Project Summary: Maternal obesity with increased circulating inflammatory markers can lead to adverse pregnancy outcomes, such as preeclampsia (PE). Clinical signs of PE include maternal hypertension and proteinuria during the second half of gestation. Importantly, maternal hypertension only resolves after delivery of the placenta and the fetus, which is often preterm. The etiology of this is unknown. It is our hypothesis that the maternal gut microbiome as a result of hyperphagia contributes to heightened inflammation and subsequent abnormal fetoplacental development. The overarching goal of these proposed studies is to test the hypothesis that maternal hyperphagia-induced obesity and gut dysbiosis in PE leads to altered short chain fatty acids (SCFA) signaling through embryonic free fatty acid receptor, GPR43. This in turn contributes to aberrant in utero fetal programming and cardiometabolic disease. We will test our hypothesis in the BPH/5 mouse model of superimposed PE combining novel in vivo and ex vivo experiments. In Aim 1, we will determine if the maternal gut microbiome milieu contributes to pro- inflammatory and/or anti-inflammatory SCFA signaling at the maternal-fetal interface during pregnancy. Also, if oral supplementation with Lactobacillus (LB) improves PE outcomes in mice with spontaneous PE. NFΚB factors will be measured in BPH/5+LB and BPH/5 mice depleted of LB. In Aim 2, we will embryo transfer to ascertain the maternal versus embryonic contribution to SCFA signaling. BPH/5+LB and -LB, and Gpr43-/- embryos will be transferred to high and low acetate dams. In Aim 3, offspring outcomes will be assessed to determine whether reversal of maternal obesity via pair-feeding and/or LB+ prevents aberrant fetal cardiac angiogenesis and adult onset cardiometabolic dysfunction. These experiments will combine the gold standard radiotelemetric blood pressure recording with metabolic cages to measure cardiometabolic fitness in offspring when maternal gut dysbiosis is reversed and PE signs are attenuated. These findings will provide groundbreaking prenatal mechanisms to prevent adult-onset cardiometabolic disease, hypertension, in PE born offspring.