{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:02:57Z","timestamp":1792526577967,"version":"4.5.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Recurrent pregnancy loss (RPL), particularly its unexplained form (URPL), represents a formidable challenge in reproductive medicine. Although traditionally attributed to local immune imbalances at the maternal-fetal interface, this perspective may not fully account for the condition\u2019s upstream etiological drivers and recurrent nature. This review transcends this limitation by proposing and systematically substantiating an integrative \u2018gut-systemic-decidual\u2019 model of immunometabolic dysregulation. We posit that a key pathological cascade in many URPL cases may originate with distal gut dysbiosis, which, through imbalanced metabolite profiles and the leakage of inflammatory molecules such as lipopolysaccharide (LPS), triggers systemic \u2018metabolic endotoxemia\u2019 and fundamentally reprograms the metabolic state of circulating immune cells. This systemic \u2018first hit\u2019 is compounded when these \u2018pre-sensitized\u2019 cells migrate to an equally metabolically stressed and \u2018hostile\u2019 decidual microenvironment\u2014a \u2018second hit\u2019 characterized by hypoxia and high lactate. This culminates in the functional collapse of the core sentinels of maternal-fetal tolerance, namely regulatory T (Treg) and decidual natural killer (dNK) cells, due to profound metabolic misprogramming. Ultimately, this integrated model elevates the etiological understanding of URPL from a \u2018local conflict\u2019 to that of a \u2018systemic disease,\u2019 paving the way for the development of dynamic warning systems that integrate multi-omics data and for the design of multi-level precision intervention strategies targeting patient stratification and preventive approaches for the gut, systemic metabolism, and the local microenvironment.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1746620","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:36:25Z","timestamp":1768973785000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["From gut dysbiosis to decidual hostility: the immuno-metabolic crosstalk driving recurrent pregnancy loss"],"prefix":"10.3389","volume":"16","author":[{"given":"Yimin","family":"Shi","sequence":"first","affiliation":[{"name":"Traditional Chinese Medicine Department, Shandong Provincial Maternal and Child Health Care Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufeng","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Shandong Provincial Key Traditional Chinese Medical Discipline of Clinical Chinese Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1362784","article-title":"Maternal gut microbiota in the health of mothers and offspring: from the perspective of immunology","volume":"15","author":"Lu","year":"2024","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1037","article-title":"Regulatory T cells 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