Intrauterine Growth Restriction Piglets Research Articles

Maternal chitosan oligosaccharide supplementation during late gestation and lactation optimizes placental function in sows and intestinal function in 21-day-old IUGR suckling piglets

Maternal dietary supplementation with chitosan oligosaccharide (COS) has been considered as a potential intervention to mitigate the occurrence of intrauterine growth restriction (IUGR) and improve postnatal growth. The present study investigated the effect of COS as a dietary supplement for sows during late gestation and lactation on their productivity, placental function, and the intestinal health of IUGR piglets. From day (d) 85 of late gestation to d 21 of lactation, 30 sows were randomly divided into either a control group (basal diet) or a COS group (basal diet + 100 mg kg−1 COS). At d 21 of lactation, eight normal and eight IUGR littermates from eight litters belong to control sows, as well as eight IUGR littermates from COS sows, were selected for further analysis. The results showed a significant reduction in the number of stillbirths and mummies in COS groups (p < 0.05). Maternal dietary supplementation with COS also significantly up-regulated the expression levels of GLUT1, GLUT3, and VEGFA mRNA in the placenta of IUGR piglets compared to those in control group (p < 0.05). Furthermore, there was a significant decrease in MDA content and a significant increase in GSH content in the placenta of IUGR piglets from COS sows compared to those from control group (p < 0.05). Additionally, the expression levels of MUC2 and occludin mRNA as well as claudin1 protein significantly up-regulated in the jejunum of 21-day-old IUGR piglets from COS sows group compared to those from control group (p < 0.05). Moreover, IL-10 mRNA expression level was significantly increased while MDA content was significantly reduced in the jejunum of 21-day-old IUGR piglets from COS sows group compared to those from control group (p < 0.05). The results indicated that maternal dietary COS supplementation during late gestation effectively reduced the incidence of stillbirths and mummies, potentially linked to enhanced placental function, reduced oxidative stress, and improved immune status. Furthermore, maternal dietary COS supplementation exhibited positive impact on intestinal digestive and absorptive function, intestinal barrier integrity, intestinal antioxidant capacity and immune status in 21-day-old suckling IUGR piglets.

233 Exploring the impact of intrauterine growth restriction on fecal microbiota and metabolome in pigs

Abstract Intrauterine growth restriction (IUGR) poses a significant challenge in swine production, affecting approximately 20% of piglets and resulting in increased mortality rates, metabolic disturbances, compromised intestinal development, and altered microbial colonization. This phenomenon arises as the IUGR fetus adapts to limited oxygen and nutrient supply in utero by reallocating blood flow towards vital organs, particularly the brain, consequently leading to a greater brain-to-liver weight ratio (BrW/LW) at birth. Our study aimed to comprehensively investigate the repercussions of IUGR on fecal microbiota composition and plasma metabolome profiles in pigs from birth through to slaughter. To elucidate these effects, we conducted computed tomography scans on piglets within 24 h of birth to assess brain and liver weights accurately. Subsequently, we selected two groups of piglets based on the BrW/LW. Specifically, 12 piglets with the greatest BrW/LW (IUGR; BrW/LW: 1.00 ± 0.09) and 12 with the least BrW/LW (NORM; BrW/LW: 0.36 ± 0.04). From these piglets we collected fecal and blood samples at specific time points: during lactation (T1: d 16 ± 0.6), after the starter period (T2: d 63 ± 8.6), and at the onset (T3: d 119 ± 11.4) and conclusion (T4: d 162 ± 14.3) of the finisher period. Throughout the study, all pigs received identical diets to eliminate dietary confounders. In the lactation, starter and grower but not finisher period, IUGR piglets grew 47, 19 and 14% slower, respectively compared with their NORM littermates. Our findings revealed that fecal microbial α-diversity remained unaffected by IUGR across all time points examined, indicating a stable microbial richness within the gut microbiota of IUGR and NORM pigs. However, β-diversity, reflecting inter-group microbial community variation, exhibited significant differences at T1 (P = 0.002), T2 (P = 0.079), and T3 (P = 0.027), suggesting distinct microbial compositions between IUGR and NORM pigs at these stages. Specifically, IUGR pigs displayed a greater abundance of Clostridium sensu stricto 1 and Romboutsia at T1, Prevotellaceae NK3B31 group, Rikenellaceae RC9 gut group, and Alloprevotella at T2, and p-2534-18B5 gut group at T3. Conversely, the NORM group exhibited increased concentrations of Ruminococcus at T1, HT002 at T2, and Prevotella_9 at T3. Furthermore, while plasma metabolite analysis revealed no significant differences between IUGR and NORM pigs at T1, decreased arginine levels were observed in the IUGR group compared with NORM at T2 (P < 0.05). In conclusion, our study underscores the profound and persistent impact of IUGR on fecal microbiota composition in pigs from birth to the initial stages of the finisher period, while suggesting minimal alterations in the blood metabolome profile throughout various growth stages. These findings provide valuable insights into the long-term consequences of IUGR on swine health and production. This research received funding from the European Union’s Horizon 2020 research and innovation program under a Marie Sklodowska-Curie grant (agreement no. 955374).

