Effects of maternal methyl donor intake during pregnancy on ileum methylation and function in an intrauterine growth restriction pig model

Background Intrauterine growth retardation(IUGR)affects intestinal growth,morphology,and function,which leads to poor growth performance and high mortality.The present study explored whether maternal dietary methyl donor(MET)supplementation alleviates IUGR and enhances offspring’s growth performance by improving intestinal growth,function,and DNA methylation of the ileum in a porcine IUGR model.Methods Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery.After farrowing,8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum.Results The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets.Moreover,maternal MET supplementation significantly reduced the plasma concentrations of isoleucine,cysteine,urea,and total amino acids in sows and newborn pig-lets.It also increased lactase and sucrase activity in the jejunum of newborn piglets.MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets.DNA methylation analysis of the ileum showed that MET supplementation increased the methyla-tion level of DNA CpG sites in the ileum of newborn piglets.Down-regulated differentially methylated genes were enriched in folic acid binding,insulin receptor signaling pathway,and endothelial cell proliferation.In contrast,up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosyn-thetic process.Conclusions Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets,which may be associated with better intestinal function and methylation status.

Antenatal taurine reduces cerebral cell apoptosis in fetal rats with intrauterine growth restriction

From pregnancy to parturition, Sprague-Dawley rats were daily administered a low protein diet to establish a model of intrauterine growth restriction. From the 12th day of pregnancy, 300 mg/kg taurine was daily added to food until spontaneous delivery occurred. Brain tissues from normal neonatal rats at 6 hours after delivery, neonatal rats with intrauterine growth restriction, and neo- natal rats with intrauterine growth restriction undergoing taurine supplement were obtained for fur- ther experiments. The terminal deoxyribonucleotidyl transferase （TdT）-mediated biotin-16-dUTP nick-end labeling assay revealed that the number of apoptotic cells in the brain tissue of neonatal rats with intrauterine growth restriction significantly increased. Taurine supplement in pregnant rats reduced cell apoptosis in brain tissue from neonatal rats with intrauterine growth restriction. Immu- nohistochemical staining revealed that taurine supplement increased glial cell line-derived neuro- trophic factor expression and decreased caspase-3 expression in the cerebral cortex of intrauterine growth-restricted fetal rats. These results indicate that taurine supplement reduces cell apoptosis through the glial cell line-derived neurotrophic factor-caspase-3 signaling pathway, resulting in a protective effect on the intrauterine growth-restricted fetal rat brain.

Intrauterine growth restriction alters growth performance, plasma hormones,and small intestinal microbial communities in growing-finishing pigs

Background: The interaction of the gut microbiota with key metabolic and physiological processes may be associated with poor growth outcomes in animals born with intrauterine growth restriction(IUGR).Results: Growth performance, plasma hormone concentrations, and intestinal microbiota composition were analyzed in IUGR pigs and in normal birth weight(NBW) pigs when the NBW pigs reached 25, 50, and 100 kg of body weight(BW). Compared to NBW pigs, IUGR pigs had lower initial, weaned, and final BW, and lower average daily gain and average daily feed intake in all the considered time points. In the 25 kg BW group, IUGR pigs had higher concentrations of plasma ghrelin and pancreatic polypeptide(PP), but lower insulin concentration than NBW pigs, while the situation was reversed in the 50 kg BW group. As compared to NBW pigs, IUGR pigs had higher microbial alpha diversity in the jejunum and ileum;in the 50 and 100 kg BW groups, IUGR pigs had higher Firmicutes abundance but lower Proteobacteria abundance in the jejunum, and lower Lactobacillus abundance in the jejunum and ileum;in the 25 kg BW group, IUGR pigs showed higher unclassified Ruminococcaceae abundance in the ileum;and in 25 and 50 kg BW groups, IUGR pigs showed lower Ochrobactrum abundance in the jejunum.Spearman's correlation revealed that Lactobacillus was negatively correlated with growth performance, while unclassified Ruminococcaceae was positively correlated. Predictive metagenomic analysis detected significantly different expression of genes in the intestinal microbiota between IUGR and NBW pigs, suggesting different metabolic capabilities between the two groups.Conclusions: Growing-finishing IUGR pigs showed lower growth performance, higher microbial alpha diversity, and differences in plasma hormone concentrations compared to NBW pigs. Alterations in the abundance of Firmicutes,Proteobacteria, Ruminococcaceae, Lactobacillus, and Ochrobactrum in the small intestine may be associated with IUGR, and may therefore serve as a future target for gut microbiota intervention in growing-finishing IUGR pigs.

