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Publications and source records attributed to Lye, S. J..
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Malnutrition can influence maternal physiology and programme offspring development. Yet, in pregnancy, little is known about how dietary challenges that influence maternal phenotype affect gut structure and function. Emerging evidence suggests that interactions between the environment, multidrug resistance (MDR) transporters and microbes may influence maternal adaptation to pregnancy and regulate fetoplacental development. We hypothesised that the gut holobiont (host and microbes) during pregnancy adapts differently to suboptimal maternal diets, evidenced by changes in the gut microenvironment, morphology, and expression of key protective MDR transporters during pregnancy. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD)5.5-18.5, or fed 60% high fat diet (HF) for eight weeks before and during pregnancy. At GD18.5, maternal small intestinal (SI) architecture (H&E), proliferation (Ki67), P-glycoprotein (P-gp - encoded by Abcb1a/b) and breast cancer resistance protein (BCRP/Abcg2) MDR transporter expression and levels of pro-inflammatory biomarkers were assessed. Circulating inflammatory biomarkers and maternal caecal microbiome composition (G3 PhyloChipTM) were measured. MDR transporter expression was also assessed in fetal gut. HF diet increased maternal SI crypt depth and proinflammatory load, and decreased SI expression of Abcb1a mRNA, whilst UN increased SI villi proliferation and Abcb1a, but decreased Abcg2, mRNA expression. There were significant associations between Abcb1a and Abcg2 mRNA levels with relative abundance of specific microbial taxa. Using a systems physiology approach we report that common nutritional adversities provoke adaptations in the pregnancy holobiont in mice, and reveal new mechanisms that could influence reproductive outcomes and fetal development.
A critical component of early human placental development includes migration of extravillous trophoblasts (EVTs) into the decidua. EVTs migrate toward, and displace vascular smooth muscle cells (SMCs) surrounding several uterine structures, including spiral arteries. Shallow trophoblast invasion features in several pregnancy complications including preeclampsia. Maternal obesity is a risk factor for placental dysfunction, suggesting that factors within an obese environment may impair early placental development. Herein, we tested the hypothesis that palmitic acid, a saturated fatty acid circulating at high levels in obese women, induces an inflammatory response in EVTs that hinders their capacity to migrate toward SMCs. We found that SMCs and SMC-conditioned media stimulated migration and invasion of an EVT-like cell line, HTR8/SVneo. Palmitic acid impaired EVT migration and invasion toward SMCs, and induced expression of several vasoactive and inflammatory mediators in EVTs, including endothelin, interleukin (IL)-6, IL8, and PAI1. PAI1 was increased in plasma of women with early-onset preeclampsia, and PAI1-deficient EVTs were protected from the anti-migratory effects of palmitic acid. Using first trimester placental explants, palmitic acid exposure decreased EVT invasion through Matrigel. Our findings reveal that palmitic acid induces an inflammatory response in EVTs and attenuates their migration through a mechanism involving PAI1. High levels of palmitic acid in pathophysiological situations like obesity may impair early placental development and predispose to placental dysfunction.
The placenta promotes fetal growth through nutrient transfer and selective barrier systems. An optimally developed placenta can adapt to changes in the pregnancy environment, buffering the fetus from adverse exposures. We hypothesised that the placenta adapts differently to suboptimal maternal diets, evidenced by changes in placental morphology, developmental markers, and key transport systems. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD)5.5-18.5, or fed 60% high fat diet (HF) eight weeks before and during pregnancy. At GD18.5, placental morphometry, development, and transport were assessed. Junctional and labyrinthine areas of UN and HF placentae were smaller than CON by >10%. Fetal blood space area and fetal blood space:fetal weight ratios were reduced in HF vs. CON and UN. Trophoblast giant cell marker Ctsq mRNA expression was lower in UN vs. HF, and expression of glycogen cell markers Cx31.1 and Pcdh12 was lower in HF vs. UN. Efflux transporter Abcb1a mRNA expression was lower in HF vs. UN, and Abcg2 expression was lower in UN vs. HF. mRNA expression of fatty acid binding protein Fabppm was higher in UN vs. CON and HF. mRNA and protein levels of the lipid transporter FAT/CD36 were lower in UN, and FATP4 protein levels were lower in HF vs. UN. UN placentae appear less mature with aberrant transport. HF placentae adapt to excessive nutrient supply. Understanding placental adaptations to common nutritional adversities may reveal mechanisms underlying the developmental origins of later disease.