The role of the gut and reproductive tract microbiota in the development, diagnosis, and treatment of endometriosis

Endometriosis is an inflammatory disorder. Caused by the proliferation of endometrial tissue outside the uterine mucosa. Progression results from elaborate interactions among hormonal, immunological, and environmental factors. Growing evidence indicates that the gut and reproductive tract microbiota play a key role in the pathogenesis of endometriosis. In patients with endometriosis, an increase in potentially pathogenic taxa, including Escherichia, Gardnerella, and Streptococcus, is observed. Dysbiosis leads to the translocation of bacterial endotoxins (Lipopolysaccharide (LPS)), activation of the TLR4/NF -κB pathway, and increased production of pro -inflammatory cytokines (IL -6, IL -8, TNF -α), which promote angiogenesis and the proliferation of endometrial foci. Furthermore, disturbances in the activity of the enzyme β -glucuronidase, part of the oestrobolome, increase the pool of active oestrogens, playing a role in disease progression. Despite the growing number of studies, further prospective studies involving larger populations are needed to standardise diagnostic methods and confirm the therapeutic potential of microbiome modulation in treating endometriosis.

endometriosis, gut microbiota, reproductive tract microbiota, estrabolome 1. INTRODUCTION Endometriosis is an inflammatory disease involving the growth of the uterine lining outside the uterus. Depending on the location, different names and forms of the disease can be distinguished. Adenomyosis is a type of endometriosis located within the uterine wall. Superficial endometriosis is characterised by foci on the surface of the peritoneum. Deep endometriosis is a condition in which endometrial cells grow beyond the female reproductive organs. A case of deep endometriosis has even been described in which endometrial foci were in the central nervous system (Meggyesy et al., 2020). It most commonly affects young women of reproductive age, affecting 10% of women. Medical Science To Cite: Malinowski M, Krasowski M, Kalinowska A, Pietras W, Koziel A, Kurek Z, Jentkiewicz A, Haj Obeid E, Ulrych J, Krupa J. The role of the gut and reproductive tract microbiota in the development, diagnosis, and treatment of endometriosis. Medical Science 2026; 30: e9ms3757 doi: https://doi.org/10.54905/disssi.v30i167.e9ms3757 Authors’ Affiliation: 1Medical University of Warsaw, 61 Żwirki i Wigury Street, 02-091 Warsaw, Poland 2Poznań University of Medical Science, 10 Fredry Street, 61-701 Poznan, Poland ⃰ Corresponding author: Maciej Malinowski, Medical University of Warsaw, 61 Żwirki i Wigury Street, 02-091 Warsaw, Poland E-mail: [email protected] Contact List Maciej Malinowski [email protected] Michał Krasowski [email protected] Alicja Kalinowska [email protected] Wiktoria Pietras [email protected] Adrian Koziel [email protected] Zofia Kurek [email protected] Aleksander Jentkiewicz [email protected] Esmail Haj Obeid [email protected] Jakub Ulrych [email protected] Jan Krupa [email protected] Orcid List Maciej Malinowski 0009-0003-7637-6290 Michał Krasowski 0009-0006-6243-1246 Alicja Kalinowska 0009-0000-9011-843X Wiktoria Pietras 0009-0003-2887-8755 Adrian Koziel 0009-0006-6096-5850 Zofia Kurek 0009-0002-4156-8666 Aleksander Jentkiewicz 0009-0008-4224-4069 Esmail Hai Obeid 0009-0008-5165-1221 Jakub Ulrych 0009-0004-7460-965X Jan Krupa 0009-0001-2175-806X Peer-Review History Received: 16 August 2025 Reviewed & Revised: 25/August/2025 to 29/December/2025 Accepted: 07 January 2026 Published: 21 January 2026 Peer-review Method External peer-review was done through double-blind method. Medical Science pISSN 2321–7359; eISSN 2321–7367 © The Author(s) 2026. Open Access. This article is licensed under a Creative Commons Attribution License 4.0 (CC BY 4.0)., which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. DISCOVERY SCIENTIFIC SOCIETY REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 2 of 8 Sampson's theory is the most popular among the existing theories (Konickx et al., 2019), which claims that in a new environme nt, retrograde menstrual blood flow may facilitate the transplantation and growth of endometrial fragments. This theory supports the typical locations of endometriosis foci, such as the adnexal region, uterosacral ligaments, or the pouch of Douglas. Neverthe less, the anatomical obstruction to menstrual blood outflow or proven retrograde flow is not