Milk Osteopontin for Gut, Immunity and Brain Development in Preterm Pigs.
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ABSTRACT:
SUBMITTER: Aasmul-Olsen K
PROVIDER: S-EPMC8400468 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human milk is rich in nutritional factors, such as alpha-lactalbumin (?-Lac), and important for neonatal development, but nutrient supplementation may be required for optimal growth. Using a pig model, we hypothesized that ?-Lac-enriched whey protein concentrate (WPC) supplementation improves neonatal development. Cesarean-delivered preterm pigs were fed either dilute bovine milk (REF) or REF milk supplemented with WPC with normal (STANDARD-ALPHA) or high (HIGH-ALPHA) ?-Lac. Clinical, gut, immune and cognitive endpoints (open field, T-maze) were assessed and tissues collected at Day 19. The growth of STANDARD-ALPHA and HIGH-ALPHA were higher than REF (31 vs. 19 g/kg/d). Most organ weights, gut, immunity and brain variables were similar between WPC groups. HIGH-ALPHA had a higher bone mineral content, colon microbial diversity and an abundance of specific bacteria and microbial metabolites, and tended to show a faster food transit time (p = 0.07). Relative to REF, WPC pigs showed higher relative organ weights, blood amino acids, blood neutrophil function, and microbial metabolites, but lower brush-border enzyme activities and plasma cortisol. Cognition outcomes did not differ among the groups. In conclusion, WPC supplementation of milk improved some growth, gut and immunity parameters in preterm pigs. However, increasing the ?-Lac content beyond human milk levels had limited effects on the immature gut and developing brain.
| S-EPMC7020014 | biostudies-literature
Project description:Chorioamnionitis (CA), resulting from intra-amniotic inflammation, is a frequent cause of preterm birth and exposes the immature intestine to bacterial toxins and/or inflammatory mediators before birth via fetal swallowing. This may affect intestinal immune development, interacting with the effects of enteral feeding and gut microbiota colonization just after birth. Using preterm pigs as model for preterm infants, we hypothesized that prenatal exposure to gram-negative endotoxin influences postnatal bacterial colonization and gut immune development. Pig fetuses were given intra-amniotic lipopolysaccharide (LPS) 3 days before preterm delivery by cesarean section and were compared with littermate controls (CON) at birth and after 5 days of formula feeding and spontaneous bacterial colonization. Amniotic fluid was collected for analysis of leukocyte counts and cytokines, and the distal small intestine was analyzed for endotoxin level, morphology, and immune cell counts. Intestinal gene expression and microbiota were analyzed by transcriptomics and metagenomics, respectively. At birth, LPS-exposed pigs showed higher intestinal endotoxin, neutrophil/macrophage density, and shorter villi. About 1.0% of intestinal genes were affected at birth, and DMBT1, a regulator of mucosal immune defense, was identified as the hub gene in the co-expression network. Genes related to innate immune response (TLR2, LBP, CD14, C3, SFTPD), neutrophil chemotaxis (C5AR1, CSF3R, CCL5), and antigen processing (MHC II genes and CD4) were also affected, and expression levels correlated with intestinal neutrophil/macrophage density and amniotic fluid cytokine levels. On day 5, LPS and CON pigs showed similar sensitivity to necrotizing enterocolitis, endotoxin levels, morphology, immune cell counts, gene expressions, and microbiota composition (except for difference in some low-abundant species). Our results show that CA markedly affects intestinal genes at preterm birth, including genes related to immune cell infiltration. However, a few days later, following the physiological adaptations to preterm birth, CA had limited effects on intestinal structure, function, gene expression, bacterial colonization, and necrotizing enterocolitis sensitivity. We conclude that short-term, prenatal intra-amniotic inflammation is unlikely to exert marked effects on intestinal immune development in preterm neonates beyond the immediate neonatal period.
