{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:34:16Z","timestamp":1790091256012,"version":"4.0.1"},"reference-count":122,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Pregnancy loss is a common and multifactorial complication of human reproduction, traditionally attributed to fetal chromosomal abnormalities, maternal anatomical and endocrine disorders, and immune dysfunction. Growing evidence now indicates that the maternal microbiome, particularly within the reproductive tract, plays a critical role in implantation, placental development, and the maintenance of immune tolerance during early pregnancy. Importantly, the influence of the microbiome on miscarriage appears to be strongly modulated by host genetic background and immune regulation. Methods: This narrative review summarizes current evidence linking alterations in the vaginal, endometrial, placental, and gut microbiomes to miscarriage, with a specific focus on host genetics and immune\u2013microbial interactions. Results: We discuss how genetic variation in innate and adaptive immune pathways, inflammatory signaling, and mucosal barrier function may shape host responses to microbial communities, thereby influencing susceptibility to PL. In addition, we highlight emerging data on microbiome-driven regulation of gene expression and epigenetic modifications in the endometrium and decidua, emphasizing the role of microbial metabolites in immune tolerance and placental function. Conclusions: By integrating findings from microbiome research, host genomics, immunology, and epigenetics, this review proposes a framework in which miscarriage is viewed as a consequence of disrupted host\u2013microbe crosstalk rather than isolated pathology. Finally, we address key methodological challenges and outline future research directions aimed at advancing mechanistic understanding and translational applications.<\/jats:p>","DOI":"10.3390\/genes17030259","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T10:33:02Z","timestamp":1772101982000},"page":"259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Miscarriage and the Microbiome: Host Genetics, Immunity, and the Reproductive Tract Ecosystem"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3036-7212","authenticated-orcid":false,"given":"Nektaria","family":"Zagorianakou","sequence":"first","affiliation":[{"name":"Department of Nursing, School of Health Sciences, University of Ioannina, Scientific Laboratory for Innovative Technologies in Internal Medicine, Preventive Medicine and Overall Care, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9981-7488","authenticated-orcid":false,"given":"Stylianos","family":"Makrydimas","sequence":"additional","affiliation":[{"name":"Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3333-2620","authenticated-orcid":false,"given":"Efthalia","family":"Moustakli","sequence":"additional","affiliation":[{"name":"Department of Nursing, School of Health Sciences, University of Ioannina, 4th Kilometer National Highway Str. Ioannina-Athens, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3904-7175","authenticated-orcid":false,"given":"Ioannis","family":"Mitrogiannis","sequence":"additional","affiliation":[{"name":"Harris Birthright Research Centre for Fetal Medicine, King\u2019s College London, 16\u201320 Windsor Walk, London SE5 8BB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Makrydimas","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, University Hospital of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/S0140-6736(21)00682-6","article-title":"Miscarriage matters: The epidemiological, physical, psychological, and economic costs of early pregnancy loss","volume":"397","author":"Quenby","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1515\/mr-2022-0030","article-title":"Understanding recurrent pregnancy loss: Recent advances on its etiology, clinical diagnosis, and management","volume":"2","author":"Cao","year":"2023","journal-title":"Med. 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