always associated with endometriosis. Risk factors include: disturbances in menstrual blood flow, anatomical defects, prolonged oestrogen exposure, short menstrual cycles, low birth weight, or exposure to toxins (Konickx et al., 2019; Caporossi et al., 2021). Recently, increasing significance has been attr ibuted to the role of dysbiosis in the gut and vaginal microbiota, which has the potential to amplify inflammation and disrupt hormonal bal ance (Molina et al., 2020). As endometrial implants shed just like the normal endometrium, they naturally correspond with the menstrual cycle. An intensified inflammatory process occurs, nerve-receptor transmission increases, and patients' perception of pain is heightened. This is the first and most common symptom of endometriosis. What is more, the heavy menstrual bleeding and painful sexual intercourse (dyspareunia) occur as well. In the long term, endometriosis can be a factor playing a role in an ectopic pregnancy, premature birth, or even infertility. The well-established standard for its diagnosis is laparoscopy. The treatment for endometriosis includes pharmacological, surgical, an d with supportive methods, depending on symptoms, the location of changes, and the patient's future reproductive plans. The pharmacotherapy is mainly based on hormonal drugs. In refractory cases or deep infiltrating endometriosis, surgical treatment (most commonly laparoscopic) is used, aimed at removing the disease outbreaks. Supportive treatment includes physiotherapy, a specific diet therapy, probiotic therapy, and psychological support. Currently, all treatment methods are symptomatic. Recently established treatment approaches include examining the gut and reproductive tract microbiota as potential targets for causal treatment. Nonetheless, the therapy should be individualised an d long- term-oriented. Henceforth, the aim of this paper is to present the current state of research and knowledge on the role of the gut and reproductive tract microbiota in the pathogenesis and treatment of endometriosis, with particular emphasis on immunological, hormonal, and inflammatory mechanisms. Figure 1. Prisma Flowchart REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 3 of 8 2. REVIEW METHODS For this review, we searched PubMed and Google Scholar for articles published. Electronic literature searches were performed with a restriction to particular publication years (January , 1999 – July, 2025), using the following English search terms: endometriosis, gut microbiota, reproductive tract microbiota, oestrobolome. Inclusion criteria included literature treating clinical trials, systematic reviews, and original papers, as well as meta -analyses concerning the influence of the microbiome on the development of endometriosis, all published in English. Exclusion criteria, however, included studies with weak methodology and publications written in languag es other than English (Figure 1). 3. RESULTS & DISCUSSION Recent publications clearly indicate dysbiosis in the intestinal microbiota and reproductive organs. The disease develops as a result of colonisation by pathogenic Escherichia, Gardnerella, Prevotella and a decrease in the number of protective Lactobacillus and Bifidobacterium bacteria. This disequilibrium promotes activation of the TLR4 and NF -kB pathways by LPS, leading to chronic inflammation. In turn, elevated concentrations of IL -6, IL -8, and TNF -alpha promote the growth of ectopic endometrial foci outside the uterine cavity. Increased β -glucuronidase activity increases serum estrogen levels. Under the influence of estrogen, the endometrium undergoes increased proliferation. In a short time, this can lead to clinical symptoms and exacerbation of the disease. The microbiome varies depending on lesion stage and anatomical location, with some bacterial taxa exhibiting protective effects and others increasi ng disease risk. Animal models have confirmed a causal link, as transplantation of microbiota from affected individuals induced endometr iotic lesions in healthy animals. Modulation of the microbiota, including increased levels of short -chain fatty acids (SCFAs), reduced lesion growth by influencing macrophage polarisation. The diversity of substances secreted by the microbiome and its composition ena bles the development of diagnostic methods and screening tests in the future. To this end, diagnostics should be improved, and fun ding for clinical trials should be increased (Table 1). Table 