Feeding Parenteral Nutrition in the Neonatal Period Programs Dyslipidemia in Adulthood in Yucatan Miniature Pigs

BackgroundEarly nutritional challenges can lead to permanent metabolic changes, increasing risk of developing chronic diseases later in life. Total parenteral nutrition (TPN) is a life-saving nutrition regimen, used especially in intrauterine growth-restricted (IUGR) neonates. Early TPN feeding alters metabolism, but whether these alterations are permanent is unclear. Programmed metabolism is likely caused by epigenetic changes due to imbalances of methyl nutrients. ObjectivesWe sought to determine whether feeding TPN in early life would increase risk of developing dyslipidemia in adulthood and whether supplementing the methyl nutrients betaine and creatine to TPN would prevent this development. We also sought to determine whether IUGR exacerbates the effects of neonatal TPN on lipid metabolism in adulthood. MethodsFemale piglets (n = 32; 7 d old) were used in 4 treatments: 24 normal-weight piglets were randomly assigned to sow-fed (SowFed), standard TPN (TPN-control), and TPN with betaine and creatine (TPN-B+C); 8 IUGR piglets were fed control TPN (TPN-IUGR) as a fourth group. After 2 wk of treatment, all pigs were then fed a standard solid diet. At 8 mo old, central venous catheters were implanted to conduct postprandial fat tolerance tests. ResultsFeeding TPN in the neonatal period led to dyslipidemia in adulthood, as indicated by higher postprandial triglyceride (TG) levels in TPN-control (P < 0.05), compared with SowFed. IUGR piglets were particularly sensitive to neonatal TPN feeding, as TPN-IUGR piglets developed obesity and dyslipidemia in adulthood, as indicated by greater backfat thickness (P < 0.05), higher liver TG (P < 0.05), slower postprandial TG clearance (P < 0.05), and elevated fasting plasma nonhigh-density lipoprotein-cholesterol (P < 0.01), and nonesterified fatty acids (P < 0.001), compared with TPN-control. ConclusionsFeeding TPN in early life increases the risk of developing dyslipidemia in adulthood, especially in IUGR neonates; however, methyl nutrient supplementation to TPN did not prevent TPN-induced changes in lipid metabolism.

Thriving or Striving: Comparing Intra-Uterine Growth Restricted, Low Birth Weight and Normal Birth Weight Piglets within the First 24 Hours.

This observational study explored the early-life challenges of intra-uterine growth restricted (IUGR), low birth body weight (LBW), and normal birth body weight (NBW) piglets. The aim was to understand the impact of birth weight and intra-uterine growth restriction phenotype on neonatal survival and behavior. Based on weight and phenotype, piglets were classified as IUGR (n = 32), LBW (n = 34), and NBW (n = 29) immediately after birth. The piglets were litter- and sex-matched. Vitality scores were assigned based on motor activity and breathing and complemented with an assessment of umbilical cord condition, rectal temperature, crown-rump length (CRL), time to reach the udder, time to suckle, colostrum intake, and weight gain over 24 h. Beyond the lower birth weight, reduced CRL, and higher mortality rate, IUGR piglets faced several other challenges compared with LBW and NBW piglets. Growth-impaired piglets often struggled to engage in early feeding behaviors and displayed consistently lower rectal temperatures at 1, 3 and 24 h after birth. IUGR piglets showed inadequate colostrum intake and weight loss, which were also observed for LBW counterparts. In contrast, no significant differences were observed in vitality scores and umbilical cord conditions across the groups. In conclusion, our findings underscore the impact of intra-uterine growth restriction on neonatal piglets, emphasizing the need for specialized care strategies to improve survival and health outcomes in IUGR.

Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR), when a fetus does not grow as expected, is associated with a reduction in hepatic functionality and a higher risk for chronic liver disease in adulthood. Utilizing early developmental plasticity to reverse the outcome of poor fetal programming remains an unexplored area. Focusing on the biochemical profiles of neonates and previous transcriptome findings, piglets from the same fetus are selected as models for studying IUGR. The cellular landscape of the liver is created by scRNA-seq to reveal sex-dependent patterns in IUGR-induced hepatic injury. One week after birth, IUGR piglets experience hypoxic stress. IUGR females exhibit fibroblast-driven T cell conversion into an immune-adapted phenotype, which effectively alleviates inflammation and fosters hepatic regeneration. In contrast, males experience even more severe hepatic injury. Prolonged inflammation due to disrupted lipid metabolism hinders intercellular communication among non-immune cells, which ultimately impairs liver regeneration even into adulthood. Additionally, Apolipoprotein A4 (APOA4) is explored as a novel biomarker by reducing hepatic triglyceride deposition as a protective response against hypoxia in IUGR males. PPARα activation can mitigate hepatic damage and meanwhile restore over-expressed APOA4 to normal in IUGR males. The pioneering study offers valuable insights into the sexually dimorphic responses to hepatic injury during IUGR.

