Search Results (32)

The gut microbiota, acting as a critical extrinsic endocrine organ, is profoundly involved in the pathological evolution and therapeutic response of hormone-dependent malignancies. This review elucidates the core mechanisms governing the microbiota, endocrine, and immune triple-axis. Multi-omic and biochemical evidence demonstrates that microbial metabolic networks, comprising the estrobolome, androbolome, and progestobolome/corticobolome, rely on enzymatic systems such as β-glucuronidases (GUS) and steroid-17,20-desmolases to execute hormone deconjugation and structural modification, thereby modulating systemic steroid exposure. Concurrently, microbe-derived metabolites, such as secondary bile acids and purine derivatives, act as inter-kingdom messengers. These metabolites remodel the tumor immune microenvironment by antagonizing hormone receptors and activating specific signaling axes, such as the Inosine-A2AR pathway. By modulating localized immune cells like effector T cells and myeloid cells, they play a pivotal role in tumor immune evasion. Furthermore, pharmacomicrobiomics reveals a bidirectional regulation between anti-tumor agents and the gut microbiota, where endocrine and immunotherapeutic drugs can induce microbial dysbiosis, while specific gut taxa contribute to primary or acquired resistance by enzymatically inactivating drugs (e.g., reductive inactivation of Enzalutamide) or providing hormonal precursors through bypass pathways. Facing translational challenges, such as real-world microbiome complexity and the colonization resistance of indigenous flora, we propose treating the human body as a unified host–microbe holobiont system. Future research should leverage gnotobiotic models and genetic causal inference to establish functional causality. These efforts will facilitate the development of precision tools, including ubiquitin–proteasome system (UPS) modulators, microbial enzyme inhibitors, and engineered live biotherapeutics. Collectively, these systems biology strategies offer a robust framework for overcoming therapeutic resistance in hormone-dependent malignancies. Full article

Menopause represents a key transitional phase in women’s health, characterized by declining estrogen levels and increased risk for cardiometabolic, musculoskeletal, and urogenital disorders. Beyond its endocrine roots, emerging evidence highlights the gut microbiome as a critical modulator of systemic hormonal balance. This review synthesizes current understanding of the bidirectional relationship between estrogen and the gut microbiome and its implications for women’s health during menopause. Evidence from current studies reveals distinct findings across populations, reflecting the complexity of estrogen regulation in part by the gut microbiome (i.e., estrobolome). While no ideal gut microbial composition has been identified for women across stages of perimenopause, likely due to geographically unique gut microbiome profiles among healthy women, greater microbial diversity has been positively associated with improved estrogen regulation. Conversely, reduced diversity and altered Firmicutes/Bacteroidetes ratios have been linked to biomarkers of inflammation during perimenopause, which is a key driver across many perimenopausal symptoms. Although hormone replacement therapy remains the primary clinical intervention during perimenopause, we highlight emerging evidence on the adjuvant potential of diet, synbiotics, phytoestrogens, and strain-specific probiotics in modulating the estrogen–gut microbiome axis for improved health span trajectories and better symptom management. Future longitudinal studies integrating diet, gut microbiome profiles and symptom trajectories are essential to clarify these mechanisms across ethnicity and geography. Ultimately, understanding localized diet–microbiome interactions will enable the development of accessible, personalized, and non-hormonal strategies to complement and increase agency in proactive management during the perimenopausal transition. Full article