1: The impact of gut and reproductive tract microbiome on the development, diagnosis, and treatment of endometriosis. Study Aspect Key findings Pathophysiological relevance Hicks et al., 2025 Microbiota dysbiosis Decrease concentration: Lactobacillus, Bifidobacterium Increase concentration: Escherichia, Prevotella, Gardnerella Induction of inflammation Khan et al., 2010 Inflammatory pathways ↑ LPS ↑ TLR4/NF-κB Chronic inflammatory response Machado et al., 2022 Wang et al., 2021 Inflammatory mediators ↑ IL-6 ↑ IL-8 ↑ TNF-α Progression and persistence of endometriotic lesions Kwa et al., 2016 Estrobolome ↑ β- glucuronidase Increased levels of estrogens Ji et al., 2023 Wang et al., 2025). Angiogenesis ↑ pro-angiogenic factors Vascularization and survival of ectopic lesions Quaranta et al., 2019 Liu et al., 2024 Causal evidence Microbiota transplantation induces lesions (animal models) Confirms microbiota involvement Li et al., 2024 Microbiota modulation ↑ SCFAs-macrophage polarization Reduced lesion growth Toffoli et al., 2025 Clinical potential Microbiome profiles as biomarkers Targeted diagnosis and therapy Current State of Research and Knowledge The Physiological Role of the Gut Microbiome A description of the physiological role of the gut microbiome’s all functions is beyond the scope of this publication; nevert heless, to highlight the enormous role it plays in our body, it is worth recalling that the number of cells making up the gut microflora is several times greater than the number of cells in our body. We now know that its role goes beyond the digestive system as it includes influences on the immune, hormonal, and nervous systems, as well as on the pathogenesis of gynaecological diseases such as REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 4 of 8 endometriosis (Polycystic Ovary Syndrome – (PCOS)) and fertility disorders. It additionally plays an important role in the metabolism of nutrients and the production of (Short -Chain Fatty Acids (SCFA)). The compound exhibits anti -inflammatory properties by sealing the intestinal membrane. It mobilises the immune system and activates dendritic cells, Th17 lymphocytes, and Treg cells (Li et al., 2024). Dysbiosis then leads to excessive immune activation and a chronic inflammatory state, which ultimately promotes the developme nt of inflammatory, metabolic, autoimmune, and neoplastic diseases. The Physiological Role of the Female Reproductive Tract Microbiome The microbiota of the female reproductive tract, notably of the vagina, is dominated under physiological conditions by bacter ia of the Lactobacillus genus (L. crispatus, L. iners, L. gasseri, L. jensenii). They produce lactic acid, they maintain an acidic environment (pH < 4.5), which serves as protection for them from infections and a support for local mucosal immunity. A stable vaginal microbiome ser ves as a barrier against pathogens while also ensuring immunological tolerance to natural bodily changes, such as during the menstrual cycle or pregnancy. Disturbances in this state of balance result in dysbiosis. Most commonly referred to as bacterial vaginosis, it is characterised by a decrease in Lactobacillus abundance and a predominance of anaerobic bacteria ( Gardnerella, Prevotella, Atopobium) (Wang et al., 2021). Clinically, this is associated with increased susceptibility to reproductive and urinary tract infections. Modern sequencing techniques have shown the presence of specific bacteria in the uterine cavity and peritoneal fluid (Chen et al., 2017). This has raised new questions about their role in the initiation and progression of endometrial changes. Gut and genital dysbiosis can lead to the translocation of bacterial endotoxins (e.g., LPS), which activate the TLR4/NF -κB pathway. The result is the production of pro -inflammatory cytokines (IL -6, IL -8, TNF -α), promoting angiogenesis and the proliferation of endometrial foci. Studies have long unravelled the differences in the composition of the gut, vaginal, and endometrial microb iota in women with endometriosis compared to healthy women. Among other findings, there was a decrease in beneficial (e.g., Lactobacillus and Bifidobacterium) and an increase in the proportion of potentially pathogenic bacteria (e.g. Escherichia, Streptococcus, Gardnerella). More and more attention is being drawn to the increased prevalence of Phascolarctobacterium in patients' faeces, which serves as a possible diagnostic biomarker (Hicks et al., 2025). Initial