Morphometric traits to estimate brain and liver weight and their ratio for the diagnosis of intrauterine growth restriction in newborn piglets

Intrauterine growth restriction (IUGR) is defined as inadequate foetal growth during gestation. In response to placenta insufficiency, IUGR piglets prioritise brain development as a survival mechanism. This adaptation leads to a higher brain-to-liver weight ratio (BrW/LW) at birth. This study assessed the potential of using morphometric traits to estimate brain (BrW) and liver (LW) weights, enabling non-invasive diagnosis of IUGR in newborn piglets. At birth, body weight (BtW) of individual piglets (n = 144) was recorded. One day (± 1) after birth, BrW and LW were measured with computed tomography (n = 94) or by weighing the organs after natural death or euthanasia (n = 50). Additionally, 20 morphometric traits were captured from images of each piglet and correlated with the BrW and LW. The morphometric traits that showed a r ≥ 0.70 in linear correlation with the BrW or LW were selected. Each selected trait was combined as an independent variable with BtW to develop multiple linear regression models to predict the BrW and LW. Six models were chosen based on the highest adjusted R2 value: three for estimating BrW and three for LW. The dataset was then randomly divided into a training (75% of the data) and a testing (remaining 25%) subsets. Within the training subset, three equations to predict the BrW and three to predict the LW were extrapolated from the six selected models. The equations were then applied to the testing subset. The accuracy of the equations in predicting organ weight was assessed by calculating mean absolute and mean absolute percentage error (MAE and MAPE) between predicted and actual BrW and LW. To predict the BrW/LW, an equation including BtW and the two morphometric traits which better predicted BrW and LW was used. In the testing dataset, the equation combining ear distance and BtW better estimated the BrW. The equation performed with a MAE of 1.95 and a MAPE of 0.06 between the true and estimated weight of the brain. For the liver, the equation combining the abdominal area delimited by a square and BtW displayed the best performance, with a MAE of 9.29 and a MAPE of 0.17 between the true and estimated weight. Finally, the MAE and MAPE between the actual and estimated BrW/LW were 0.14 and 0.17, respectively. These findings suggest that specific morphometric traits can be used to estimate brain and liver weights, facilitating accurate and non-invasive identification of IUGR in newborn piglets.

Dietary supplementation with dihydroartemisinin improves intestinal barrier function in weaned piglets with intrauterine growth retardation by modulating the gut microbiota.

The aim of this study was to investigate whether dietary dihydroartemisinin (DHA) supplementation could improve intestinal barrier function and microbiota composition in intrauterine growth restriction (IUGR) weaned piglets. Twelve normal birth weight (NBW) piglets and 24 IUGR piglets at 21 d of age were divided into three groups, which were fed a basal diet (NBW-CON and IUCR-CON groups) and an 80mg/kg DHA diet (IUGR-DHA group). At 49 d of age, eight piglets of each group with similar body weights within groups were slaughtered, and serum and small intestine samples were collected. The results showed that IUGR piglets reduced growth performance, impaired the markers of intestinal permeability, induced intestinal inflammation, decreased intestinal immunity, and disturbed the intestinal microflora. Dietary DHA supplementation increased average daily gain, average daily feed intake, and body weight at 49 d of age in IUGR-weaned piglets (P < 0.05). DHA treatment decreased serum diamine oxidase activity and increased the numbers of intestinal goblet cells and intraepithelial lymphocytes, concentrations of jejunal mucin-2 and ileal trefoil factor 3, and intestinal secretory immunoglobin A and immunoglobin G (IgG) concentrations of IUGR piglets (P < 0.05). Diet supplemented with DHA also upregulated mRNA abundances of jejunal IgG, the cluster of differentiation 8 (CD8), major histocompatibility complex-I (MHC-I), and interleukin 6 (IL-6) and ileal IgG, Fc receptor for IgG (FcRn), cluster of differentiation 8 (CD4), CD8, MHC-I, IL-6 and tumor necrosis factor α (TNF-α), and enhanced mRNA abundance and protein expression of intestinal occludin and ileal claudin-1 in IUGR piglets (P < 0.05). In addition, DHA supplementation in the diet improved the microbial diversity of the small intestine of IUGR piglets and significantly increased the relative abundance of Actinobacteriota, Streptococcus, Blautia and Streptococcus in the jejunum, and Clostridium sensu_ stricto_in the ileum (P < 0.05). The intestinal microbiota was correlated with the mRNA abundance of tight junction proteins and inflammatory response-related genes. These data suggested that DHA could improve the markers of intestinal barrier function in IUGR-weaned piglets by modulating gut microbiota. DHA may be a novel nutritional candidate for preventing intestinal dysfunction in IUGR pigs.