| S-EPMC7098537 | biostudies-literature
Project description:Preterm neonates are highly sensitive to systemic infections in early life but little is known about systemic immune development following preterm birth. We hypothesized that preterm neonates have immature systemic immunity with distinct developmental trajectory for the first several weeks of life, relative to those born at near-term or term. Using pigs as a model, we characterized blood leukocyte subsets, antimicrobial activities and TLR-mediated cytokine production during the first weeks after preterm birth. Relative to near-term and term pigs, newborn preterm pigs had low blood leukocyte counts, poor neutrophil phagocytic rate, and limited cytokine responses to TLR1/2/5/7/9 and NOD1/2 agonists. The preterm systemic responses remained immature during the first postnatal week, but thereafter showed increased blood leukocyte numbers, NK cell proportion, neutrophil phagocytic rate and TLR2-mediated IL-6 and TNF-α production. These immune parameters remained different between preterm and near-term pigs at 2-3 weeks, even when adjusted for post-conceptional age. Our data suggest that systemic immunity follows a distinct developmental trajectory following preterm birth that may be influenced by postnatal age, complications of prematurity and environmental factors. Consequently, the immediate postnatal period may represent a window of opportunity to improve innate immunity in preterm neonates by medical, antimicrobial or dietary interventions.
| S-EPMC5103294 | biostudies-literature
Project description:Optimal nutrition is important after preterm birth to facilitate normal brain development. Human milk is rich in sialic acid and preterm infants may benefit from supplementing formula with sialyllactose to support neurodevelopment. Using pigs as models, we hypothesized that sialyllactose supplementation improves brain development after preterm birth. Pigs (of either sex) were delivered by cesarean section at 90% gestation and fed a milk diet supplemented with either an oligosaccharide-enriched whey with sialyllactose (n = 20) or lactose (n = 20) for 19 days. Cognitive performance was tested in a spatial T-maze. Brains were collected for ex vivo magnetic resonance imaging (MRI), gene expression, and sialic acid measurements. For reference, term piglets (n = 14) were artificially reared under identical conditions and compared with vaginally born piglets naturally reared by the sow (n = 12). A higher proportion of sialyllactose supplemented preterm pigs reached the T-maze learning criteria relative to control preterm pigs (p < 0.05), and approximated the cognition level of term reference pigs (p < 0.01). Furthermore, supplemented pigs had upregulated genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in hippocampus. Sialyllactose supplementation did not lead to higher levels of sialic acid in the hippocampus or change MRI endpoints. Contrary, these parameters were strongly influenced by postconceptional age and postnatal rearing conditions. In conclusion, oligosaccharide-enriched whey with sialyllactose improved spatial cognition, with effects on hippocampal genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in preterm pigs. Dietary sialic acid enrichment may improve brain development in infants.
| S-EPMC6628371 | biostudies-literature
Project description:Background: Preterm infants are exposed to different dietary inputs during their hospitalization in the neonatal intensive care unit (NICU). These include human milk (HM), with a human milk-based (HMF) or a bovine milk-based (BMF) fortifier, or formula. Milk consumption and the type of fortification will cause changes in the gut microbiota structure of preterm infants. This study aimed to characterize the gut microbiota of PT infant according to the type of feeding and the type of HM fortification and its possible association with infant's growth. Methods: Ninety-seven infants born ≤33 wks of gestation or <1,500 g were followed during the hospitalization period in the NICU after birth until discharge. Clinical and dietary information was collected, including mode of delivery, pregnancy complications, mechanical ventilation, use of antibiotics, weight, and type and amount of milk consumed. To characterize the gut microbiota composition, weekly stool samples were collected from study participants. The V3-V4 region of the 16S rRNA bacterial gene was Sequenced using Illumina MiSeq technology. Results: After birth, black maternal race, corrected gestational age (GA) and exposure to pregnancy complications, had a significant effect on gut microbial diversity and the abundance of Enterococcus, Veillonella, Bifidobacterium, Enterobacter, and Bacteroides. Over the course of hospitalization, corrected GA and exposure to chorioamnionitis remained to have an effect on gut microbial composition. Two different enterotypes were found in the gut microbiota of preterm infants. One enriched in Escherichia-Shigella, and another enriched in uncharacterized Enterobacteriaceae, Klebsiella and Clostridium sensu stricto 1. Overall, HM and fortification with HMF were the most common feeding strategies. When consuming BMF, PT infants had higher growth rates than those consuming HMF. Milk and type of fortification were significantly associated with the abundance of Clostridium sensu stricto 1, Bifidobacterium and Lactobacillus. Conclusions: This observational study shows the significant association between milk consumption and the exposure to HMF or BMF fortification in the fecal microbiota composition of preterm infants. Additionally, these results show the effect of other perinatal factors in the establishment and development of PT infant's gut microbiota.