Intrauterine growth restriction and genetic determinantsexisting findings, problems, and further direction

Fetal growth is determined largely by the nutrient supply, placental transport function, and growth hormones. Recently, gene mutation and expression, especially of those genes associated with the proteins that are related to the fetal growth, have been reported to play an important role in the development of intrauterine growth restriction(IUGR). Fetal growth epigenetics, a new concept in fetal growth, has resulted from studies on fetal programing. This paper outlines the findings of our serial studies on IUGR, and summarizes data on IUGR animal models, placental function in transferring nutrients, cell proliferation dynamics in IUGR, and experimental treatment of IUGR. We review genetic approaches to IUGR, especially those relating to growth factor genes, angiotensinogen genes and other gene mutations. We also discuss the epigenetics of fetal growth and future study directions on fetal growth restriction. These should be valuable in elucidating the mechanisms employed by the fetus and in helping to develop interventional strategies that might prevent the development of IUGR.

Long-term implications of fetal growth restriction

Fetal growth restriction(FGR),or intrauterine growth restriction(IUGR),is a complication of pregnancy where the fetus does not achieve its genetic growth potential.FGR is characterized by a pathological retardation of intrauterine growth velocity in the curve of intrauterine growth.However,the FGR definition is still debated,and there is a lack of a uniform definition in the literature.True IUGR,compared to constitutional smallness,is a pathological condition in which the placenta fails to deliver an adequate supply of oxygen and nutrients to the developing fetus.Infants with IUGR,compared to appropriately grown gestational age infants,have a significantly higher risk of mortality and neonatal complications with long-term consequences.Several studies have demonstrated how suboptimal fetal growth leads to long-lasting physiological alterations for the developing fetus as well as for the newborn and adult in the future.The long-term effects of fetal growth retardation may be adaptations to poor oxygen and nutrient supply that are effective in the fetal period but deleterious in the long term through structural or functional alterations.Epidemiologic studies showed that FGR could be a contributing factor for adult chronic diseases including cardiovascular disease,metabolic syndrome,diabetes,respiratory diseases and impaired lung function,and chronic kidney disease.In this review we discussed pathophysiologic mechanisms of FGR-related complications and potential preventive measures for FGR.

Glucose Metabolic and Gluconeogenic Pathways Disturbance in the Intrauterine Growth Restricted Adult Male Rats

Objective To explore the molecular mechanism of type 2 diabetes in intrauterine growth restricted adult rats through determination of blood glucose and expression of gluconeogenic enzymes in liver.Methods Male intrauterine growth restriction(IUGR) offspring induced by maternal protein-malnutrition and normal controls were studied.The body weights of offspring rats were weighted from birth to 12 weeks of age.Fasting plasma glucose and insulin levels were determined by glucose oxidase method and enzyme-linked immunosorbent assay(ELISA) respectively at 1 week,8 weeks,and 12 weeks.Peroxisome proliferator-activated receptor-γ coactivator-1α(PGC-1α),phosphoenolpyruvate carboxykinase(PEPCK),and glucose-6-phosphatase(G6Pase) mRNA and protein levels in liver were measured by real time RT-PCR and Western blot in newborn rats(Week 1) and adult rats(Week 12).Results Birth weights of IUGR rats were significantly lower than those of controls until 4 weeks later,when IUGR rats caught up to controls.Between 8 and 12 weeks,the growth of IUGR rats surpassed that of controls.No significant differences were observed in blood glucose and insulin levels at newborn rats between the two groups.However,by the end of 8 weeks IUGR rats developed hyperinsulinemia and high insulin resistance index.At the age of 12 weeks,IUGR rats had mild fasting hyperglycemia.In addition,hepatic PGC-1α mRNA and protein levels as well as hepatic mRNA levels of PEPCK and G6Pase at Week 1 and Week 12 in IUGR rats were all significantly higher than those of controls(P<0.05).Conclusions As a result of intrauterine malnutrition,the expression of gluconeogenic genes is exaggerated in offspring.This change stays through adulthood and may contribute to the pathogenesis of type 2 diabetes.