The human microbiome has emerged as a central regulator of health and disease; however, women-specific microbiome research has only recently gained focused scientific attention. Accumulating evidence demonstrates that microbial ecosystems across the gut, vagina, skin, breast tissue, and reproductive tract are dynamically shaped by female hormones, life-stage transitions, and environmental exposures. These interactions influence immune regulation, metabolic homeostasis, reproductive outcomes, mental health, and cancer risk, in part through microbiome-mediated endocrine pathways such as the estrobolome. Advances in high-resolution molecular technologies—including metagenomics, metabolomics, spatial and single-cell profiling, and artificial intelligence-driven modeling—have shifted microbiome research from descriptive taxonomy toward functional, mechanistic, and predictive science. These approaches highlight microbial function and metabolite production as stronger determinants of health outcomes than taxonomic composition alone. Nonetheless, major gaps persist, including limited causal evidence, methodological heterogeneity, underrepresentation of non-Western populations, and barriers to clinical translation. Microbiome-targeted interventions, including probiotics, prebiotics, postbiotics, and emerging microbiota-based therapies, have garnered increasing interest in women’s health. Select Lactobacillus and Bifidobacterium strains show potential in modulating vaginal and gastrointestinal health, pregnancy outcomes, and immune function; however, clinical effects remain highly strain-specific and context-dependent. Discrepancies between experimental findings, commercial claims, and validated clinical use underscore the need for rigorous, women-centered trials and standardized outcome measures. This narrative review synthesizes current molecular insights into the women’s microbiome across endocrine interactions, pregnancy, reproductive and metabolic health, lifestyle influences, and microbiome-based therapeutic strategies. We integrate clinical perspectives to identify diagnostic and translational challenges and propose future directions emphasizing precision microbiome medicine, validated biomarkers, careful evaluation of microbiome-targeted interventions, and inclusive research frameworks, including populations from the Gulf Cooperation Council (GCC). Collectively, this review positions the microbiome as a critical yet underutilized axis in women’s health and outlines a roadmap toward personalized, evidence-based care across the female lifespan. Full article

The human microbiota is increasingly recognized as a key component of women’s reproductive health. This narrative review examines the vaginal, endometrial, and gut microbiota and their roles in the pathogenesis of gynecologic and obstetric disorders, aiming to integrate current evidence into a clinically relevant framework. We review intrinsic (genetic, hormonal, and immunological) and extrinsic (environmental, lifestyle, and pharmacological) factors shaping microbial composition, with particular focus on dysbiosis and the role of the gut estrobolome within the microbiome in estrogen metabolism. The review synthesizes data on microbiota alterations associated with endometriosis, adenomyosis, uterine fibroids, endometrial polyps and hyperplasia, gynecologic malignancies, pelvic inflammatory disease, bacterial vaginosis, infertility, and adverse obstetric outcomes, including preterm birth and fetal growth restriction. Methodological approaches used to characterize the reproductive tract microbiota, such as vaginal swabs, endometrial sampling, and fecal analysis, are critically discussed, together with limitations related to low-biomass environments and contamination risk. Evidence regarding therapeutic modulation of the microbiota, including antibiotics, probiotics, hormonal therapies, and emerging microbiota-based interventions, is summarized, alongside the impact of gynecologic surgery on microbial translocation and long-term microbial balance. Overall, the available literature supports an association between microbiota alterations and multiple reproductive conditions, although causality remains incompletely established. Further standardized and longitudinal studies are needed to clarify mechanisms and guide microbiota-informed diagnostic and therapeutic strategies. Full article

Background and Objectives: Endometriosis is a chronic, estrogen-dependent inflammatory disease with multifactorial pathogenesis. Increasing evidence suggests that alterations in the gut and reproductive tract microbiota may contribute to disease development, progression, and associated symptoms through immune, hormonal, and metabolic mechanisms. This systematic review aimed to synthesize current human evidence on microbiota composition and function in women with endometriosis. Materials and Methods: A systematic literature search was conducted according to PRISMA 2020 guidelines across PubMed, Embase, Web of Science, Scopus, and the Cochrane Library. Observational human studies published in English between January 2015 and September 2025 evaluating gut, vaginal, cervical, endometrial, or peritoneal microbiota in women with endometriosis were included. Two reviewers independently screened studies, extracted data, and performed a qualitative synthesis due to methodological heterogeneity. Results: Nineteen studies were included, encompassing gut and reproductive tract samples analyzed primarily by 16S rRNA sequencing. Across cohorts, endometriosis was consistently associated with microbial dysbiosis characterized by enrichment of Proteobacteria and Firmicutes and depletion of Bacteroidetes, Lactobacillus, and Bifidobacterium. Increased abundance of opportunistic taxa, particularly Escherichia coli, Streptococcus, and Klebsiella, was frequently reported. Functionally, dysbiosis was linked to increased β glucuronidase activity, enhanced estrogen enterohepatic recirculation, reduced short-chain fatty acid production, and activation of pro-inflammatory immune pathways. Several studies reported correlations between microbial profiles, disease stage, pelvic pain, and infertility. Conclusions: Current evidence supports a reproducible association between gut microbiota dysbiosis and endometriosis. Altered microbial composition and function may contribute to chronic inflammation, hormonal imbalance, and disease persistence. Longitudinal and multi-omic studies are needed to clarify causality and to evaluate microbiota-based diagnostic and therapeutic strategies. Full article

