{"paper_id":"5a81aa66-51b3-4355-aa1f-105985f0a2cc","body_text":"The human gut microbiota is increasingly recognised as a critical regulator of systemic physiology and disease, including endometriosis. In 2023, a report by Muraoka and colleagues on the potential role of Fusobacteria in this enigmatic condition further intensified interest in this field [Citation1]. Once considered primarily a gynaecological disorder, endometriosis is now widely understood as a systemic disease with complex hormonal, immune, and metabolic dimensions. Despite substantial advances in identifying molecular contributors to disease progression, important gaps remain in elucidating the mechanisms that sustain local oestrogen dominance and chronic inflammation within endometriotic lesions. In this context, growing attention has turned to the estrobolome, the subset of the gut microbiome involved in oestrogen metabolism. Recent reviews have synthesised current knowledge on the role of the estrobolome in endometriosis [Citation2,Citation3].\nAmong its diverse functions, the estrobolome has the capacity to metabolise host steroids, particularly oestrogens, leading to its conceptualisation as the aggregate of microbial genes and taxa capable of processing oestrogenic compounds. Early definitions focused on bacterial enzymes such as β-glucuronidase and β-glucosidase, which deconjugate hepatic oestrogen conjugates and enable their reabsorption into the circulation via the enterohepatic pathway. This microbial reactivation plays a fundamental role in regulating circulating levels of active oestrogens and oestrogen metabolites throughout the body. Consequently, the estrobolome functions as an endocrine organ with direct implications for oestrogen-dependent physiology and disease susceptibility [Citation4].\nEmerging evidence supports a link between alterations in the estrobolome and the pathogenesis of endometriosis. Gut dysbiosis—defined as an imbalance in microbial communities—may increase systemic oestrogen levels through enhanced deconjugation and reabsorption, thereby promoting a hyperestrogenic environment that favours lesion persistence. Several bacterial genera, including Bacteroides, Bifidobacterium, Escherichia coli, and Lactobacillus, are known producers of β-glucuronidase and other enzymes involved in oestrogen metabolism. Collective shifts in these microbial populations may therefore substantially influence host oestrogen profiles.\nFurthermore, studies suggest that women with endometriosis may exhibit distinct estrobolome signatures, characterised by differential microbial taxa abundance and increased faecal concentrations of oestrogens and their metabolites. Although some observations remain preliminary, these findings support the hypothesis that estrobolome activity not only influences systemic hormone levels but may also correlate with specific clinical phenotypes of the disease.\nThe interplay between the estrobolome and endometriosis extends beyond oestrogen recycling alone. The gut microbiota also modulates host immunity, intestinal barrier integrity, and metabolic signalling, all of which intersect with the chronic inflammatory profile characteristic of endometriosis. Dysbiosis may increase intestinal permeability, allowing translocation of microbial products that trigger systemic immune activation [Citation5]. In the context of endometriosis, such immune disturbances can reinforce a pro-inflammatory microenvironment, thereby promoting lesion persistence and pain.\nHormonal and immune crosstalk also operates bidirectionally. Oestrogens themselves influence gut microbial composition, while immune mediators altered in endometriosis can, in turn, reshape bacterial communities. This feedback loop positions the estrobolome as both a contributor to and a responder within the altered endocrine and immune landscapes of endometriosis, underscoring the systemic complexity of the disease.\nUnderstanding how the estrobolome influences endometriosis opens several avenues for therapeutic exploration. Microbiome compositional profiling may serve as a biomarker for disease risk, activity, or treatment response. Given the central role of oestrogen in endometriosis, targeting microbial enzymes involved in oestrogen metabolism—such as through selective β-glucuronidase inhibition—could represent a novel adjunct to hormonal therapies. In addition, modulation of the gut microbiome via dietary interventions, probiotics, or prebiotics offers an appealing non-hormonal approach to influence systemic oestrogen dynamics. Although clinical evidence remains limited, these strategies are consistent with emerging microbiome-based interventions across endocrine and inflammatory diseases.\nIntegrating estrobolome assessments into clinical research may refine the phenotyping of endometriosis, particularly in patients who are refractory to conventional hormonal or surgical therapies. Stratification based on microbial and metabolic profiles could help identify subgroups more likely to benefit from tailored interventions, including microbiota-targeted strategies.\nIn parallel, continued use of animal models and mechanistic studies is essential to disentangle causal relationships, specifically whether estrobolome alterations act as drivers of disease onset or arise as consequences of systemic dysregulation. Recent findings indicate that microbiota manipulation in murine models can attenuate lesion progression and associated symptoms, suggesting the presence of modifiable cause–effect pathways with therapeutic potential [Citation6].\nIn summary, the estrobolome represents a paradigm shift in our understanding of endometriosis. By positioning the gut microbiota at the intersection of hormonal regulation and chronic inflammation, it offers both novel mechanistic insight and meaningful translational potential. Although challenges remain in defining precise causal pathways and developing effective interventions, the emergence of the estrobolome as a contributor to endometriosis pathogenesis underscores the need for broader, systems-level approaches to research and treatment. As endometriosis is increasingly recognised not as a localised gynaecological disorder but as a complex systemic condition, the estrobolome is likely to play a central role in future investigative and therapeutic strategies.\nAcknowledgements\nThis editorial has been fully written, revised and approved by Ludwig Kiesel.\nDisclosure statement\nThe author declares having no potential conflicts of interest.\nFunding\nThis editorial was not funded.\nData availability statement\nData sharing is not applicable to this manuscript as it does not create or analyse data.\nReferences\n- Muraoka A, Suzuki M, Hamaguchi T, et al. Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts. Sci Transl Med. 2023;15(700):eadd1531. doi: 10.1126/scitranslmed.add1531\n- Nannini G, Cei F, Amedei A. Unraveling the contribution of estrobolome alterations to endometriosis pathogenesis. Curr Issues Mol Biol. 2025;47(7):502. doi: 10.3390/cimb47070502\n- Saponara S, Scicchitano F, D'Alterio MN, et al. Could the estrobolome have a role in endometriosis pathogenesis and infertility? A systematic review. BMC Womens Health. 2025;26(1):43. doi: 10.1186/s12905-025-04195-z\n- Plottel CS, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. 2011;10(4):324–335. doi: 10.1016/j.chom.2011.10.003\n- Facciotti F, Di Stefano G, Maragno P, et al. Microbiome dysbiosis and endometriosis: a systematic scoping review of current literature and knowledge gaps. Hum Reprod Open. 2025;2025(4):hoaf061. doi: 10.1093/hropen/hoaf061\n- Xu Y, Zhu Y, Wu X, et al. Gut microbiota-derived acetate ameliorates endometriosis via JAK1/STAT3-Mediated M1 macrophage polarisation. Microb Biotechnol. 2025;18(8):e70202. doi: 10.1111/1751-7915.70202","source_license":"CC-BY-4.0","license_restricted":false}