INTRAUTERINE GROWTH RETARDATION AT FULL TERM PREGNANCIES WITH ENDOCRINE FACTORS

Objective To investigate the relationship between intrauterine growth retardation (IUGR) and endocrine parameters so as to assess the effects or the main endocrine ractors on IUGR. The concentrations of growth hormone(GH), insulin, T3, T4 and TSH were measured in umbilical cord blood, amniotic fluid and maternal serum.Methods The samples were collected from 23 pregnant women who were diagnosed as the full term IUGR, 42 normal full term pregnant women with normal infants’ weight were taken as control. Growth hormone and insulin were measured by radioimmunoassay. T3, T4 and TSH were investigated by micro-radioimmunoassay. Results The concentrations of growth hormone, insulin and T4 in umbilical cord blood were lower in IUGR than that in control group(GH4. 63μ/L vs 7. o1μg/L, insulin 1o. 68μIU/ml vs 31. 44μIU/ml, T487. 39nmol/L vs 138. 1onmol/L. P <o. o5, o. o5 and o. o5, respectively). The TSH concentration in umbilical cord blood was higher in IUGR than in control group (1o. 84μmIU/L vs 5. 75μmIU/L, P <o. o1 ). The concentration of growth hormone in maternal serum and the concentration of insulin in amniotic fluid were also lower in IUGR group than in control group(GH 1. 77μg/L vs 2. 74μg/L,P <o. o1, insulin 5. 84μIU/ml vs 15. 64μIU/ml, P <o. o1). Conclusion This study confirms that full term neonates with IUGR are abnormal in endocrine factors. The inadequacy of growth hormone may be one of the causes of IUGR. The relatlve scarcity of growth hormone and insulin seems to be a factor to compromise the fetus’ metabolism. Besides, the early hypothyrosis of infants with IUGR might protect them from unfavorable environment in the uterine.

Low maternal leptin levels in preeclamptic women with fetal growth restriction

Objective: We hypothesized that preeclamptic women with intrauterine growth restriction (IUGR) would have lower concentrations of leptin compared to women with normal fetal growth. Methods: A crosssectional study was performed in 20 cases of IUGR and 20 normal fetuses born to women diagnosed with preeclampsia. Blood samples were collected from mothers at term gestation and with fetal birth weight less than 2500 grams would categorized as IUGR. The subjects were recruited by consecutive sampling conducted in Hasan Sadikin Hospital and several network hospitals during the period of September-November 2012. Results: A significant difference (p = 0.015) in maternal serum leptin levels was found between IUGR (22.1 ng/ml) and normal fetuses (36.5 ng/ml). Serum levels of leptin in preeclamptic women with IUGR were lower than normal fetuses. Spearman correlation test between maternal serum leptin levels and birth weight in IUGR did not demonstrate a significant correlation, with r = -0.321 (p = 0.168). Conclusion: The maternal leptin concentrations in IUGR are lower than the normal fetus in preeclampsia cases, but there was not enough evidence to support that leptin is associated with birth weight in IUGR.

The Proteome Landscape of Human Placentas for Monochorionic Twins with Selective Intrauterine Growth Restriction

In perinatal medicine,intrauterine growth restriction(IUGR)is one of the greatest challenges.The etiology of IUGR is multifactorial,but most cases are thought to arise from placental insufficiency.However,identifying the placental cause of IUGR can be difficult due to numerous confounding factors.Selective IUGR(sIUGR)would be a good model to investigate how impaired placentation affects fetal development,as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors.Herein,we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins.Specifically,we identified a total of 5481 proteins,of which 233 were differentially expressed(57 up-regulated and 176 down-regulated)in IUGR twins.Bioinformatics analysis indicates that these differentially expressed proteins(DEPs)are mainly associated with cardiovascular system development and function,organismal survival,and organismal development.Notably,34 DEPs are significantly enriched in angiogenesis,and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed.Moreover,we found decreased expression of metadherin(MTDH)in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro.Collectively,our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins,and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.