Central precocious puberty (CPP) may be influenced by gut microbiota through changes in short-chain fatty acids (SCFAs), β-glucuronidase activity, and enterohepatic estrogen recycling. This narrative review integrates current evidence from human and animal studies exploring microbial contributions to pubertal timing. Across multiple cohorts, CPP is associated with loss of SCFA-producing commensals, such as Bacteroides, and increased abundance of taxa like Alistipes, Ruminococcus, and Lachnoclostridium. These microbial shifts are linked to altered SCFA profiles, diminished anti-inflammatory and neuroendocrine modulation, and enhanced reabsorption of estrogens via microbial β-glucuronidase activity. Experimental models support a causal connection: gut dysbiosis accelerates pubertal onset, whereas microbiota-targeted interventions can restore hormonal balance and delay activation of the HPG axis. While some overlap with obesity-associated microbiota exists, the endocrine-specific microbial changes observed in CPP suggest partially distinct mechanisms. Overall, the gut microbiota emerges as both a modulator and potential biomarker of early pubertal onset. Its integration into pediatric endocrine frameworks could improve early risk assessment and guide future interventions, though further validation through standardized, longitudinal, and diverse population studies is still required. Full article

Background/Objectives: Diet–microbiota interactions shape ageing; however, their sex-specific dimensions remain poorly defined. Human studies rarely stratify analyses by sex, while most evidence of sex-dependent microbial and metabolic responses comes from preclinical models. This review synthesizes current findings on the sex-specific pathways linking diet, microbiota, and healthy ageing. Methods: A narrative review was conducted by integrating human observational studies, randomized controlled trials, and mechanistic animal research. Evidence was organized into four domains: (1) age-related changes in gut microbial composition; (2) microbiota-derived metabolites; (3) dietary patterns and functional nutrients; and (4) sex-specific endocrine and immunometabolism interactions influenced by the gut microbiota. Results: Ageing is characterized by dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, expansion of Proteobacteria, and reduced production of key metabolites including butyrate, indoles, and polyamines. Dietary fiber, polyphenols, omega-3 fatty acids, and plant-based proteins help restore these pathways and mitigate inflammaging. Sex differences persist into later life: women show reduced estrobolome activity and SCFA decline after menopause, whereas men display higher levels of pro-atherogenic metabolites such as trimethylamine N-oxide (TMAO). Nutritional interventions, probiotics, and microbial metabolites exhibit sex-dependent responses in both human and animal studies. Conclusions: Diet–microbiota interactions shape ageing outcomes through sex-specific metabolic, hormonal, and immunological pathways. Incorporating sex as a biological variable is essential for developing personalized, nutrition-based strategies to support healthy ageing. Full article

The gut microbiota, a dynamic and metabolically active microbial ecosystem, plays a pivotal role in regulating host digestion, immune homeostasis, metabolism, and hormone signaling. Among its specialized functions, the estrobolome (a collection of bacterial genes involved in estrogen metabolism) has emerged as a key regulator of systemic estrogen levels. Through microbial β-glucuronidase activity, estrogens undergo deconjugation and reabsorption, influencing the pathogenesis of hormone-receptor-positive breast cancers. Disruption of the gut microbial balance, termed dysbiosis, can result from dietary changes, antibiotic use, environmental toxins, and psychosocial stress. Dysbiosis alters intestinal permeability, immune responses, and microbial metabolite profiles, contributing to chronic inflammation and endocrine disruption. Mechanistic links between gut microbiota and breast cancer include altered estrogen recirculation, immunomodulation, shifts in microbial metabolites (e.g., SCFAs, bile acids, tryptophan derivatives), and stress-mediated signaling through the microbiota–gut–brain axis. Accumulating preclinical and clinical evidence reveals distinct microbial signatures in breast cancer patients, supporting a causal or contributory role of gut dysbiosis in tumorigenesis. In parallel, biotics (including probiotics, prebiotics, synbiotics, and postbiotics) offer promising avenues for modulating the microbiota. Certain strains of Lactobacillus (L.) and Bifidobacterium (B.) exhibit anti-inflammatory and estrogen-modulating effects, while dietary fibers and microbial metabolites may enhance epithelial integrity and immunocompetence. This review critically examines the interplay between gut microbiota and breast cancer, elucidates the mechanistic pathways involved, and evaluates the current evidence on microbiota-targeted interventions. We also highlight research gaps, safety considerations, and the potential for integrating microbiome modulation into personalized oncologic care. This review uniquely integrates mechanistic pathways with those supported by preclinical and clinical evidence on biotics, highlighting microbiome-based precision strategies for breast cancer prevention and management. Full article