attempts at microbiota modulation, probiotics, diet, antibiotics, and, in animal models, faecal microbiota transplantation. Suggest that influencing the microbiome may reduce inflammation, limit the development of foci, and relieve pain symptoms. Gut Microbiota and Endometriosis In recent years, the gut microbiota has gained particular significance as a potential factor modulating the development and p rogression of endometriosis. A growing body of data indicates that its composition and functions can influence the immune response. The primary factor associated with endometriosis development is increased intestinal permeability to pathogenic bacteria, which interfere s with the normal microbiome. These disturbances lead to chronic inflammatory states, which are a risk factor for disease development. This leads to an accumulation of inflammatory cytokines (including TNF-α, IL-6, IL-8) and Vascular Growth Factors (VEGF). Angiogenesis and inflammation enable the survival of endometrial implants in a new location. As early as 1999, Garcia -Velasco and Arici conducted in vitro studies showing that IL -8 significantly increases the adhesion of cells to fibronectin, the main extracellular matrix protein, in a dose -dependent manner, and further, the neutralisation of IL -8 with monoclonal antibodies partially blocked this effect, corroborating its important role in this process. The authors suggest that IL -8 is present in elevated concentrations. May function as an autocrine and paracrine factor, supporting the adhesion, proliferation, and angiogenesis of endometrial foci (1999), wh ich overall s that the peritoneal inflammatory microenvironment promotes the initiation of endometriosis, strengthening the early stages of endometrial cell implantation (Garcia-Velasco and Arici,1999). Currently, there is no way to determine exactly what causes endometriosis. Many hypotheses have arisen on this topic, one of which is the bacterial contamination hypothesis. The authors demonstrated that (LPS) – the main component of the cell membrane of Gram-negative bacteria, notably from Escherichia coli , can enter the peritoneal cavity with menstrual blood as a result of retrograde menstruation. Studies have found that E. coli contamination in the control group was larger. (LPS) activates the TLR4 and NF -kB pathways, augmenting the inflammatory response. Active macrophages secrete TNF -alpha, IL -6, and IL -8. This process supports angiogenesis, followed by endometrial proliferation of ectopic endometrial lesions. Clinical studies have demonstrated gut dy sbiosis, and several taxa have been identified as more abundant in the study group, including the classes Bacilli, Clostridia, Coriobacteriia, and Gammaproteobacteria (Ji et al., 2023; Wang et al., 2025). REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 5 of 8 Nevertheless, a change in the microbiome does not always favour disease development. Anaerotruncus, Olsenella, and Ruminococcaceae may increase the risk of developing endometriosis, whereas Eubacterium ruminantium, Holdemania, and Sutterella have a protective effect (Dang et al., 2024). The evidence of animal experiments supports this thesis (Chadchan et al., 2023), as it has been proven that transplanting faecal microbiota from mice with endometriosis to healthy animals induces the development of lesions. A correlation has been discovered between bacterial species and the location of endometriosis. Carriage of Blantia, Oscillospira, and Adlercreutzia increases the risk of ovarian and peritoneal disease (Tang et al., 2024). The microbiomes of female patients at different stages of disease progression were compared. Taxonomic analysis showed that in the early stage, bacteria such as Saccharofermentans, Prevotella, or Bacteroides predominated; however, in the late stage, Bartonella and Snodgrassella were the ones to show greater abundance. As a result of the findings overall, Prevotella ruminicola and Bacteroides caecimuris were associated with a milder clinical course (Xu et al., 2025; Cai et al., 2025). A study including 38 patients with endometriosis and 20 healthy women was conducted, focusing on assessing levels of Mannose - Binding Lectin (MBL), the activity of the lectin pathway (LP), and associated changes in the endometrial microbiota. The auth ors demonstrated that elevated plasma (MBL) levels correlate with disease advancement, but they were not linked to polymorphisms in the MBL2 gene. Patients with elevated LPS concentrations