Lactobacillus amylovorus Promotes Lactose Utilization in Small Intestine and Enhances Intestinal Barrier Function in Intrauterine Growth Restricted Piglets

BackgroundIntrauterine growth restriction (IUGR) resulted in high mortality and many physiological defects of piglets, causing huge economic loss in the swine industry. Lactobacillus amylovorus (L. amylovorus) was identified as one of the main differential bacteria between IUGR and normal piglets. However, the effects of L. amylovorus on the growth performance and intestinal health in IUGR piglets remained unclear. ObjectivesThis study aimed to investigate the promoting effects of L. amylovorus Mafic1501, a new strain isolated from normal piglets, on the growth performance and intestinal barrier functions in IUGR piglets. MethodsNewborn mice or piglets were assigned into 3 groups: CON (normal birth weight, control), IUGR (low birth weight), and IUGR+L. amy (low birth weight), administered with sterile saline or L. amylovorus Mafic1501, respectively. Growth performance, lactose content in the digesta, intestinal lactose transporter, and barrier function parameters were profiled. IPEC-J2 cells were cultured to verify the effects of L. amylovorus Mafic1501 on lactose utilization and intestinal barrier functions. ResultsL. amylovorus Mafic1501 elevated body weight and average daily gain of IUGR mice and piglets (P < 0.05). The lactose content in the ileum was decreased, whereas gene expression of glucose transporter 2 (GLUT2) was increased by L. amylovorus Mafic1501 in IUGR piglets during suckling period (P < 0.05). Besides, L. amylovorus Mafic1501 promoted intestinal barrier functions by increasing the villus height and relative gene expressions of tight junctions (P < 0.05). L. amylovorus Mafic1501 and its culture supernatant decreased the lactose level in the medium and upregulated gene expressions of transporter GLUT2 and tight junction protein Claudin-1 of IPEC-J2 cells (P < 0.05). ConclusionL. amylovorus Mafic1501 improved the growth performance of IUGR piglets by promoting the lactose utilization in small intestine and enhancing intestinal barrier functions. Our results provided the new evidence of L. amylovorus Mafic1501 for its application in the swine industry.

Intrauterine growth restriction defined by increased brain-to-liver weight ratio affects postnatal growth and protein efficiency in pigs

Intrauterine growth restriction (IUGR) refers to impaired foetal growth during gestation, resulting in permanent stunting effects on the offspring. This study aimed to investigate the effects of IUGR on growth performance, body composition, blood metabolites, and meat quality of pigs from birth (n = 268) to slaughter (n = 93). IUGR piglets have prioritised brain development as a foetal adaptive reaction to placental insufficiency. This survival mechanism results in a higher brain-to-liver weight ratio (BrW/LW). One day (±1) after birth, computed tomography (CT) was performed on each piglet to assess their brain and liver weights. A threshold value of 0.78 (mean + SD) was chosen to divide the piglets into two categories – NORM (BrW/LW < 0.78) and IUGR (BrW/LW > 0.78). Moreover, each piglet was classified as either normal (score 1), mild IUGR (score 2), or severe IUGR (score 3) based on the head morphology. BW was recorded weekly, and average daily gain (ADG) was calculated for lactation, starter, grower, and finisher periods. Body composition was assessed after weaning (29.6 ± 0.7 d), at 20 kg (64 ± 7.2 d), 100 kg (165 ± 12.3 d), and on the carcasses using Dual-energy X-ray absorptiometry (DXA). Content and deposition rates of single nutrients, as well as energy and CP efficiency, were measured at 20 and 100 kg. Feed intake was recorded from 20 kg to slaughter. Meat quality was assessed on the carcasses. A total of 70% of the piglets assigned a score of 3 were NORM according to their BrW/LW. The IUGR category showed a lower ADG in the lactation (P < 0.01), starter (P = 0.07), and grower phases (P < 0.05) and a reduced CP efficiency in the grower–finisher period (P < 0.01) compared to the NORM group. IUGR pigs had a lower gain-to-feed ratio in the finisher period (P = 0.01) despite similar average daily feed intake, and they required more days (P < 0.01) to reach the slaughter weight. Additionally, their meat was darker (P = 0.01) than that of NORM pigs. The BrW/LW was inversely proportional to the ADG from birth to slaughter and negatively correlated with the CP deposition rate and efficiency in the grower–finisher period (P < 0.01). Furthermore, the higher the BrW/LW, the longer it took the pigs to reach the slaughter weight (P < 0.01). In conclusion, the identification of IUGR piglets based on the head morphology does not always agree with an increased BrW/LW. IUGR affects growth performance from birth to slaughter, CP efficiency in the grower–finisher period and meat quality.

Synthesis of glycine from 4-hydroxyproline in tissues of neonatal pigs with intrauterine growth restriction.

