a trend toward lower microbial diversity and a microbiota more similar to that of men than to that of premenopausal women. The study also identified a reduction in the predicted metabolic potential of pathways related to hormone metabolism (Peters et al., 2022a). Smaller studies have similarly reported changes in specific taxa, including reductions in Firmicutes and Ruminococcus following menopause (Peters et al., 2022b).
However, these findings are not consistently reproduced in larger cohorts. In the HELIUS study, which included 5166 participants, menopausal status explained only 0.2% of the variation in β-diversity, while Shannon diversity was marginally higher in postmenopausal women (Vriend et al., 2024). Consistent with this limited effect, a 2026 meta-analysis of seven cross-sectional studies found no significant differences in α-diversity, Bacteroidetes, Firmicutes, or the Bacteroidetes:Firmicutes ratio between pre- and postmenopausal women, although substantial heterogeneity was observed across studies (Saravinovska et al., 2026).
Several factors may contribute to these discrepancies. Menopause is strongly intertwined with chronological aging, making it difficult to distinguish the effects of reproductive aging from those of age itself. Differences in BMI, diet, lifestyle, geography, medication use, study populations, and sequencing and bioinformatic approaches may further influence the results. Moreover, broad measures of microbial diversity or phylum-level composition may be insufficient to capture functionally relevant changes. Functional characteristics, such as the abundance of genes involved in estrogen metabolism and β-glucuronidase activity, may provide a more informative measure of the potential interaction between the microbiota and host hormonal status (Peters et al., 2022a; Saravinovska et al., 2026). Overall, current evidence does not support a consistent, menopause-specific shift in gut microbial diversity or broad taxonomic composition.
Evidence from estrogen-deficiency models
Animal models provide stronger evidence for a causal link between estrogen deficiency, the gut microbiota, and postmenopausal health outcomes than currently available human studies. In ovariectomized mice, estrogen deficiency promoted microbiota-dependent expansion of Th17 cells and TNF-producing T cells, accompanied by increased bone loss. Germ-free mice were protected from trabecular bone loss, supporting a causal role for the microbiota in this phenotype (Yu et al., 2021). Several interventions targeting the gut microbiota—including fecal microbiota transplantation, Rothia, lactulose, and probiotics—attenuated bone loss and, in some cases, improved intestinal barrier function. These findings provide experimental support for a gut–bone axis influenced by estrogen status. However, ovariectomy produces an abrupt and profound loss of estrogen that differs substantially from the gradual hormonal transition occurring during natural menopause, limiting direct extrapolation to women.
Potential health consequences
- Bone health: human studies provide some evidence linking the postmenopausal microbiota to bone metabolism, although the evidence remains limited. In a small study, postmenopausal women receiving hormone therapy had a different gut microbiota from non-users, and members of the genus Clostridia were associated with lower bone turnover (Xiong et al., 2025). Probiotic interventions have produced inconsistent results. Lactobacillus reuteri 6475 reduced bone loss in older women with low bone density (Nilsson et al., 2018), whereas a larger trial involving 239 women in early postmenopause found no effect on bone loss after two years of supplementation (Gregori et al., 2024). These contrasting results suggest that effects may depend on the bacterial strain, population, baseline bone status, or stage of menopause.
- Cardiometabolic health: menopause-associated differences in the gut microbiota have also been linked to less favourable cardiometabolic profiles. In the study by Peters et al. (2022a), microbiome features associated with the menopausal transition were related to cardiometabolic risk factors. Similarly, the duodenal microbiota of postmenopausal women not receiving hormone therapy differed from that of younger women and hormone therapy users, while the non-users also had higher fasting glucose concentrations (Leite et al., 2022). However, these observations are correlational and cannot establish whether microbiome changes contribute to cardiometabolic risk or instead reflect differences in age, hormone therapy, diet, adiposity, or other metabolic factors.
- Vasomotor symptoms: the metabolism of soy isoflavones provides one of the clearest examples of a microbiota-dependent phenotype potentially relevant to menopausal symptoms. Certain gut bacteria convert daidzein into equol, a metabolite with greater estrogenic activity than its precursor. Individuals who produce equol may therefore respond differently to soy isoflavones than non-producers. A meta-analysis found that equol supplementation reduced hot-flash frequency and severity in equol non-producers, although evidence from isoflavone intervention trials overall remains inconsistent (Daily et al., 2019). This suggests that individual differences in microbial metabolism may contribute to variability in response to dietary interventions, but does not establish a general causal role for the gut microbiota in vasomotor symptoms.
- Cognition, mood, and other outcomes: evidence linking the postmenopausal gut microbiota to cognition, mood, sleep, or other menopausal outcomes remains comparatively limited. Although mechanistic hypotheses involving microbial metabolites, inflammation, and the gut–brain axis are plausible, rigorous primary human studies directly testing these relationships are still scarce. These outcomes should therefore be considered promising areas for investigation rather than established consequences of menopause-related microbiome changes.
Conclusions
The available evidence supports a plausible biological link between estrogen status and the gut microbiota, with the estrobolome providing a potential mechanism through which microbial activity could influence estrogen metabolism. Animal studies, particularly those using estrogen-deficiency models, further support a causal role for the microbiota in some menopause-related outcomes, such as bone loss. However, evidence from humans remains considerably less conclusive. Associations between menopause and gut microbiota composition are inconsistent, most studies are cross-sectional, and clinical trials targeting the microbiota have produced mixed results.