Supplemental Clostridium butyricum modulates lipid metabolism by reshaping the gut microbiota composition and bile acid profile in IUGR suckling piglets

Background Intrauterine growth restriction(IUGR)can cause lipid disorders in infants and have long-term adverse effects on their growth and development.Clostridium butyricum(C.butyricum),a kind of emerging probiotics,has been reported to effectively attenuate lipid metabolism dysfunctions.Therefore,the objective of this study was to investigate the effects of C.butyricum supplementation on hepatic lipid disorders in IUGR suckling piglets.Methods Sixteen IUGR and eight normal birth weight(NBW)neonatal male piglets were used in this study.From d 3to d 24,in addition to drinking milk,the eight NBW piglets(NBW-CON group,n=8)and eight IUGR piglets(IUGR-CON group,n=8)were given 10 mL sterile saline once a day,while the remaining IUGR piglets(IUGR-CB group,n=8)were orally administered C.butyricum at a dose of 2×108colony-forming units(CFU)/kg body weight(suspended in 10 mL sterile saline)at the same frequency.Results The IUGR-CON piglets exhibited restricted growth,impaired hepatic morphology,disordered lipid metabolism,increased abundance of opportunistic pathogens and altered ileum and liver bile acid(BA)profiles.However,C.butyricum supplementation reshaped the gut microbiota of the IUGR-CB piglets,characterized by a decreased abundance of opportunistic pathogens in the ileum,including Streptococcus and Enterococcus.The decrease in these bile salt hydrolase(BSH)-producing microbes increased the content of conjugated BAs,which could be transported to the liver and function as signaling molecules to activate liver X receptorα(LXRα)and farnesoid X receptor(FXR).This activation effectively accelerated the synthesis and oxidation of fatty acids and down-regulated the total cholesterol level by decreasing the synthesis and promoting the efflux of cholesterol.As a result,the growth performance and morphological structure of the liver improved in the IUGR piglets.Conclusion These results indicate that C.butyricum supplementation in IUGR suckling piglets could decrease the abundance of BSH-producing microbes(Streptococcus and Enterococcus).This decrease altered the ileum and liver BA profiles and consequently activated the expression of hepatic LXRαand FXR.The activation of these two signaling molecules could effectively normalize the lipid metabolism and improve the growth performance of IUGR suckling piglets.

LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR

Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.

胎兒UA和MCA血流監測早期診斷IUGR價值

目的本研究探討胎兒UA及MCA血流指標在診斷胎兒生長受限的價值。方法2020.01~2022.12期間本院產前超聲檢查及分娩,IUGR組胎兒26例,30例健康胎兒為對照組,孕婦年齡27~43歲,平均31±3.2歲,孕週32~39週,平均35.16±2.74週,測孕婦的UA-PI、UARI、MCA-PI、MCA-RI值,測胎兒出生後5分鐘Apgar score,計算各指標在診斷IUGR靈敏度及特異度。結果IUGR組,UA-PI異常16例,UA-RI異常12例,MCA-PI異常6例,MCA-RI異常5例。對照組UA-PI異常4例,UA-RI異常2例,MCA-PI異常2例,MCA-RI異常2例。胎兒出生5分鐘Apgar score,IUGR組UA-PI或UA-RI異常胎兒中分別0~3分1及0例,4~6分2及2例,7~10分23及24例,MCA-PI或RI異常胎兒中0~1分都為0例,4~6分1及0例,7~10分25及26例。對照組,胎兒UA-PI或UA-RI異常的產後5分鐘的Apgar score,0~3分都為0例,4~6分為1及0例,7~10分為29及30例,胎兒MCA-PI或MCA-RI異常的產後生兒5分鐘的Apgar score,0~3分都是0例,4~6分分別為1及0例,7~10分都是30例。UA-PI對早期診斷IUGR的靈敏度最高,但其特異度則是最低,UA-RI及MCA-PI及MCA-RI的特異度高達93.3%。結論胎兒UA和MCA監測在早期診斷IUGR有重要臨床價值,UA指標對IUGR敏感性高於MCA指標。

Dietary rumen-protected L-arginine or N-carbamylglutamate attenuated fetal hepatic inflammation in undernourished ewes suffering from intrauterine growth restriction