This study tested the hypothesis that the synthesis of glycine from 4-hydroxyproline (an abundant amino acid in milk and neonatal blood) was impaired in tissues of piglets with intrauterine growth restriction (IUGR), thereby contributing to a severe glycine deficiency in these compromised neonates. At 0, 7, 14, and 21 days of age, IUGR piglets were euthanized, and tissues (liver, small intestine, kidney, pancreas, stomach, skeletal muscle, and heart) were obtained for metabolic studies, as well as the determination of enzymatic activities, cell-specific localization, and expression of mRNAs for glycine-synthetic enzymes. The results indicated relatively low enzymatic activities for 4-hydroxyproline oxidase (OH-POX), proline oxidase, serine hydroxymethyltransferase, threonine dehydrogenase (TDH), alanine: glyoxylate transaminase, and 4-hydroxy-2-oxoglutarate aldolase in the kidneys and liver from 0- to 21-day-old IUGR pigs, in the pancreas of 7- to 21-day-old IUGR pigs, and in the small intestine and skeletal muscle (except TDH) of 21-day-old IUGR pigs. Accordingly, the rates of conversion of 4-hydroxyproline into glycine were relatively low in tissues of IUGR piglets. The expression of mRNAs for glycine-synthetic enzymes followed the patterns of enzymatic activities and was also low. Immunohistochemical analyses revealed the relatively low abundance of OH-POX protein in the liver, kidney, and small intestine of IUGR piglets, and the lack of OH-POX zonation in their livers. These novel results provide a metabolic basis to explain why the endogenous synthesis of glycine is insufficient for optimum growth of IUGR piglets and have important implications for improving the nutrition and health of other mammalian neonates including humans with IUGR.

Dietary Methionine Restriction Alleviates Hyperglycemia in Pigs with Intrauterine Growth Restriction by Enhancing Hepatic Protein Kinase B Signaling and Glycogen Synthesis

BackgroundIndividuals with intrauterine growth restriction (IUGR) are prone to developing type 2 diabetes mellitus (T2DM). Dietary methionine restriction (MR) improves insulin sensitivity and glucose homeostasis in individuals with normal birth weight (NBW). ObjectiveThis study investigated the effects of MR on plasma glucose concentration and hepatic and muscle glucose metabolism in pigs with IUGR. MethodsThirty female NBW and 60 same-sex spontaneous IUGR piglets (Landrace × Yorkshire) were selected. After weaning (day 21), the piglets were fed diets with adequate methionine (NBW-CON and IUGR-CON) or 30% less methionine (IUGR-MR) (n = 6). At day 180, 1 pig with a body weight near the mean of each replication was selected for biochemical analysis. ResultsThe IUGR-CON group showed 41.6%, 68.6%, and 67.1% higher plasma glucose concentration, hepatic phosphoenolpyruvate carboxykinase activity, and glucose-6-phosphatase activity, respectively, than the NBW-CON group (P < 0.05). Muscle glycogen content and glycogen synthase activity were 36.9% and 38.8% lower, respectively, in the IUGR-CON than the NBW-CON group (P < 0.05), respectively, and there was decreased hepatic and muscle protein kinase B phosphorylation in the IUGR-CON group (P < 0.05). Compared with the IUGR-CON pigs, the IUGR-MR pigs had 28.7% lower plasma glucose concentrations (P < 0.05), which were similar to those of the NBW-CON pigs (P ≥ 0.05). The hepatic glycogen content and glycogen synthase activity of the IUGR-MR pigs were 62.9% and 50.8% higher than those of the IUGR-CON pigs (P < 0.05) and 53.5% and 84.3% higher than the NBW-CON pigs (P < 0.05), respectively. The IUGR-MR pigs’ hepatic and muscle protein kinase B phosphorylation was higher than that of the IUGR-CON pigs (P < 0.05) and similar to that of the NBW-CON pigs (P ≥ 0.05). ConclusionsMR attenuates hyperglycemia in IUGR pigs by enhancing hepatic protein kinase B signaling and glycogen synthesis, implying a potential nutritional strategy to prevent type 2 diabetes mellitus in IUGR offspring.

Pituitary-Gland-Based Genes Participates in Intrauterine Growth Restriction in Piglets.

Intrauterine growth restriction (IUGR) is a major problem associated with piglet growth performance. The incidence of IUGR is widespread in Rongchang pigs. The pituitary gland is important for regulating growth and metabolism, and research has identified genes associated with growth and development. The pituitary gland of newborn piglets with normal birth weight (NBW group, n = 3) and (IUGR group, n = 3) was collected for transcriptome analysis. A total of 323 differentially expression genes (DEGs) were identified (|log2(fold-change)| > 1 and q value < 0.05), of which 223 were upregulated and 100 were downregulated. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that the DEGs were mainly related to the extracellular matrix, regulation of the multicellular organismal process, tissue development and angiogenesis, which participate in the growth and immune response in IUGR piglets. Moreover, 7 DEGs including IGF2, THBS1, ITGA1, ITGA8, EPSTI1, FOSB, and UCP2 were associated with growth and immune response. Furthermore, based on the interaction network analysis of the DEGs, two genes, IGF2 and THBS1, participated in cell proliferation, embryonic development and angiogenesis. IGF2 and THBS1 were also the main genes participating in the IUGR. This study identified the core genes involved in IUGR in piglets and provided a reference for exploring the effect of the pituitary gland on piglet growth.