Future research should prioritize longitudinal studies that follow women across the menopausal transition, allowing the effects of declining estrogen to be distinguished from those of chronological aging. Greater emphasis should also be placed on microbial function—including estrogen-metabolizing capacity and microbial metabolites—rather than taxonomic composition alone. Better control of major confounders such as age, BMI, diet, medication use, and hormone therapy will be essential. Finally, well-designed intervention trials should consider individual factors such as menopausal stage, age, BMI, baseline microbiome composition, and microbial metabolic capacity to determine whether specific women are more likely to benefit from microbiome-targeted interventions.
References
Daily, J. W., Ko, B. S., Ryuk, J., Liu, M., Zhang, W., & Park, S. (2019). Equol Decreases Hot Flashes in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Journal of medicinal food, 22(2), 127–139. https://doi.org/10.1089/jmf.2018.4265
Ervin, S. M., Li, H., Lim, L., Roberts, L. R., Liang, X., Mani, S., & Redinbo, M. R. (2019). Gut microbial β-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens. The Journal of biological chemistry, 294(49), 18586–18599. https://doi.org/10.1074/jbc.RA119.010950
Flores, R., Shi, J., Fuhrman, B., Xu, X., Veenstra, T. D., Gail, M. H., Gajer, P., Ravel, J., & Goedert, J. J. (2012). Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. Journal of translational medicine, 10, 253. https://doi.org/10.1186/1479-5876-10-253
Fuhrman, B. J., Feigelson, H. S., Flores, R., Gail, M. H., Xu, X., Ravel, J., & Goedert, J. J. (2014). Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. The Journal of clinical endocrinology and metabolism, 99(12), 4632–4640. https://doi.org/10.1210/jc.2014-2222
Gregori, G., Pivodic, A., Magnusson, P., Johansson, L., Hjertonsson, U., Brättemark, E., & Lorentzon, M. (2024). Limosilactobacillus reuteri 6475 and Prevention of Early Postmenopausal Bone Loss: A Randomized Clinical Trial. JAMA network open, 7(6), e2415455. https://doi.org/10.1001/jamanetworkopen.2024.15455
Leite, G., Barlow, G. M., Parodi, G., Pimentel, M. L., Chang, C., Hosseini, A., Wang, J., Pimentel, M., & Mathur, R. (2022). Duodenal microbiome changes in postmenopausal women: effects of hormone therapy and implications for cardiovascular risk. Menopause (New York, N.Y.), 29(3), 264–275. https://doi.org/10.1097/GME.0000000000001917
Nilsson, A. G., Sundh, D., Bäckhed, F., & Lorentzon, M. (2018). Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. Journal of internal medicine, 284(3), 307–317. https://doi.org/10.1111/joim.12805
Peters, B. A., Lin, J., Qi, Q., Usyk, M., Isasi, C. R., Mossavar-Rahmani, Y., Derby, C. A., Santoro, N., Perreira, K. M., Daviglus, M. L., Kominiarek, M. A., Cai, J., Knight, R., Burk, R. D., & Kaplan, R. C. (2022). Menopause Is Associated with an Altered Gut Microbiome and Estrobolome, with Implications for Adverse Cardiometabolic Risk in the Hispanic Community Health Study/Study of Latinos. mSystems, 7(3), e0027322. https://doi.org/10.1128/msystems.00273-22
Peters, B. A., Santoro, N., Kaplan, R. C., & Qi, Q. (2022). Spotlight on the Gut Microbiome in Menopause: Current Insights. International journal of women's health, 14, 1059–1072. https://doi.org/10.2147/IJWH.S340491
Saravinovska, K., Santi, D., Costantino, F., Prete, A., Šojat, A. S., Spaggiari, G., Ivović, M., Lambrinoudaki, I., Armeni, E., Jurišić, A., Mihajlović, S., Vujović, S., & Marina, L. V. (2026). The impact of estrogen status on the gut microbiome: a systematic review and meta-analysis. Frontiers in endocrinology, 17, 1780806. https://doi.org/10.3389/fendo.2026.1780806
Vriend, E. M. C., Galenkamp, H., Herrema, H., Nieuwdorp, M., van den Born, B. H., & Verhaar, B. J. H. (2024). Machine learning analysis of sex and menopausal differences in the gut microbiome in the HELIUS study. NPJ biofilms and microbiomes, 10(1), 152. https://doi.org/10.1038/s41522-024-00628-z
Wang, H., Shi, F., Zheng, L., Zhou, W., Mi, B., Wu, S., & Feng, X. (2025). Gut microbiota has the potential to improve health of menopausal women by regulating estrogen. Frontiers in endocrinology, 16, 1562332. https://doi.org/10.3389/fendo.2025.1562332
Xiong, J., Li, L., Ao, M., Tu, Y., Tu, K., & Li, L. (2025). Effects of menopausal hormone therapy on gut microbiota in postmenopausal women and the relationship with bone metabolism. Frontiers in medicine, 12, 1682925. https://doi.org/10.3389/fmed.2025.1682925
Yu, M., Pal, S., Paterson, C. W., Li, J. Y., Tyagi, A. M., Adams, J., Coopersmith, C. M., Weitzmann, M. N., & Pacifici, R. (2021). Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells. The Journal of clinical investigation, 131(4), e143137. https://doi.org/10.1172/JCI143137