This study aimed to explore whether dietary rumen-protected L-arginine(RP-Arg)or N-carbamylglutamate(NCG)supplementation to feed-restricted pregnant ewes counteracts fetal hepatic inflammation and innate immune dysfunction associated with intrauterine growth retardation(IUGR)in ovine fetuses.On d 35 of pregnancy,twin-bearing Hu ewes(n=32)were randomly assigned to 4 treatment groups(8 ewes and 16 fetuses per group)and fed diets containing 100%of the NRC requirements(CON),50%of the NRC requirements(RES),RES+RP-Arg(20 g/d)(RESA),or RES+NCG(5 g/d)(RESN).At 08:00 on d 110 of gestation,fetal blood and liver tissue samples were collected.The levels of triglyceride,free fatty acid,cholesterol andβ-hydroxybutyrate in the fetal blood of RESA and RESN groups were lower(P<0.05)than those of the RES group,but were higher(P<0.05)than those of the CON group.The interleukin(IL)-6 and IL-1 levels in fetal blood and liver tissue as well as the myeloid differentiation primary response 88(MyD88),transforming growth factorβ(TGFβ),and nuclear factor kappa B(NF-κB)mRNA levels in the fetal liver were decreased(P<0.05)by the NCG or RP-Arg supplementation compared to the RES treatment.Similarly,the toll-like receptor(TLR)-4,MyD88,TGFβ,and p-c-Jun N-terminal kinase(JNK)protein levels in the fetal liver were reduced(P<0.05)in the NCG and RP-Arg-supplemented groups compared to the RES group.These results showed that dietary supplementation of RP-Arg or NCG to underfed pregnant ewes could protect against IUGR fetal hepatic inflammation via improving lipid metabolism,down-regulating the TLR-4 and the inflammatory JNK and NF-icB signaling pathways,and decreasing cytokine production in ovine fetal blood and liver tissue.

Dietary N-carbamylglutamate or L-arginine improves fetal intestinal amino acid profiles during intrauterine growth restriction in undernourished ewes

Our previous studies demonstrated that prenatal in utero growth restriction impairs postnatal intestinal function.Thus,improving postpartal intestinal absorption capacity and growth by manipulating the maternal diet prepartum is of importance.This work was conducted to determine whether supplementation of N-carbamylglutamate(NCG)or rumen-protected L-arginine(RP-Arg)increased fetal intestinal amino acid(AA)profiles in intrauterine growth retardation(IUGR)fetuses.On d 35 of gestation,Hu ewes(n=32)carrying twin fetuses were randomized into 4 groups(8 ewes and 16 fetuses in each group),where diets were as follows:100%of nutrient requirements recommended by National Research Council(NRC,2007)(CON);50%of nutrient requirements recommended by NRC(2007)(RES);RES+RPArg(20 g/d),(RES+ARG);and RES+NCG(5 g/d),(RES+NCG).On d 110 of gestation,both fetal and maternal tissues were collected and weighed.Compared with RES,solute carrier family 1,member 5(SLC1A5)was upregulated(P<0.05)within fetal jejunum,duodenum and ileum when supplementing NCG and RP-Arg.Relative to RES,RP-Arg or NCG supplementation to RES resulted in upregulation(P<0.05)of peptide transporter 1 protein abundance within the fetal ileum.NCG or RP-Arg supplementation to RES also upregulated phosphorylated mechanistic target of rapamycin(pmTOR)-to-mTOR ratio in the fetal ileum induced by IUGR(P<0.05).As a result,during IUGR,supplementation of Arg or NCG affected intestinal AA profiles in the fetus in part through controlling mTOR signal transduction as well as AA and peptide transport.Future studies should be conducted to understand the role(if any)of the placenta on the improvement of growth and AA profiles independent of the fetal intestine.This would help demonstrate the relative contribution of intestinal uptake in fetal life.