Altered Liver Metabolism, Mitochondrial Function, Oxidative Status, and Inflammatory Response in Intrauterine Growth Restriction Piglets with Different Growth Patterns before Weaning.

Frequent occurrence of intrauterine growth restriction (IUGR) causes huge economic losses in the pig industry. Accelerated catch-up growth (CUG) in the early stage of life could restore multiple adverse outcomes of IUGR offspring; however, there is little knowledge about this beneficial phenomenon. We previously found that nutrient absorption related to intestinal function was globally promoted in CUG-IUGR piglets before weaning, which might be the dominant reason for CUG, but what this alteration could lead to in subsequent liver metabolism is still unknown. Firstly, a Normal, CUG, and non-catch-up growth (NCUG) piglet model before weaning was established by dividing eighty litters of newborn piglets into normal birth weight (NBW) and IUGR groups according to birth weight, and those piglets with IUGR but above-average weanling body weight were considered CUG, and the piglets with IUGR still below average body weight were considered NCUG at weaning day (d 26). Liver samples were collected and then systematically compared in glycolipid metabolism, mitochondrial function, antioxidant status, and inflammatory status among these three different growth models. Enhanced hepatic uptake of fatty acids, diminished de novo synthesis of fatty acids, and increased oxidation of fatty acids were observed in CUG livers compared to Normal and NCUG. In contrast, the NCUG liver showed enhanced glucose uptake and gluconeogenesis compared to Normal and CUG. We also observed deteriorating hepatic vacuolation in NCUG piglets, while increasing hepatic lipid deposition in CUG piglets. Besides, the expression of genes related to mitochondrial energy metabolism and biogenesis was reduced in CUG piglets and the phosphorylation level of AMPK was significantly higher compared to Normal (p < 0.05). Moreover, NCUG liver showed decreased T-AOC (p < 0.01) and GSH-PX (p < 0.05), increased MDA concentrations (p < 0.01), upregulated phosphorylation levels of ERK and NF-κB (p < 0.05), and elevated pro-inflammatory factors IL-1β, IL-6 and TNF-α (p < 0.05) compared to Normal. Furthermore, correlation analysis revealed a significant positive correlation between glucose metabolism and inflammatory factors, while a negative correlation between mitochondrial function-related genes and fatty acid transport. NGUG piglets showed simultaneous enhancement of glucose uptake and gluconeogenesis, as well as reduced antioxidant capacity and increased inflammatory status, whereas CUG comes at the expense of impaired hepatic mitochondrial function and pathological fat accumulation.

Integrative Analysis of Liver Metabolomics and Transcriptomics Reveals Oxidative Stress in Piglets with Intrauterine Growth Restriction.

Simple SummaryAlthough the correlation between oxidative stress and liver metabolic dysfunction has been established in piglets with intrauterine growth restriction, detailed information concerning the molecular mechanisms that facilitate this relationship remains limited. In the present study, metabolomic and transcriptomic techniques were used to investigate differences in gene expression and metabolites in the liver of piglets in intrauterine growth restriction and normal birth weight groups to systematically analyze the potential mechanism of metabolic characteristics induced by oxidative stress in the liver of intrauterine growth restriction piglets. Our results revealed that the intrauterine growth restriction piglets were involved in a variety of metabolic abnormalities, including mitochondrial dysfunction, imbalance of fatty acid composition, disruption to sources of one-carbon unit supply, and abnormal galactose conversion, which may be responsible for oxidative stress in the liver.The correlation between oxidative stress and liver metabolic dysfunction in piglets with intrauterine growth restriction (IUGR) remains limited. Therefore, the objective of the present study was to investigate potential mechanisms of metabolic characteristics induced by oxidative stress in the livers of IUGR piglets using metabolomic and transcriptomic analysis. Analysis of the phenotypic characteristics showed that the liver weight of the intrauterine growth restriction piglets was significantly lower than that of normal birth weight piglets. Intrauterine growth restriction piglets exhibited disordered hepatic cord arrangement and vacuolization as well as excessive lipid accumulation in hepatocytes. In addition, the activities of antioxidant enzymes were significantly decreased in the liver of the intrauterine growth restriction piglets, whereas the level of the lipid peroxidation marker MDA was significantly increased. Finally, our findings revealed that intrauterine growth restriction piglets were involved in a variety of metabolic abnormalities, including mitochondrial dysfunction, imbalance of fatty acid composition, disruption to sources of one-carbon unit supply, and abnormal galactose conversion, which may be responsible for oxidative stress in the liver. In summary, these data provided a detailed theoretical reference for revealing the hepatic metabolic characteristics of intrauterine growth restriction piglets.