were more likely to be carriers of pathogenic Gardnerella and Prevot ella bacteria (Wang et al., 2025). However, Lactobacillus significantly reduced LPS concentration. This was noted by the team (Tof foli et al., 2025) in their study. They suggest that LPS may serve as a marker of disease progression in the future. They noted that this requires further research. Some substances secreted by bacteria have protective properties, e.g., SCFA. It alleviates inflammation and reduces disease symptoms (Su et al., 2024). Faecal microbiota transplantation (FMT), from healthy donors increases SCFA concentration. This r esults in the activation of the tyrosine kinases JAK1/STAT3 pathway within the lesions. The consequence of this was the polarisation of macrophages towards the M1 phenotype (Quaranta et al., 2019; Liu et al., 2024). The oestrobolome is a term introduced by Plottel and Blaser in 2011, defining the set of bacterial genes in the gut microbiot a whose enzymatic products participate in oestrogen metabolism. The key enzyme in this process is β -glucuronidase, produced by bacterial species (e.g., Escherichia coli, Bacteroides, Clostridium). Oestrogens are metabolised and conjugated with glucuronic or sulphuric acid in the liver. Next, it is then excreted with bile into the intestines. In the intestine, bacteria producing β -glucuronidase can break down conjugated oestrogens. Restoring their active form. Active oestrogens are reabsorbed into the circulation (enterohepatic circ ulation). Regular oestrobolome activity facilitates the maintenance of the appropriate level of oestrogens in the body, as shown in stu dies (Kwa et al., 2016), and disturbances in this process can appear as hypooestrogenaemia or hyperoestrogenaemia. The latter can also directly influence endometrial growth in other locations or the development of oestrogen-dependent tumours (Hu et al., 2023). Plottel and Blaser analysed faecal and urine samples from 51 patients (27 with endometriosis, 24 healthy). In the faeces of p atients with endometriosis, elevated levels of oestrogen metabolites were found: oestriol, 16 -epioestriol, 16α -hydroxyoestrone, and 2 - methoxyoestradiol. On the contrary, such differences were not observed in urine samples. The authors emphasise that despite t he lack of clear signs of gut dysbiosis, the altered microbiota composition and increased concentrations of active oestrogen metaboli tes in faeces may indicate subtle interactions between the gut microbiome and the oestrobolome in the pathogenesis of endometriosis. This evidence shows a role for the microbiota in locally modulating oestrogen metabolism, which may further support disease development. This data support the hypothesis that the gut oestrobolome can truly impact the pool of active oestrogens in the enterohepati c circulation, consequently facilitating the progression of endometriosis (Pai et al., 2023). Studies on mouse models have conf irmed that administration of β-glucuronidase causes an increase in LPS concentration and macrophage infiltration. This leads to an increase in the inflammatory response and disease progression (Wei et al., 2023). Reproductive Tract Microbiota and Endometriosis For a long time, it was believed that the cervical barrier provided adequate protection of the uterine cavity against colonis ation by microorganisms from the vagina and the external environment. However, thanks to advances in sequencing techniques and the expansion of diagnostic methods. We know that the microflora of the reproductive tract consists of many species of bacteria ( Hugerth et al., 2024). In patients with chronic endometritis, there was a significant decrease in the dominance of Lactobacillus bacteria in both the vagina and the uterus. What is essential is that transplanting vaginal microbiota from such patients into animal models resul ts in endometrial inflammation, a risk factor for endometriosis. A reverse trial was conducted, in which the introduction of the pr otective strain Lactobacillus murinus showed an anti-inflammatory effect in animals. This way, a link was proven between infection of the lower REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 6 of 8 reproductive tract, including the vagina, and an increased risk of endometriosis (Elizur et al., 2014). Female reproductive tract dysbiosis also increases the risk of infertility, ectopic pregnancy, and endometrial cancer (Wessels et al., 2021). Patients are marked by decreased levels of Lactobacillus