早期营养干预改善IUGR大鼠胰岛素抵抗及其与血清瘦素的关系

【目的】探讨生后早期不同饮食构成喂养对宫内生长迟缓(IUGR)大鼠胰岛素抵抗的远期影响及其与瘦素、腹部内脏脂肪的相关关系。【方法】IUGR新生雌鼠48只和正常新生雌鼠10只随机分为5组予下述相应饮食饲料喂养母鼠3周:①IUGR模型组(S/N组)予常规饮食,②IUGR高碳水化合物饮食组(A组),③IUGR高脂肪饮食组(B组),④IUGR高蛋白质饮食组(C组)⑤正常对照组(C/N组)予常规饮食。第4周起各组幼鼠断乳后均予常规饮食饲料喂养至实验结束。各组大鼠于12周(成年期)分别测定体质量、肾周脂肪质量(肾脂)、血清瘦素、血糖、胰岛素并计算胰岛素敏感指数(ISI)、胰岛素抵抗指数(IRI)。【结果】12周时IUGR模型组大鼠肾脂增多,血清瘦素和IRI升高、ISI下降(P<0.05)。IUGR高蛋白饮食组体质量(242.6±17.5)g虽高于C/N组(192.1±37.2)g,但与S/N组(213.4±27.3)g比较无显著性差异(P>0.05),且不伴肾脂(1.46±0.67)g增多,血清瘦素(0.43±0.26)μg/L、ISI(4.47±0.45)和IRI(0.78±0.45)也与正常对照组(1.41±0.42)g,(0.42±0.34)μg/L,4.46±0.42和0.77±0.31比较差异无统计学意义(P>0.05)。【结论】生后哺乳期给予高蛋白质饮食早期营养干预然后恢复正常饮食,可使IUGR大鼠既能达到体格追赶生长。

Treatment of immune dysfunction in intrauterine growth restriction piglets via supplementation with dimethylglycine sodium salt during the suckling period

This study aimed to investigate the mechanism of small intestinal immune dysfunction in intrauterine growth restriction(IUGR)newborn piglets and relieve this dysfunction via dimethylglycine sodium salt(DMG-Na)supplementation during the suckling period.Thirty sows(Duroc×[Landrace×Yorkshire])were selected,and 1 male newborn piglet with normal birth weight(NBW)and 1 male newborn piglet with IUGR were obtained from each sow.Among them,10 NBW and 10 IUGR newborns were euthanized without suckling.The other 20 NBW newborns were allocated to the group named NCON,which means NBW newborns fed a basic milk diet(BMD)(n=10),and the group named ND,which means NBW newborns fed BMD supplemented with 0.1%DMG-Na(n=10);the other 20 IUGR newborns were assigned to the group named ICON,which means IUGR newborns fed BMD(n=10),and the group named ID,which means IUGR newborns fed BMD supplemented with 0.1%DMG-Na(n=10).The newborns were fed BMD from 7 to 21 d of age and euthanized at 21 d of age to collect serum and small intestinal samples.The growth performance,small intestinal histological morphology and sub-organelle ultrastructure,serum immunoglobulin,small intestinal digestive enzyme activity,inflammatory cytokine level,and jejunum mRNA and protein expression of the toll-like receptor 4(TLR4)/nucleotide-binding oligomerization domain protein(NOD)/nuclear factor-k B(NF-k B)network deteriorated in the ICON group compared to that in the NCON group.The small intestinal histological morphology and suborganelle ultrastructure,serum immunoglobulin,small intestinal digestive enzyme activity,and inflammatory cytokine level improved(P<0.05)in the ID group compared to those in the ICON group.The jejunum mRNA and protein expression of the TLR4/NOD/NF-k B network improved(P<0.05)in the ID group compared to that in the ICON group.In conclusion,the activity of the TLR4/NOD/NF-k B pathway was inhibited in the IUGR newborns,which in turn led to their jejunum immune dysfunction and reduced their performance.By ingesting DMG-Na,the IUGR newborns activated the TLR4/NOD/NF-k B pathway,thereby improving their unfavorable body state during the suckling period.

Dietary dimethylglycine sodium salt supplementation alleviates redox status imbalance and intestinal dysfunction in weaned piglets with intrauterine growth restriction

There are few studies on the mechanism of redox status imbalance and intestinal dysfunction in intrauterine growth restricted(IUGR)newborn piglets.Here,we investigated the mechanism of jejunum dysfunction in weaned piglets with IUGR and the mechanism through which dimethylglycine sodium salt(DMG-Na)supplementation improving the imbalance of their redox status.In this work,a total of 10 normal birth weight(NBW)newborn piglets and 20 IUGR newborn piglets were obtained.After weaning at 21 d,they were assigned to 3 groups(n=10/group):NBW weaned piglets fed standard basal diets(NBWC);one IUGR weaned piglets fed standard basal diets(IUGRC);another IUGR weaned piglets from the same litter fed standard basal diets plus 0.1%DMG-Na(IUGRD).The piglets in these 3 groups were sacrificed at 49 d of age,and the blood and jejunum samples were collected immediately.The growth performance values in the IUGRC group were lower(P<0.05)than those in the NBWC group.Jejunum histomorphological parameters,inflammatory cytokines,and digestive enzyme activity as well as serum immunoglobulin were lower(P<0.05)in the IUGRC group than those in the NBWC group.Compared with these in the NBWC group,the redox status of serum,jejunum,and mitochondria and the expression levels of jejunum redox status-related,cell adhesion-related,and mitochondrial function-related genes and proteins were suppressed in the IUGRC group(P<0.05).However,compared with those in the IUGRC group,the growth performance values,jejunum histomorphological parameters,inflammatory cytokines,digestive enzyme activity,serum immunoglobulin,redox status of serum,jejunum,and mitochondria,and the expression levels of jejunum redox status-related,cell adhesion-related,and mitochondrial function-related genes and proteins were improved(P<0.05)in the IUGRD group.In conclusion,dietary DMG-Na supplementation alleviates redox status imbalance and intestinal dysfunction in IUGR weaned piglets mainly by activating the sirtuin 1(SIRT1)/peroxisome proliferatoractivated receptorgcoactivator-1a(PGC1a)pathway,thereby improving their unfavorable body state.