Metabolome, microbiome, and gene expression alterations in the colon of newborn piglets with intrauterine growth restriction.

Newborn animals with intrauterine growth restriction (IUGR) are characterized by impaired intestinal structure and function; however, their intestinal microbiota and metabolome profiles have not been fully identified. The present study investigated the differences in colonic microbiota, metabolomics, and barrier function-related gene expression profiles between the IUGR and normal birth weight (NBW) piglets at 7, 21, and 28 days of age. Forty-eight piglets (24 NBW and 24 IUGR) from 24 litters were assigned to assess the differences in colonic microbiota, metabolomics, and gene expression between IUGR and NBW piglets. Compared with the NBW piglets, IUGR piglets showed decreased Shannon index and increased Simpson index at 7 days of age and Chao1 index at 21 days of age (p < 0.05). The IUGR piglets had lower abundances of Firmicutes, Subdoligranulum, Ruminococcaceae_UCG-002, and Ruminococcaceae_UCG-003 at 7 days of age, and Bacteroidetes, Phascolarctobacterium, and Ruminococcaceae_UCG-005 at 21 days of age, when compared with the NBW piglets (p < 0.05). Metabolomics analysis showed significant changes in 147 metabolites mainly involved in organic acids and their derivatives in the colon. Six differential metabolic pathways were significantly enriched, including purine metabolism, amino sugar/nucleotide sugar metabolism, ubiquinone/other terpenoid-quinone biosynthesis, phenylalanine/tyrosine/tryptophan biosynthesis, phenylalanine metabolism, and histidine metabolism. Spearman’s correlation analysis further demonstrated significant correlations between colonic microbiota and metabolites. In addition, colonic isobutyrate at 7 days of age, isovalerate and total short-chain fatty acids (SCFAs) at 21 days of age, and acetate, propionate, butyrate, and total SCFAs levels at 28 days of age were lower and isovalerate was higher at 28 days of age in the IUGR piglets than in the NBW piglets (p < 0.05). Furthermore, the mRNA expression of zonula occludens (ZO)-1 at 7 days of age, ZO-1, occludin, and interleukin (IL)-4 at 21 days of age were down-regulated in the IUGR piglets, whereas tumor necrosis factor (TNF)-α and nuclear factor-kappa B (NF-κB) at 28 days of age were up-regulated, when compared with the NBW piglets (p < 0.05). The findings suggest that the IUGR pigs present abnormal microbiota and nutrient metabolism in the colon, which may further affect the intestine barrier function by regulating gene expressions.

L-Leucine supplementation reduces growth performance accompanied by changed profiles of plasma amino acids and expression of jejunal amino acid transporters in breast-fed intra-uterine growth-retarded piglets.

Previously, we provided an evidence that l-Leucine supplementation facilitates growth performance in suckling piglets with normal birth weight. However, it remains hitherto obscure weather breast-fed piglets displaying intra-uterine growth restriction (IUGR) show a similar effect in response to l-Leucine provision. In this study, 7-d-old sow-reared IUGR piglets were orally administrated with l-Leucine (0, 0·7, 1·4 or 2·1 g/kg BW) twice daily for 2 weeks. Increasing leucine levels hampered the growth performance of suckling IUGR piglets. The average daily gain of IUGR piglets was significantly reduced in 1·4 g/kg BW and 2·1 g/kg BW l-Leucine supplementation groups (P < 0·05). Except for ornithine and glutamine, the plasma concentrations of other amino acids were abated as l-Leucine levels increased (P < 0·05). Leucine supplementation led to reduction in the levels of urea, blood ammonia, blood glucose, TAG and total cholesterol, as well as an elevation in the level of LDL-cholesterol in suckling IUGR piglets (P < 0·05). In addition, 1·4 g/kg BW of l-Leucine enhanced the mRNA expression of ATB0,+, whereas decreased the mRNA abundances of CAT1, y + LAT1, ASCT2 and b0,+AT in the jejunum (P < 0·05). Concomitantly, the jejunum of IUGR piglets in l-Leucine group contains more ATB0,+ and less SNAT2 protein than in the control (P < 0·05). Collectively, l-Leucine supplementation impairs growth performance in breast-fed IUGR piglets, which may be associated with depressed nutritional conditions and alterations in the uptake of amino acids and the expression of amino acid transporters in the small intestine.

Prenatal transcript levels and metabolomics analyses reveal metabolic changes associated with intrauterine growth restriction and sex.