bacteria. This is typical for a healthy vaginal microbiome. In addition, there is colonisation by species that increase the risk of endometriosis: Gardnerella, Atopobium, Prevotella, or Megasphaera (Sessa et al., 2024). In patients with endometriosis, Escherichia coli was more frequently detected in menstrual blood and endometrial smears, a findi ng that is significant given the presence of LPS bacterial endotoxins capable of activating TLR4 receptors and intensifying local inf lammatory reactions (Khan et al., 2010). Higher levels of endotoxins and (Heat Shock Proteins (HSP70)) were found in the menstrual and peritoneal fluid of patients with endometriosis, which increases the chances of survival and proliferation of endometrial cel ls via the TLR4 signalling pathway (Khan et al., 2013). Due to diagnostic difficulties and the lack of a specific disease marker, considerable funding has been allocated to research on this topic, resulting in the creation of a specialised predictive model. The algorithm created enables differentiation between the microbiome of the vagina and the reproductive tract in sick and healthy patients with an accuracy of 81% sensitivity and 88% specificity (MacSharry et al., 2024). The significance of the microbiome in the pathogenesis of endometriosis is also supported by studies examining its composition in sick patients. Specific patterns of IgG glycosylation in serum and urine may be another marker of the disease (MacSharry et al., 2024; Li et al., 2025). Currently, however, the tests have not found any clinical application due to high diagnostic costs and the complexity of the process. The inoculation with Fusobacterium in animal models resulted in exacerbation of endometriosis, whereas antibiotic treatment significantly decreased the number and mass of disease foci (Muraoka et al., 2023). Due to the lack of causal treatment, howe ver, much attention is devoted to new methods and hopes for the future are placed in probiotics. Progress in observations indicates a high therapeutic potential targeted at the microbiome Lactobacillus spp , as the dominant component of healthy vaginal flora, not only strengthens the mucosal barrier but also limits the colonisation of pathogens (e .g., Gardnerella vaginalis , E. coli), consequently lowering the production of pro -inflammatory cytokines (IL -6, IL -8, TNF -α). It inhibits the action of endotoxins, which is notably important in treatment (Machado et al., 2022; Wang et al., 2021). Given current eviden ce, the female reproductive tract microbiome is no longer associated solely with infections requiring antibiotic treatment; it is now a source of knowledge for future diagnostic and therapeutic methods. 4. CONCLUSION More and more studies indicate that dysbiosis promotes the development of the disease. Both intestinal and reproductive tract microbiome disorders promote the progression of endometriosis through particular mechanisms. Activation of TLR4 receptors by LPS molecules and the subsequent activation of the NF -κB inflammatory pathway lead to the proliferation of ectopic endometrial foci. An additional influence is the increased concentration of estrogens, which is affected by the estrobolome. Currently, pathogenic and protective bacteria have been identified. In the future, this division may allow for greater precision and earlier diagnosis of patients. Animal studies indicate that disruption of the microbiota may influence the development or inhibition of disease lesions. Res earchers emphasise the future therapeutic impact of disease regression in animals. The studies describe molecules secreted by bacteria that may have the potential to alleviate the development of the disorder. SCFAs have immunomodulatory effects, reduce inflammation, and limit the activation of immune system cells. Their low concentration correlated with the development of endometriosis. Promising results and evidence from animal models deliver a meaningful understanding of future diagnostic and clinical therapies. However, further research is required to completely understand the se relationships and their potential clinical applications. Acknowledgments The authors have no acknowledgments to disclose. Informed consent Not applicable. Ethical approval Not applicable. This article does not contain any studies with human participants or animals performed by any of the authors. REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 7 of 8 Funding This research did not receive any external funding like specific grant from funding agencies in the public, commercial, or nonprofit sectors. Conflict of interest The authors declare that they have no conflicts of interests, competing financial interests or personal relationships that could have influenced the work reported in this paper. Data and materials availability All data associated with this study will be available based on reasonable request to the Corresponding Author.