The breast microbiome remains stable throughout a woman’s life. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The breast microbiome demonstrates dynamic adaptability during lactation, responding to maternal physiological changes and infant interactions. This microbial plasticity modulates local immune responses, maintains epithelial integrity, and supports tissue homeostasis, thereby influencing both breast health and milk composition. Disruptions in this balance, the dysbiosis, are closely linked to inflammatory breast conditions such as mastitis. Risk factors for breast cancer (BC) include genetic mutations, late menopause, obesity, estrogen metabolism, and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties. Perturbations of this set of bacterial genes and metabolites, called the estrobolome, increases circulating estrogens and the risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T-cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T-cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T-cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy. Full article

Endometriosis (EMS) is a long-term inflammatory disease. It represents one of the most prevalent gynecological conditions, impacting an estimated 5% of reproductive women. Therefore, endometriosis contributes to substantial worldwide health challenges and healthcare costs. In EMS disease, endometrial glandular and stromal tissues are abnormally located outside the uterus. Similarly to the natural endometrium, these tissues grow and proliferate in response to estrogen-dependent signals. The pain and limited effectiveness of treatments are often linked to the inflammatory reaction triggered by EMS-associated ectopic tissue. This is especially amplified during the peaks of estrogen release that occur as the menstrual cycle transitions from the proliferative phase to ovulation. Maintaining the integrity of the mucosal lining, defending against pathogenic insults, and controlling physiological processes are all made possible by a healthy, balanced state of gut biomass. Additionally, numerous intestinal bacteria have been discovered to possess estrogen-metabolizing enzymes, which affect the estrobolome and, consequently, influence estrogen-related disorders. Therefore, there is increasing interest in understanding the role of microbiota and the estrobolome in endometriosis pathogenesis. This review will focus on the role of microbiota and the impact of estrobolome alterations in endometriosis pathogenesis. Full article

Fertility is a dynamic, multifactorial process governed by hormonal, immune, metabolic, and environmental factors. Recent evidence highlights the gut microbiota as a key systemic regulator of reproductive health, with notable impacts on endometrial function, implantation, pregnancy maintenance, and the timing of birth. This review examines the gut–endometrial axis, focusing on how gut microbial communities influence reproductive biology through molecular signaling pathways. We discuss the modulatory roles of microbial-derived metabolites—including short-chain fatty acids, bile acids, and tryptophan catabolites—in shaping immune tolerance, estrogen metabolism, and epithelial integrity at the uterine interface. Emphasis is placed on shared mechanisms such as β-glucuronidase-mediated estrogen recycling, Toll-like receptor (TLR)-driven inflammation, Th17/Treg cell imbalance, and microbial translocation, which collectively implicate dysbiosis in the etiology of gynecological disorders including endometriosis, polycystic ovary syndrome (PCOS), recurrent implantation failure (RIF), preeclampsia (PE), and preterm birth (PTB). Although most current evidence remains correlational, emerging insights from metagenomic and metabolomic profiling, along with microbiota-depletion models and Mendelian randomization studies, underscore the biological significance of gut-reproductive crosstalk. By integrating concepts from microbiology, immunology, and reproductive molecular biology, this review offers a systems-level perspective on host–microbiota interactions in female fertility. Full article

