Gut microbes emerge as potential players in estrogen-driven cancers

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Jun 25 2026

Scientists say gut microbes may do more than recycle estrogen, but turning the endocrine-microbiome axis into a cancer therapy target will require stronger causal and clinical evidence.

Review: Beyond estrobolome 1.0: unraveling endocrine-microbiome axis as a driver and therapeutic target in hormone-driven cancers. Image Credit: Explode / Shutterstock

In a recent review published in the journal npj Biofilms and Microbiomes, researchers reviewed current evidence on how interactions between the microbiome and the endocrine system influence hormone-driven cancers and explored their potential as future therapeutic targets.

Background

Estrogen receptor-positive breast cancer and many endometrial malignancies are major hormone-driven cancers, with estrogen recognized as a key driver of several cancers. Researchers also noted that trillions of microorganisms living in the human body may influence hormone metabolism. These microbes can alter hormone availability, produce hormone-like compounds, and regulate immune and inflammatory responses, which may contribute to cancer development. Understanding this relationship may improve future cancer prevention and treatment strategies. Further mechanistic and longitudinal research is needed to understand how these interactions work at the biological level and to distinguish causal pathways from associations.

From the estrobolome to a broader endocrine-microbiome network

The gut microbiome plays a broader role in hormone regulation than previously recognized. Previous research has focused on the estrobolome, a group of gut bacteria that determine how estrogen is recycled via enzymes such as β-glucuronidase and sulfatases. These enzymes can reactivate estrogen conjugates by removing specific chemical markers, thereby extending the body's exposure to active estrogen. This function of the estrobolome may be linked to hormone-dependent cancers, like estrogen receptor-positive breast cancer and endometrial cancer.

Recent evidence suggests that the microbiome functions as an active endocrine partner rather than simply recycling hormones. The gut microbiota responds to host signals and can process dietary nutrients to produce biologically active molecules, influencing multiple endocrine, metabolic, and tissue-level pathways beyond the gut. Their metabolites also regulate inflammation, immunity, and metabolism, creating a bidirectional endocrine-microbiome axis in which hormones shape microbial communities while microbes modify endocrine signaling.

How do gut microbes modify estrogen activity?

The microbiome regulates estrogen through multiple pathways. Besides β-glucuronidase, bacterial enzymes can either reactivate estrogen or convert it into less active forms. Therefore, the same microbial community may increase or decrease estrogen exposure depending on its composition, diet, medications, and disease status.

Gut microbes can also convert some plant-based compounds into metabolites that resemble hormones. One known example of this is S-equol, which is produced by the enzymatic conversion of soy isoflavones by certain intestinal microbes. Unlike estradiol, S-equol preferentially binds to estrogen receptor beta, suggesting it may mimic or modulate estrogen signaling in a tissue-specific manner.

Other microbial metabolites, including enterolignans, also influence estrogen signaling. Since not everyone harbors the bacteria required to produce these compounds, microbial metabolites may eventually help identify cancer risk and guide personalized endocrine therapies.

Hormonal influence on the microbiome

Hormones and the microbiome continuously influence each other. While gut microbes regulate hormone metabolism, hormones shape microbial diversity and activity. Hormonal changes during puberty, pregnancy, menopause, or hormone therapy alter microbial metabolism, including bile acid, carbohydrate, and steroid pathways. In turn, these gut microbiome metabolites may influence hormone availability and immune responses.

Studies also show that bacteria can detect host-derived hormonal signals and adjust their growth and behavior accordingly. These findings suggest that life stages characterized by hormonal changes may represent critical periods during which the microbiome influences long-term hormone exposure and disease susceptibility.

The endocrine-microbiome axis in cancer development

Disruptions in the endocrine-microbiome axis may promote cancer through several mechanisms. Microbial imbalance, or dysbiosis, is associated with chronic low-grade inflammation and may contribute to increased exposure to microbial molecules that activate inflammatory pathways. This inflammatory environment may also alter insulin and metabolic signaling, which can work alongside estrogen to promote tumor progression.

Studies suggest that breast, uterine, and endometrial tissues may host distinct microbial communities that may influence local estrogen metabolism, immune responses, and inflammation without altering circulating hormone levels. Some microbial products can damage deoxyribonucleic acid (DNA) or modify gene regulation through epigenetic mechanisms, while others produce short-chain fatty acids that affect chromatin structure and cellular signaling. Together, these local and systemic effects may contribute to hormone-driven carcinogenesis, although evidence in humans remains largely observational.

Potential therapeutic opportunities

The microbiome may also influence responses to endocrine therapies. The activity of gut bacteria may affect endocrine drug metabolism, including tamoxifen metabolite levels and systemic exposure to endoxifen, its principal active metabolite. Similarly, aromatase inhibitors may affect the composition of the gut microbiota. Although promising, stronger clinical evidence is required before microbiome-guided treatment becomes routine.

Researchers are investigating microbiome-targeted methods like probiotics, prebiotics, selective enzyme inhibitors, defined microbial consortia, live biotherapeutic products, and fecal microbiota transplantation (FMT).

Experimental studies suggest these strategies can reduce harmful microbial enzyme activity or increase beneficial hormone-like metabolites. However, most of this evidence is based on laboratory studies or biomarker studies, rather than clinical trials examining cancer outcomes. 

Additionally, there are ongoing challenges related to FMT safety, donor selection, and standardized procedures. The authors noted that defined consortia and live biotherapeutics may offer safer, more controllable alternatives to crude FMT, but these approaches also require clinical validation.

Challenges and future perspectives

Despite rapid advances, important challenges remain, as most human studies demonstrate associations rather than direct cause-and-effect relationships. In addition, variations in diet, medications, menopausal status, geographic location, and lab techniques make it difficult to compare studies.

Longitudinal studies with standardized methods for future research, using multi-omic approaches, multi-kingdom profiling that includes the virome and mycobiome, sex-stratified analyses, and carefully designed experimental models will be necessary to identify potentially beneficial microbial biomarkers and therapeutic targets for clinical use.

Conclusion

The review concluded that the endocrine-microbiome axis represents an important but evolving framework for understanding hormone-driven cancers. Current evidence supports the role of gut microorganisms in regulating estrogen metabolism, inflammation, and local tissue environments, although direct causal relationships in humans remain limited.

Emerging microbiome-based therapies, including probiotics, prebiotics, selective enzyme inhibition, defined consortia, live biotherapeutics, and FMT, have shown promising preclinical and early translational results but require validation in clinical trials.

The authors emphasized that standardized research methods, longitudinal multi-omics studies, multi-kingdom profiling, sex-stratified analyses, and mechanistic investigations are essential for identifying clinically actionable microbial targets and advancing future therapeutic strategies. Until then, the endocrine-microbiome axis should be viewed as a high-priority translational hypothesis rather than a validated clinical target.

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