1. Cai Z, Zhou Z, Huang S, Ma S, Chen Y, Cao Y, Ma Y. Gut microbiome in patients with early -stage and late -stage endometriosis. BMC Women’s Health 2025; 25(1):163. doi: 10.1186/s12905-025-03689-0. 2. Caporossi L, Capanna S, Viganò P, Alteri A, Papaleo B. From Environmental to Possible Occupational Exposure to Risk Factors: What Role Do They Play in the Aetiology of Endometriosis? Int J Environ Res Public Health 2021; 18(2): 532. doi:10.3390/ijerph18020532. 3. Chadchan SB, Naik SK, Popli P, Talwar C, Putluri S, Ambati CR, Lint MA, Kau AL, Stallings CL, Kommagani R. Gut microbiota and microbiota -derived metabolites promote endometriosis. Cell Death Discov 2023; 9(1):28. doi:10.1038/ s41420-023-01309-0. 4. Chen C, Song X, Wei W, Zhong H, Dai J, Lan Z, Li F, Yu X, Feng Q, Wang Z, Xie H, Chen X, Zeng C, Wen B, Zeng L, Du H, Tang H, Xu C, Xia Y, Xia H, Yang H, Wang J, Wang J, Madsen L, Brix S, Kristiansen K, Xu X, Li J, Wu R, Jia H. The microbiota continuum along the female reproductive tract and its relation to uterine -related diseases. Nat Commun 2017; 8(1):875. doi:10.1038/s41467-017-00901-0. 5. Dang C, Chen Z, Chai Y, Liu P, Yu X, Liu Y, Liu J. Assessing the relationship between gut microbiota and endometriosis: a bidirectional two -sample mendelian randomisation analysis. BMC Women’s Health 2024; 24(1):123. doi:10.1186/s12905 -024- 02945-z. 6. Elizur SE, Lebovitz O, Weintraub AY, Eisenberg VH, Seidman DS, Goldenberg M, Soriano D. Pelvic inflammatory disease in women with endometriosis is more severe than in those without. Aust N Z J Obstet Gynaecol 2014; 54(2):162 -5. doi: 10.1111/ajo.12189. 7. Garcia-Velasco JA, Arici A. Interleukin -8 stimulates the adhesion of endometrial stromal cells to fibronectin. Fertil Steril 1999; 72(2):336-40. doi:10.1016/s0015-0282(99)00223-x. 8. Hicks C, Leonardi M, Chua XY, Mari -Breedt L, Espada M, El - Omar EM, Condous G, El -Assaad F. Oral, Vaginal, and Stool Microbial Signatures in Patients With Endometriosis as Potential Diagnostic Non -Invasive Biomarkers: A Prospective Cohort Study. BJOG 2025; 132(3):326-336. doi:10.1111/1471-052 8.17979. 9. Hu S, Ding Q, Zhang W, Kang M, Ma J, Zhao L. Gut microbial beta-glucuronidase: a vital regulator in female estrogen metabolism. Gut Microbes 2023; 15(1):2236749. doi:10.1080/19 490976.2023.2236749. 10. Hugerth LW, Krog MC, Vomstein K, Du J, Bashir Z, Kaldhusdal V, Fransson E, Engstrand L, Nielsen HS, Schuppe- Koistinen I. Defining Vaginal Community Dynamics: daily microbiome transitions, the role of menstruation, bacteriophages, and bacterial genes. Microbiome 2024; 12(1): 153. doi:10.1186/s40168-024-01870-5. 11. Ji X, Yang Q, Zhu XL, Xu L, Guo JY, Rong Y, Cai YL. Association between gut microbiota and endometriosis: a two-sample Mendelian randomisation study. Front Microbiol 2023; 14:1188458. doi:10.3389/fmicb.2023.1188458. 12. Khan KN, Kitajima M, Hiraki K, Yamaguchi N, Katamine S, Matsuyama T, Nakashima M, Fujishita A, Ishimaru T, Masuzaki H. Escherichia coli contamination of menstrual blood and effect of bacterial endotoxin on endometriosis. Fertil Steril 2010; 94(7):2860-3.e1-3. doi:10.1016/j.fertnstert.2010 .04.053. 13. Khan KN, Kitajima M, Inoue T, Tateishi S, Fujishita A, Nakashima M, Masuzaki H. Additive effects of inflammation and stress reaction on Toll -like receptor 4-mediated growth of endometriotic stromal cells. Hum Reprod 2013; 28(10):2794 - 803. doi:10.1093/humrep/det280. 14. Koninckx PR, Ussia A, Adamyan L, Wattiez A, Gomel V, Martin DC. Pathogenesis of endometriosis: the genetic/ epigenetic theory. Fertil Steril 2019; 111(2):327 -340. doi: 10.1016/j.fertnstert.2018.10.013. 15. Kwa M, Plottel CS, Blaser MJ, Adams S. The Intestinal Microbiome and Estrogen Receptor -Positive Female Breast REVIEW | OPEN ACCESS Medical Science 30, e9ms3757 (2026) 8 of 8 Cancer. J Natl Cancer Inst 2016; 108(8):djw029. doi:10.1093/ jnci/djw029. 16. Li C, Xu X, Zhao X, Du B. The inconsistent pathogenesis of endometriosis and adenomyosis: insights from endometrial metabolome and microbiome. mSystems 2025; 10(5):e0020225. doi:10.1128/msystems.00202-25. 