The Placenta–Gut Microbiota Axis in Gestational Diabetes Mellitus: Molecular Mechanisms, Crosstalk, and Therapeutic Perspectives

Gestational diabetes mellitus (GDM) is a multifactorial metabolic disorder arising from impaired insulin sensitivity and altered maternal-fetal energy regulation. Beyond classical mechanisms involving β-cell dysfunction and pregnancy-induced insulin resistance, emerging evidence suggests a bidirectional interaction between the maternal gut microbiota and the placenta, forming a dynamic placenta-gut axis. Microbial dysbiosis alters levels of metabolites, inflammatory mediators, and bile acids, which influence placental signaling, trophoblast metabolism, immune activation, and nutrient transport. Conversely, the placenta secretes hormones, cytokines, lipids, and exosomal miRNAs that shape maternal metabolism and potentially modulate the gut microbiota. This review synthesizes current mechanistic insights underlying the placenta-gut microbiota axis in GDM, describes immune and metabolic crosstalk, and highlights therapeutic opportunities targeting this inter-organ communication system. Addressing these interactions may advance precision strategies for managing GDM and improving outcomes across generations.