Endometriosis (EM) is a common estrogen-dependent chronic inflammatory disorder affecting reproductive-aged women, yet its pathogenesis remains incompletely understood. Recent evidence suggests that the gut microbiota significantly influence immune responses, estrogen metabolism, and systemic inflammation, potentially contributing to EM progression. This narrative review explores the relationship between the gut microbiota and EM, emphasizing microbial dysbiosis, inflammation, estrogen regulation, and potential microbiome-targeted therapies. Studies published within the last 30 years were included, focusing on the microbiota composition, immune modulation, estrogen metabolism, and therapeutic interventions in EM. The selection criteria prioritized peer-reviewed articles, clinical trials, meta-analyses, and narrative reviews investigating the gut microbiota’s role in EM pathophysiology and treatment. Microbial dysbiosis in EM is characterized by a reduced abundance of beneficial bacteria (Lactobacillus, Bifidobacterium, and Ruminococcaceae) and an increased prevalence of pro-inflammatory taxa (Escherichia/Shigella, Streptococcus, and Bacteroides). The gut microbiota modulate estrogen metabolism via the estrobolome, contributing to increased systemic estrogen levels and lesion proliferation. Additionally, lipopolysaccharides (LPS) from Gram-negative bacteria activate the TLR4/NF-κB signaling pathway, exacerbating inflammation and EM symptoms. The interaction between the gut microbiota, immune dysregulation, and estrogen metabolism suggests a critical role in EM pathogenesis. While microbiota-targeted interventions offer potential therapeutic benefits, further large-scale, multi-center studies are needed to validate microbial biomarkers and optimize microbiome-based therapies for EM. Integrating microbiome research with precision medicine may enhance the diagnostic accuracy and improve the EM treatment efficacy. Full article

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection between estrobolome impairment and gynecological diseases has been suggested in animal models. Nevertheless, in humans, coherent evidence on the estrobolome alteration and functionality of the female reproductive tract is still lacking. The objective of this study was to explore alterations in estrogen-related signaling and the putative link with endometrial dysbiosis. Methods: Women with infertility and repeated implantation failure (RIF, N = 40) were enrolled in order to explore the putative link between estrogen metabolism and endometrial dysbiosis. Endometrial biopsies were used to measure inflammatory and growth factor molecules. β-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1β and HIF-1α) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. β-glucuronidase activity and the expression of ERβ were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to β-glucuronidase activity and to ERβ expression, thus suggesting that an alteration of the estrogen-activating enzyme may affect the expression of ERs as well. Conclusions. Overall, these preliminary data suggested a link between endometrial dysbiosis and estrobolome impairment as possible synergistic contributing factors to women infertility and RIF. Full article

The interplay between enterohepatic circulation and the gut microbiota is the main driver determining systemic levels of estrogens and their metabolites. Nevertheless, the role of potentially probiotic microorganisms in estrogen metabolism has not been investigated so far. In this work, we have explored the ability of six Ligilactobacillus salivarius strains isolated from human milk and vaginal samples to degrade and/or conjugate parental estrogens in vitro and under aerobic conditions. The quantification of estrogens and their derivatives was carried out in cell-free supernatants by LC-QQQ-MS. All the tested L. salivarius strains achieved an average degradation rate of estrone and estriol of 98% and 55%, respectively, whereas 17β-estradiol was preferentially conjugated (up to 40%). The presence of seven out of ten genes encoding enzymes relevant for estrogen metabolism was further confirmed by PCR, highlighting their genetic potential for degrading, conjugating and/or deconjugating estrogens. The tested L. salivarius strains may be considered potential probiotics affecting the fate of endogenous estrogens. Clinical trials targeting populations with estrogen-dependent conditions will be required to elucidate the true potential of these strains for the restoration and maintenance of a healthy host estrobolome. Full article

In recent years, the relationship between the microbiota and various aspects of health has become a focal point of scientific investigation. Although the most studied microbiota concern the gastrointestinal tract, recently, the interest has also been extended to other body districts. Female genital tract dysbiosis and its possible impact on pathologies such as endometriosis, polycystic ovary syndrome (PCOS), pelvic inflammatory disease (PID), and gynecological cancers have been unveiled. The incursion of pathogenic microbes alters the ecological equilibrium of the vagina, triggering inflammation and compromising immune defense, potentially fostering an environment conducive to cancer development. The most common types of gynecological cancer include cervical, endometrial, and ovarian cancer, which occur in women of any age but especially in postmenopausal women. Several studies highlighted that a low presence of lactobacilli at the vaginal level, and consequently, in related areas (such as the endometrium and ovary), correlates with a higher risk of gynecological pathology and likely contributes to increased incidence and worse prognosis of gynecological cancers. The complex interplay between microbial communities and the development, progression, and treatment of gynecologic malignancies is a burgeoning field not yet fully understood. The intricate crosstalk between the gut microbiota and systemic inflammation introduces a new dimension to our understanding of gynecologic cancers. The objective of this review is to focus attention on the association between vaginal microbiota and gynecological malignancies and provide detailed knowledge for future diagnostic and therapeutic strategies. Full article