17. Li Z, Xiong W, Liang Z, Wang J, Zeng Z, Kołat D, Li X, Zhou D, Xu X, Zhao L. Critical role of the gut microbiota in immune responses and cancer immunotherapy. J Hematol Oncol 2024; 17(1):33. doi:10.1186/s13045-024-01541-w. 18. Liu M, Peng R, Tian C, Shi J, Ma J, Shi R, Qi X, Zhao R, Guan H. Effects of the gut microbiota and its metabolite short -chain fatty acids on endometriosis. Front Cell Infect Microbiol 2024; 14:1373004. doi:10.3389/fcimb. 2024.1373004. 19. Machado A, Foschi C, Marangoni A. Editorial: Vaginal dysbiosis and biofilms. Front Cell Infect Microbiol 2022; 12:976057. doi:10.3389/fcimb.2022.976057. 20. MacSharry J, Kovács Z, Xie Y, Adamczyk B, Walsh C, Reidy F, McAuliffe FM, Kilbane MT, Twomey PJ, Rudd PM, Wingfield M, Butler M, van Sinderen D, Glover L, Saldova R. Endometriosis specific vaginal microbiota links to urine and serum N -glycome. Sci Rep 2024; 14(1):25372. doi:10.1038/ s41598-024-76125-2. 21. Meggyesy M, Friese M, Gottschalk J, Kehler U. Case Report of Cerebellar Endometriosis. J Neurol Surg A Cent Eur Neurosurg 2020; 81(4):372-376. doi:10.1055/s-0040-1701622. 22. Molina NM, Sola-Leyva A, Saez-Lara MJ, Plaza-Diaz J, Tubić- Pavlović A, Romero B, Clavero A, Mozas -Moreno J, Fontes J, Altmäe S. New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future? Biomolecules 2020; 10(4):593. doi: 10.3390/biom10040593. 23. Muraoka A, Suzuki M, Hamaguchi T, Watanabe S, Iijima K, Murofushi Y, Shinjo K, Osuka S, Hariyama Y, Ito M, Ohno K, Kiyono T, Kyo S, Iwase A, Kikkawa F, Kajiyama H, Kondo Y. 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. 24. Pai AH, Wang YW, Lu PC, Wu HM, Xu JL, Huang HY. Gut Microbiome-Estrobolome Profile in Reproductive -Age Women with Endometriosis. Int J Mol Sci 2023; 24(22):16301. doi:10.3390/ijms242216301. 25. Quaranta G, Sanguinetti M, Masucci L. Faecal Microbiota Transplantation: A Potential Tool for Treatment of Human Female Reproductive Tract Diseases. Front Immunol 2019; 10:2653. doi:10.3389/fimmu. 2019.02653. 26. Sessa R, Filardo S, Viscardi MF, Brandolino G, Muzii L, Di Pietro M, Porpora MG. Characterization of the vaginal microbiota in Italian women with endometriosis: preliminary study. Arch Gynecol Obstet 2024; 310(4):2141 -2151. doi: 10.1007/s00404-024-07631-x. 27. Su C, Wan S, Ding J, Ni G, Ding H. Blood lipids mediate the effects of gut microbiome on endometriosis: a mendelian randomisation study. Lipids Health Dis 2024; 23(1):110. doi: 10.1186/s12944-024-02096-y. 28. Tang Y, Yang J, Hang F, Huang H, Jiang L. Unravelling the relationship between gut microbiota and site -specific endometriosis: a Mendelian randomisation analysis. Front Microbiol 2024; 15:1363080. doi:10.3389/fmicb.2024.1363080. 29. Toffoli M, Campisciano G, Santin A, Pegoraro S, Zito G, Spedicati B, Balduit A, Romano F, Di Lorenzo G, Mangogna A, Tesolin P, Nardone GG, Zanotta N, Sanna S, Crobu F, Kishore U, Ricci G, Bulla R, Girotto G, Agostinis C. A possible association between low MBL/lectin pathway functionality and microbiota dysbiosis in endometriosis patients. Life Sci 2025; 364:123427. doi:10.1016/j.lfs.2025.123427. 30. Wang J, Li Z, Ma X, Du L, Jia Z, Cui X, Yu L, Yang J, Xiao L, Zhang B, Fan H, Zhao F. Translocation of vaginal microbiota is involved in impairment and protection of uterine health. Nat Commun 2021; 12(1):4191. doi:10.1038/s41467 -021-24516- 8. 31. Wang J, Li Z, Ma X, Du L, Jia Z, Cui X, Yu L, Yang J, Xiao L, Zhang B, Fan H, Zhao F. Translocation of vaginal microbiota is involved in impairment and protection of uterine health. Nat Commun 2021; 12(1):4191. doi:10.1038/s41467 -021-24516- 8. 32. Wang M, Liu W, Zheng L, Ma S, Jin L, Zhao D, Li D. Broadening horizons: microbiota as a novel biomarker and potential treatment for endometriosis. Front Microbiol 2025; 16:1521216. doi:10.3389/fmicb.2025.1521216. 33. Wei Y, Tan H, Yang R, Yang F, Liu D, Huang B, OuYang L, Lei S, Wang Z, Jiang S, Cai H, Xie X, Yao S, Liang Y. Gut dysbiosis-derived β-glucuronidase promotes the development of endometriosis. Fertil Steril 2023; 120(3 Pt 2):682 -694. doi: 10.1016/j.fertnstert.2023.03.032. 34. Wessels JM, Domínguez MA, Leyland NA, Agarwal SK, Foster WG. Endometrial microbiota is more diverse in people with endometriosis than symptomatic controls. Sci Rep 2021; 11(1):18877. doi:10.1038/s41598-021-98380-3. 35. Xu Y, Zhu Y, Wu X, Peng W, Zhong Y, Cai Y, Chen W, Liu L, Tan B, Chen T. 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.