Cuiping Feng

Improving amino acid nutrition to prevent intrauterine growth restriction in mammals

Intrauterine growth restriction (IUGR) is one of the most common concerns in human obstetrics and domestic animal production. It is usually caused by placental insufficiency, which decreases fetal uptake of nutrients (especially amino acids) from the placenta. Amino acids are not only building blocks for protein but also key regulators of metabolic pathways in fetoplacental development. The enhanced demands of amino acids by the developing conceptus must be met via active transport systems across the placenta as normal pregnancy advances. Growing evidence indicates that IUGR is associated with a reduction in placental amino acid transport capacity and metabolic pathways within the embryonic/fetal development. The positive relationships between amino acid concentrations in circulating maternal blood and placental amino acid transport into fetus encourage designing new therapies to prevent or treat IUGR by enhancing amino acid availability in maternal diets or maternal circulation. Despite the positive effects of available dietary interventions, nutritional therapy for IUGR is still in its infancy. Based on understanding of the underlying mechanisms whereby amino acids promote fetal growth and of their dietary requirements by IUGR, supplementation with functional amino acids (e.g., arginine and glutamine) hold great promise for preventing fetal growth restriction and improving health and growth of IUGR offspring.

Temporal proteomic analysis reveals defects in small-intestinal development of porcine fetuses with intrauterine growth restriction

The fetus/neonate with intrauterine growth restriction (IUGR) has a high perinatal mortality and morbidity rate, as well as reduced efficiency for nutrients utilization. Our previous studies showed alterations of intestinal proteome in IUGR piglets both at birth and during the nursing period. Considering the potential long-term impacts of fetal programming and substantial increases in amounts of amniotic fluid nutrients from mid-gestation in pigs, the present study involved IUGR porcine fetuses from days 60 to 110 of gestation (mid to late gestation). We identified 59 differentially expressed proteins in the fetal small intestine that are related to intestinal growth, development and reprogramming. Our results further indicated increased abundances of proteins and enzymes associated with oxidative stress, apoptosis and protein degradation, as well as decreased abundances of proteins that are required for maintenance of cell structure and motility, absorption and transport of nutrients, energy metabolism, and protein synthesis in the fetal gut. Moreover, IUGR from middle to late gestation was associated with reduced expression of intestinal proteins that participate in regulation of gene expression and signal transduction. Collectively, these findings provide the first evidence for altered proteomes in the small intestine of IUGR fetuses, thereby predisposing the gut to metabolic defects during gestation and neonatal periods.

IUGR alters muscle fiber development and proteome in fetal pigs.

Intrauterine growth restriction (IUGR) may have permanent stunting effects on muscle growth and development of the progeny. However, underlying mechanisms are largely unknown. Recent studies comparing muscle fiber development and proteomes in IUGR and normal-body-weight (NBW) fetal pigs indicated that muscle fiber diameter were smaller in IUGR fetal pigs than in NBW fetal pigs on all three stages (d 60, d 90 and d 110) of gestation. Although the number of primary fibers did not differ between these two fetal groups on d 60 of gestation, the total number of muscle fibers in IUGR fetal pigs was lower on d 90 and 110 of gestation, when compared with NBW fetal pigs. Further proteomic analysis has shown that 37 proteins involved in energy supply and protein metabolism, structure and type of muscle fibers, proliferation and differentiation of muscle fibers, nutrient transport, intracellular environment, and tissue integrity were differentially expressed between IUGR and NBW fetal pigs. These novel findings provide some implications on the mechanisms of reduced growth and impaired development of skeletal muscle in IUGR piglets.

Proteome Differences in Placenta and Endometrium between Normal and Intrauterine Growth Restricted Pig Fetuses.

Uteroplacental tissue plays a key role in substance exchanges between maternal and fetal circulation, and, therefore, in the growth and development of fetuses. In this study, proteomics and western blotting were applied to investigate the changes of proteome in the placenta and endometrium of normal and intrauterine growth restriction (IUGR) porcine fetuses during mid to late pregnancy (D60, 90, and 110 of gestation). Our results showed that proteins participating in cell structure, energy metabolism, stress response, cell turnover, as well as transport and metabolism of nutrients were differentially expressed in placenta and endometrium between normal and IUGR fetuses. Analysis of functions of these proteins suggests reductions in ATP production and nutrients transport, increases in oxidative stress and apoptosis, and impairment of cell metabolism in IUGR fetuses. Collectively, our findings aid in understanding of the mechanisms responsible for uteroplacental dysfunction in IUGR fetus, and are expected to provide new strategies to reduce fetal growth restriction in pigs and other mammals.

