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Gut microbiome\u2010host metabolic interactions may contribute to this process, yet their role in early pregnancy remains incompletely understood. In this prospective nested case\u2010control study within the Tongji\u2010Huaxi\u2010Shuangliu Birth Cohort, 784 pregnant women, including 222 who developed GDM, underwent first\u2010trimester gut metagenomic and plasma lipidomic profiling. Cross\u2010omics analyses were performed to identify microbiome\u2010lipid associations and potential mediation patterns. Women who later developed GDM showed reduced gut microbial diversity and altered microbial profiles in early pregnancy. We identified 26 microbial species associated with GDM risk, with seven species, including\n                    <jats:italic>Ruminococcus bicirculans<\/jats:italic>\n                    (\n                    <jats:italic>R. bicirculans<\/jats:italic>\n                    ), showing concordant associations in external type 2 diabetes populations. Microbial pathways related to fatty acid and lipid biosynthesis were enriched in women at higher risk. Plasma lipidomics revealed widespread alterations, particularly among glycosphingolipid\u2010related metabolites. Integrated analyses suggested that lipidomic variation statistically accounted for part of the microbiome\u2010GDM association. A class\u2010level dihexosylceramide feature, DHC 24:1, consistent with lactosylceramide\u2010related metabolites, emerged as a potential mediator and was prioritized for exploratory follow\u2010up. Experimental analyses provided functional support for a microbiome\u2010lipid\u2010host interaction axis.\n                    <jats:italic>R. bicirculans<\/jats:italic>\n                    promoted lactosylceramide 24:1 production\n                    <jats:italic>in vitro<\/jats:italic>\n                    , bacterial colonization and metabolite administration improved insulin tolerance\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and lactosylceramide 24:1 modulated insulin\u2010stimulated AKT signaling dynamics in hepatocytes. These findings identify a gut microbiome\u2010lipid axis associated with metabolic dysregulation in pregnancy and suggest a potential mechanism linking microbial metabolism to host insulin signaling.\n                  <\/jats:p>","DOI":"10.1002\/imt2.70166","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:14:30Z","timestamp":1786371270000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A gut microbiome\u2010lipid axis in early pregnancy is associated with metabolic dysregulation and diabetes risk"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4171-9794","authenticated-orcid":false,"given":"Zhonghan","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences Shanghai Institute of Infectious Disease and Biosecurity, Zhongshan Hospital Shanghai 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