The metabolic changes associated with intrauterine growth restriction (IUGR) particularly affect the liver, which is a central metabolic organ and contributes significantly to the provision of energy and specific nutrients and metabolites. Therefore, our aim was to decipher and elucidate the molecular pathways of developmental processes mediated by miRNAs and mRNAs, as well as the metabolome in fetal liver tissue in IUGR compared to appropriate for gestational age groups (AGA). Discordant siblings representing the extremes in fetal weight at day 63 post conception (dpc) were selected from F2 fetuses of a cross of German Landrace and Pietrain. Most of the changes in the liver of IUGR at midgestation involved various lipid metabolic pathways, both on transcript and metabolite levels, especially in the category of sphingolipids and phospholipids. Differentially expressed miRNAs, such as miR-34a, and their differentially expressed mRNA targets were identified. Sex-specific phenomena were observed at both the transcript and metabolite levels, particularly in male. This suggests that sex-specific adaptations in the metabolic system occur in the liver during midgestation (63 dpc). Our multi-omics network analysis reveals interactions and changes in the metabolic system associated with IUGR and identified an important biosignature that differs between IUGR and AGA piglets.

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-κB (NF-κB) network deteriorated in the ICON group compared to that in the NCON group. The small intestinal histological morphology and sub-organelle 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-κB 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-κB 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-κB pathway, thereby improving their unfavorable body state during the suckling period.

Preweaning performance in intrauterine growth-restricted piglets: Characteristics and interventions.

Intrauterine growth restriction (IUGR) is frequently observed in pig production, especially when using highly prolific sows. IUGR piglets are born with low body weight and shape indicative of differences in organ growth. Insufficient uteroplacental nutrient transfer to the fetuses is the leading cause of growth restriction in the pig. Supplementing the sow's gestation diet with arginine and/or glutamine improves placenta growth and functionality and consequently is able to reduce IUGR incidence. IUGR piglets are at higher risk of dying preweaning and face higher morbidity than their normal-weight littermates. A high level of surveillance during farrowing and individual nutrient supplementation can reduce the mortality rates. Still, these do not reverse the long-term consequences of IUGR, which are induced by persistent structural deficits in different organs. Dietary interventions peri-weaning can optimize performance but these are less effective in combating the metabolic changes that occurred in IUGR, which affect reproductive performance later in life. IUGR piglets share many similarities with IUGR infants, such as a poorer outcome of males. Using the IUGR piglet as an animal model to further explore the structural and molecular basis of the long-term consequences of IUGR and the potential sex bias could aid in fully understanding the impact of prenatal undernutrition and finding solutions for both species and sexes.

Intrauterine Growth-Restricted Piglets Are Predisposed to Develop Metabolic Disorders in Adulthood When Fed With Parenteral Nutrition in the Neonatal Period

ObjectivesTotal parenteral nutrition (TPN) is lifesaving yet non-normal nutrition regimen during the neonatal period. However, studies have shown that TPN feeding early in life can permanently alter metabolism at later ages. Moreover, intrauterine growth restricted (IUGR) neonates also have a higher risk of developing metabolic diseases (such as obesity and dyslipidemia) in later life. Because a substantial proportion of IUGR neonates receive TPN in early life, we wondered if the metabolic effects of feeding TPN early in life would exacerbate these effects of IUGR? We hypothesized that feeding TPN to IUGR neonates would aggravate the risk of developing obesity and dyslipidemia in adulthood.MethodsSixteen normal weight female piglets (7 d old) were randomized to sow-fed (SF) or early TPN (TPN-CON); 8 (IUGR or runt) piglets were fed TPN as a third group (TPN-IUGR). After 2 weeks of TPN or suckling, all pigs were fed a normal grower diet for 8 mo. At 8 mo, catheters were implanted and in vivo metabolic tests were conducted.ResultsTPN-IUGR pigs demonstrated catch-up growth by 4 mo, and body weights were not different among groups at 8 mo. The metabolic effects of feeding TPN persisted into adulthood, as indicated by higher postprandial plasma triglycerides (TG) and fasting plasma non-esterified fatty acids (NEFA), compared to SF (P < 0.05). IUGR exacerbated TPN-induced risk for diseases by worsening obesity outcomes with greater subcutaneous fat deposition (P < 0.05) and greater ectopic TG deposition in the liver (P < 0.05) and muscle (P < 0.05). Furthermore, IUGR led to dyslipidemia as indicated by higher cholesterol in fasted plasma LDL (P < 0.05), slower postprandial TG clearance (P < 0.05), higher fasting plasma NEFA (P < 0.001) and higher plasma dimethylglycine (P < 0.05), compared to the TPN-CON. IUGR pigs had greater VLDL secretion, as suggested by higher microsomal transfer protein mRNA (P < 0.05). Early TPN programmed reduced lipogenesis, as indicated by lower fatty acid synthase mRNA (P < 0.05), compared to SF.ConclusionsCollectively, these findings conclude that although TPN is a lifesaving measure, feeding TPN to IUGR neonates has long-term metabolic consequences predisposing them to develop metabolic disorders in adulthood.Funding SourcesCanadian Institutes of Health Research.