{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:45:19Z","timestamp":1792799119445,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background\/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women\u2019s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including \u03b2-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. \u03b2-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1\u03b2 and HIF-1\u03b1) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. \u03b2-glucuronidase activity and the expression of ER\u03b2 were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to \u03b2-glucuronidase activity and to ER\u03b2 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.<\/jats:p>","DOI":"10.3390\/biom14101325","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T03:57:09Z","timestamp":1729483029000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Endometrial Dysbiosis: A Possible Association with Estrobolome Alteration"],"prefix":"10.3390","volume":"14","author":[{"given":"Giorgia","family":"Scarf\u00f2","sequence":"first","affiliation":[{"name":"Division of General Medicine, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-3087","authenticated-orcid":false,"given":"Simona","family":"Daniele","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Chelucci","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Papini","sequence":"additional","affiliation":[{"name":"Division of Gynecology and Obstetrics, Azienda Ospedaliero Universitaria Pisana and Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Epifani","sequence":"additional","affiliation":[{"name":"Department of Juridical and Economic Sciences, Pegaso Telematic University, 80143 Napoli, Italy"},{"name":"Fanfani, Diagnostics and Health, 50129 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"San Rossore Clinic Care, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Cela","sequence":"additional","affiliation":[{"name":"Division of Gynecology and Obstetrics, Azienda Ospedaliero Universitaria Pisana and Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"},{"name":"San Rossore Clinic Care, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2132-8788","authenticated-orcid":false,"given":"Ferdinando","family":"Franzoni","sequence":"additional","affiliation":[{"name":"Division of General Medicine, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7164-0553","authenticated-orcid":false,"given":"Paolo Giovanni","family":"Artini","sequence":"additional","affiliation":[{"name":"Division of Gynecology and Obstetrics, Azienda Ospedaliero Universitaria Pisana and Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"},{"name":"San Rossore Clinic Care, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.maturitas.2017.06.025","article-title":"Estrogen\u2013Gut Microbiome Axis: Physiological and Clinical Implications","volume":"103","author":"Baker","year":"2017","journal-title":"Maturitas"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41588-022-01254-1","article-title":"Single-Cell Transcriptomic Analysis of Endometriosis","volume":"55","author":"Fonseca","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"68.e1","DOI":"10.1016\/j.ajog.2016.02.036","article-title":"The Gut Microbiota: A Puppet Master in the Pathogenesis of Endometriosis?","volume":"215","author":"Laschke","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/1471-0528.15916","article-title":"Endometriosis and the Microbiome: A Systematic Review","volume":"127","author":"Leonardi","year":"2020","journal-title":"BJOG"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1093\/humupd\/dmab035","article-title":"The Role of Gut and Genital Microbiota and the Estrobolome in Endometriosis, Infertility and Chronic Pelvic Pain","volume":"28","author":"Salliss","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"620241","DOI":"10.3389\/fgene.2021.620241","article-title":"Integrated Transcriptomic and Epigenetic Study of PCOS: Impact of Map3k1 and Map1lc3a Promoter Methylation on Autophagy","volume":"12","author":"Qin","year":"2021","journal-title":"Front. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/nrc3610","article-title":"The Microbiome and Cancer","volume":"13","author":"Schwabe","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","first-page":"djw029","article-title":"The Intestinal Microbiome and Estrogen Receptor\u2013Positive Female Breast Cancer","volume":"108","author":"Kwa","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/j.1574-6941.2008.00520.x","article-title":"Distribution of \u03b2-Glucosidase and \u03b2-Glucuronidase Activity and of \u00ce2-Glucuronidase Gene Gus in Human Colonic Bacteria: \u03b2-Glycosidase Activity in Human Gut Bacteria","volume":"66","author":"Dabek","year":"2008","journal-title":"FEMS Microbiol. Ecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.chom.2011.10.003","article-title":"Microbiome and Malignancy","volume":"10","author":"Plottel","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1099\/mic.0.27712-0","article-title":"Genetic Characterization of the \u03b2-Glucuronidase Enzyme from a Human Intestinal Bacterium, Ruminococcus gnavus","volume":"151","author":"Beaud","year":"2005","journal-title":"Microbiology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1093\/humrep\/dex372","article-title":"Endometriosis Induces Gut Microbiota Alterations in Mice","volume":"33","author":"Yuan","year":"2018","journal-title":"Hum. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0226835","DOI":"10.1371\/journal.pone.0226835","article-title":"Effect of Endometriosis on the Fecal Bacteriota Composition of Mice during the Acute Phase of Lesion Formation","volume":"14","author":"Hantschel","year":"2019","journal-title":"PLoS ONE"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Prakash, A., Nourianpour, M., Senok, A., and Atiomo, W. (2022). Polycystic Ovary Syndrome and Endometrial Cancer: A Scoping Review of the Literature on Gut Microbiota. Cells, 11.","DOI":"10.3390\/cells11193038"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e13307","DOI":"10.1111\/aji.13307","article-title":"Correlation of Fecal Metabolomics and Gut Microbiota in Mice with Endometriosis","volume":"84","author":"Ni","year":"2020","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1093\/humrep\/dez041","article-title":"Antibiotic Therapy with Metronidazole Reduces Endometriosis Disease Progression in Mice: A Potential Role for Gut Microbiota","volume":"34","author":"Chadchan","year":"2019","journal-title":"Hum. Reprod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1038\/s41598-019-39700-6","article-title":"The Endobiota Study: Comparison of Vaginal, Cervical and Gut Microbiota between Women with Stage 3\/4 Endometriosis and Healthy Controls","volume":"9","author":"Ata","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1007\/s43032-019-00113-5","article-title":"The Vaginal Microbiome as a Tool to Predict rASRM Stage of Disease in Endometriosis: A Pilot Study","volume":"27","author":"Perrotta","year":"2020","journal-title":"Reprod. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cela, V., Daniele, S., Obino, M.E.R., Ruggiero, M., Zappelli, E., Ceccarelli, L., Papini, F., Marzi, I., Scarf\u00f2, G., and Tosi, F. (2022). Endometrial Dysbiosis Is Related to Inflammatory Factors in Women with Repeated Implantation Failure: A Pilot Study. J. Clin. Med., 11.","DOI":"10.3390\/jcm11092481"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cela, V., Malacarne, E., Obino, M.E.R., Marzi, I., Papini, F., Vergine, F., Pisacreta, E., Zappelli, E., Pietrobono, D., and Scarf\u00f2, G. (2021). Exploring Epithelial\u2013Mesenchymal Transition Signals in Endometriosis Diagnosis and In Vitro Fertilization Outcomes. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111681"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sobstyl, M., Brecht, P., Sobstyl, A., Mertowska, P., and Grywalska, E. (2022). The Role of Microbiota in the Immunopathogenesis of Endometrial Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105756"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1261781","DOI":"10.3389\/fendo.2023.1261781","article-title":"Estrobolome Dysregulation Is Associated with Altered Immunometabolism in a Mouse Model of Endometriosis","volume":"14","author":"Alghetaa","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gao, X., Louwers, Y.V., Laven, J.S.E., and Schoenmakers, S. (2024). Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010622"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/j.fertnstert.2021.09.014","article-title":"A Review of the Pathophysiology of Recurrent Implantation Failure","volume":"116","author":"Franasiak","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103782","DOI":"10.1016\/j.jri.2022.103782","article-title":"The Endometrial Microbiota Profile Influenced Pregnancy Outcomes in Patients with Repeated Implantation Failure: A Retrospective Study","volume":"155","author":"Zou","year":"2023","journal-title":"J. Reprod. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1093\/humrep\/deu292","article-title":"Prevalence of Chronic Endometritis in Repeated Unexplained Implantation Failure and the IVF Success Rate after Antibiotic Therapy","volume":"30","author":"Cicinelli","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Toson, B., Simon, C., and Moreno, I. (2022). The Endometrial Microbiome and Its Impact on Human Conception. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010485"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.3389\/fimmu.2019.02823","article-title":"Immunological Role of the Maternal Uterine Microbiome in Pregnancy: Pregnancies Pathologies and Alterated Microbiota","volume":"10","author":"Bardos","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/humupd\/dmy012","article-title":"How Uterine Microbiota Might Be Responsible for a Receptive, Fertile Endometrium","volume":"24","author":"Benner","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3389\/fimmu.2020.00378","article-title":"The Interplay between Reproductive Tract Microbiota and Immunological System in Human Reproduction","volume":"11","author":"Ambrosino","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41420-024-02048-6","article-title":"Interleukin-1\u03b2 Induces and Accelerates Human Endometrial Stromal Cell Senescence and Impairs Decidualization via the c-Jun N-Terminal Kinase Pathway","volume":"10","author":"Taylor","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1111\/jog.15752","article-title":"HIF-1\u03b1 Is Positively Associated with Endometrial Receptivity by Regulating PKM2","volume":"49","author":"Liang","year":"2023","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1262\/jrd.10-152H","article-title":"Live Offspring from Cryopreserved Embryos Following In Vitro Growth, Maturation and Fertilization of Oocytes Derived from Preantral Follicles in Mice","volume":"57","author":"Motohashi","year":"2011","journal-title":"J. Reprod. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jsbmb.2018.04.008","article-title":"Polycystic Ovary Syndrome (PCOS), an Inflammatory, Systemic, Lifestyle Endocrinopathy","volume":"182","author":"Patel","year":"2018","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2236749","DOI":"10.1080\/19490976.2023.2236749","article-title":"Gut Microbial Beta-Glucuronidase: A Vital Regulator in Female Estrogen Metabolism","volume":"15","author":"Hu","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/nm.2855","article-title":"Cutting SRC-1 down to Size in Endometriosis","volume":"18","author":"Dyson","year":"2012","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"103513","DOI":"10.1016\/j.jri.2022.103513","article-title":"Estrogen Receptor Beta Promotes Endometriosis Progression by Upregulating CD47 Expression in Ectopic Endometrial Stromal Cells","volume":"151","author":"Hu","year":"2022","journal-title":"J. Reprod. Immunol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/10\/1325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:16:17Z","timestamp":1760112977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/10\/1325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["biom14101325"],"URL":"https:\/\/doi.org\/10.3390\/biom14101325","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,18]]}}}