A gut microbiome‐lipid axis in early pregnancy is associated with metabolic dysregulation and diabetes risk

Abstract Gestational diabetes mellitus (GDM) reflects metabolic dysregulation that becomes clinically apparent during pregnancy and shares key pathophysiological features with broader forms of diabetes. Gut microbiome‐host metabolic interactions may contribute to this process, yet their role in early pregnancy remains incompletely understood. In this prospective nested case‐control study within the Tongji‐Huaxi‐Shuangliu Birth Cohort, 784 pregnant women, including 222 who developed GDM, underwent first‐trimester gut metagenomic and plasma lipidomic profiling. Cross‐omics analyses were performed to identify microbiome‐lipid 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 Ruminococcus bicirculans ( R. bicirculans ), 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‐related metabolites. Integrated analyses suggested that lipidomic variation statistically accounted for part of the microbiome‐GDM association. A class‐level dihexosylceramide feature, DHC 24:1, consistent with lactosylceramide‐related metabolites, emerged as a potential mediator and was prioritized for exploratory follow‐up. Experimental analyses provided functional support for a microbiome‐lipid‐host interaction axis. R. bicirculans promoted lactosylceramide 24:1 production in vitro , bacterial colonization and metabolite administration improved insulin tolerance in vivo , and lactosylceramide 24:1 modulated insulin‐stimulated AKT signaling dynamics in hepatocytes. These findings identify a gut microbiome‐lipid axis associated with metabolic dysregulation in pregnancy and suggest a potential mechanism linking microbial metabolism to host insulin signaling.