Physiological alterations associated with intrauterine growth restriction in fetal pigs: Causes and insights for nutritional optimization

Intrauterine growth restriction (IUGR) remains a major problem in swine production since the associated low birth weight leads to high rates of pre‐weaning morbidity and mortality plus permanent retardation of growth and development. Complex biological events—including genetics, epigenetics, maternal maturity, maternal nutrition, placenta efficiency, uterine capacity, and other environmental factors—can affect fetal growth and development during late gestation, as well as maturity of oocytes, duration of estrus, and both implantation and placentation of conceptuses in uteri of sows. Understanding the physiological changes related to initiation and progress of IUGR are, therefore, of great importance to formulate nutritional strategies that can mitigate IUGR in gilts and sows. Altering the nutritional status of sows prior to mating and during early‐, mid‐, and late‐gestation may be effective at increasing the uniformity of oocytes and conceptuses, decreasing variation among conceptuses during elongation and implantation, and preventing increases in within‐litter variation in fetal weights during late gestation. This review summarizes current progress on physiological alterations responsible for IUGR fetuses, as well as possible nutritional interventions to prevent the initiation and continuation of IUGR in gilts and sows.

Maternal l-glutamine supplementation during late gestation alleviates intrauterine growth restriction-induced intestinal dysfunction in piglets

Maternal dietary supplementation with l-glutamine (Gln) has been considered as an option to improve fetal growth and to prevent the occurrence of intrauterine growth restriction (IUGR). This study investigated whether maternal Gln supplementation could improve fetal growth as well as the intestinal development during late pregnancy. Sixty pregnant Landrace × Large White multiparous sows were assigned to two groups, either the group fed the control diet or the group with the diet supplemented with 1% Gln from d 85 of gestation until farrowing. One normal body weight piglet and one IUGR piglet were obtained from six litters in each group. Reproductive performance, plasma concentrations of free amino acids and related metabolites as well as piglet growth and tissue indexes were determined. Maternal Gln supplementation during late gestation increased the average birth weight, while decreasing the within-litter variation of newborn piglets. The concentrations of Gln in plasma were lower in IUGR piglets than in normal piglets. Glutamine supplementation enhanced Gln concentrations in maternal and piglet plasma and the piglet jejunum, compared with the Control group. Supplementing Gln suppressed intestinal miR-29a levels, and increased the abundance of extracellular matrix (ECM) and tight junction (TJ) proteins, resulting in increased intestinal weight and improved morphologies of the piglets. Collectively, Gln supplementation to the sow’s diet increased fetal growth, decreased the within-litter variation of newborn piglets, and alleviated the IUGR-induced intestinal impairment. These findings suggest the possibility of maternal glutamine supplementation in the prevention and treatment of IUGR in animal production and human medicine.

Developmental changes in polyamines and autophagic marker levels in normal and growth-restricted fetal pigs.

Polyamines are essential for embryonic and fetal survival, growth, and development. Additionally, polyamines may induce autophagy in mammalian cells. However, little is known about the availability of polyamines or autophagy in the porcine conceptus with intrauterine growth restriction (IUGR). The present study was performed to evaluate the developmental changes of polyamine concentrations in IUGR and normal porcine fetuses as well as autophagic marker levels in the fetal intestinal mucosa during the second half of gestation when most fetal growth occurs. Allantoic fluid (ALF), amniotic fluid (AMF), umbilical vein, and the small-intestinal mucosa were obtained from both IUGR and normal fetal pigs at d 60, 90, and 110 of gestation. Concentrations of polyamines in fetal fluids as well as protein abundances of microtubule-associated protein light chain 3B (LC3B), an autophagic marker, in the fetal small-intestinal mucosa were determined. Concentrations of polyamines varied greatly in different fetal compartments and changed substantially with advancing gestation. Concentrations of polyamines in IUGR fetal fluids and the small-intestinal mucosa were markedly different from those in their normal counterparts at d 60 and 90 of gestation, whereas most of the differences were not detected by late (d 110) gestation. Specifically, polyamine levels were lower in the umbilical vein plasma but higher in ALF and AMF from IUGR fetuses. Furthermore, enhanced levels of an autophagic marker were observed in the small-intestinal mucosa of IUGR fetuses throughout mid and late gestation in association with abnormal spermidine levels in fetal plasma. These findings support the notion that enhanced autophagy may be an important survival mechanism in IUGR fetuses. Collectively, our findings provide a new framework for future studies to define the roles for polyamines in the prevention and treatment of IUGR in both human medicine and animal production.