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Short-chain fatty acids (SCFAs), which are produced by gut microbiota from dietary fiber, have become candidates for gestational diabetes mellitus (GDM) treatment. However, the associations of circulating SCFAs with maternal-neonatal clinical parameters in GDM and further influences on placental immune-metabolic responses are unclear. Acetate, propionate, and butyrate were decreased in GDM during the second and third trimesters, especially in those with abnormal glucose tolerance at three "oral glucose tolerance test" time points. Butyrate was closely associated with acetate and propionate in correlation and dynamic trajectory analysis. Moreover, butyrate was negatively correlated with white blood cell counts, neutrophil counts, prepregnancy BMI, gestational weight gain per week before GDM diagnosis, and ponderal index but positively correlated with total cholesterol and low-density lipoprotein levels in all pregnancies. On the premise of reduced SCFA contents in GDM, the placental G-protein-coupled receptors 41 and 43 (GPR41/43) were decreased, and histone deacetylases (HDACs) were increased, accompanied by enhanced inflammatory responses. The metabolic status was disturbed, as evidenced by activated glycolysis in GDM. Maternal circulating acetate, propionate, and butyrate levels were associated with demographic factors in normal and GDM women. They influenced placental function and fetal development at birth through GPRs or HDACs, providing more evidence of their therapeutic capacity for GDM pregnancies.

Composition of Maternal Circulating Short-Chain Fatty Acids in Gestational Diabetes Mellitus and Their Associations with Placental Metabolism