早期营养对IUGR大鼠糖耐量和胰岛素敏感性的远期影响

【目的】了解宫内发育迟缓(IUGR)和生后早期蛋白质营养不良对IUGR大鼠糖耐量和胰岛素敏感指数(ISI)及胰岛素抵抗指数(IRI)的远期影响。【方法】采用被动吸烟法制作IUGR大鼠动物模型,新生正常鼠仔102只和IUGR鼠仔105只随机分为4组:①正常对照组;②IUGR模型组;③正常大鼠低蛋白饮食组(CLP组);④IUGR大鼠低蛋白饮食组(SLP组)。观察各组大鼠在生后4周(幼年期)、12周(成年期)和48周龄(老年期)时糖耐量和胰岛素释放试验变化。【结果】①SLP组大鼠宫内发育迟缓和生后早期蛋白质营养不良其远期葡萄糖-胰岛素代谢功能受损明显,至48周时空腹血糖(5.2±1.4)mmol/L已升高,胰岛素(31. 2±3.4)mU/L水平明显升高,ISI(1.7±0.4)明显下降,IRI(8.7±1.8)明显升高,与正常对照组[(4.5±1.1)mmol/L,(12.9±1.0)mU/L和2.8±0.2,2.3±0.41比较均有显著性差异(P<0.05或P<0.01)。②CLP组大鼠生后早期单纯蛋白质营养不良的远期影响主要表现为糖负荷后胰岛素对血糖升高的应答分泌反应延迟和糖耐量减低。③IUGR模型组大鼠生后即给予正常营养供给,其葡萄糖-胰岛素代谢紊乱的程度减轻,但仍有糖耐量减低。【结论】在宫内和/或生后早期机体发育的关键时期,蛋白质营养不良将对葡萄糖-胰岛素代谢功能产生长期的不良影响。

INTERGROWTH-21^(st)标准评价胎儿宫内生长受限的临床价值

目的探讨INTERGROWTH-21^(st)标准评价胎儿宫内生长受限的应用价值。方法本研究为前瞻性队列研究。收集2015年3月至2016年3月在复旦大学附属妇产科医院建卡,进行常规产前检查并入院分娩的单胎妊娠孕妇。所有入选病例孕28周之后入组,每4周做一次产前超声生长测量,直至分娩前。胎儿生长径线以INTERGROWTH-21^(st)标准计算Z-score值。分娩后随访新生儿体重等相关信息。应用Logistic回归方程建立预测公式。最后将新公式与Hadlock法预测IUGR的准确性进行对比。结果共收集符合入组条件的孕妇834例。排除失访143例后,得到对照组565例和IUGR组126例。新预测公式的敏感性、特异性、阳性预测值、阴性预测值、假阳性率、假阴性率分别为:88.9%、85.4%、57.7%、97.2%、14.6%、11.1%。Hadlock法预测的敏感性、特异性、阳性预测值、阴性预测值、假阳性率、假阴性率分别为:81.7%、82.7%、51.2%、95.3%、17.3%、18.3%。结论以INTERGROWTH-21^(st)标准计算Z-score建立新公式预测胎儿宫内生长受限的方法,与传统的Hadlock预测法相比,改善了产前诊断的敏感性和特异度,减少了假阳性和假阴性的病例,全面提高了超声预测胎儿宫内生长受限的准确性。