| S-EPMC8669825 | biostudies-literature
Project description:Background: After very preterm birth, male infants show higher mortality than females, with higher incidence of lung immaturity, neurological deficits, infections, and growth failure. In modern pig production, piglets dying in the perinatal period (up to 20%) often show signs of immature organs, but sex-specific effects are not clear. Using preterm pigs as model for immature infants and piglets, we hypothesized that neonatal survival and initial growth and immune development depend on sex. Methods: Using data from a series of previous intervention trials with similar delivery and rearing procedures, we established three cohorts of preterm pigs (90% gestation), reared for 5, 9, or 19 days before sample collection (total n = 1,938 piglets from 109 litters). Partly overlapping endpoints among experiments allowed for multiple comparisons between males and females for data on mortality, body and organ growth, gut, immunity, and brain function. Results: Within the first 2 days, males showed higher mortality than females (18 vs. 8%, P < 0.001), but less severe immune response to gram-positive infection. No effect of sex was observed for thermoregulation or plasma cortisol. Later, infection resistance did not differ between sexes, but growth rate was reduced for body (up to -40%) and kidneys (-6%) in males, with higher leucocyte counts (+15%) and lower CD4 T cell fraction (-5%) on day 9 and lower monocyte counts (-18%, day 19, all P < 0.05). Gut structure, function and necrotizing enterocolitis (NEC) incidence were similar between groups, but intestinal weight (-3%) and brush-border enzyme activities were reduced at day 5 (lactase, DPP IV, -8%) in males. Remaining values for blood biochemistry, hematology, bone density, regional brain weights, and visual memory (tested in a T maze) were similar. Conclusion: Following preterm birth, male pigs show higher mortality and slower growth than females, despite limited differences in organ growth, gut, immune, and brain functions. Neonatal intensive care procedures may be particularly important for compromised newborns of the male sex. Preterm pigs can serve as good models to study the interactions of sex- and maturation-specific survival and physiological adaptation in mammals.
| S-EPMC7905020 | biostudies-literature
Project description:Preterm microbial colonization is affected by gestational age, antibiotic treatment, type of birth, but also by type of feeding. Breast milk has been acknowledged as the gold standard for human nutrition. In preterm infants breast milk has been associated with improved growth and cognitive development and a reduced risk of necrotizing enterocolitis and late onset sepsis. In the absence of their mother's own milk (MOM), pasteurized donor human milk (DHM) could be the best available alternative due to its similarity to the former. However, little is known about the effect of DHM upon preterm microbiota and potential biological implications. Our objective was to determine the impact of DHM upon preterm gut microbiota admitted in a referral neonatal intensive care unit (NICU). A prospective observational cohort study in NICU of 69 neonates <32 weeks of gestation and with a birth weight ≤1,500 g was conducted. Neonates were classified in three groups according to feeding practices consisting in their MOM, DHM, or formula. Fecal samples were collected when full enteral feeding (defined as ≥150 cc/kg/day) was achieved. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Despite the higher variability, no differences in microbial diversity and richness were found, although feeding type significantly influenced the preterm microbiota composition and predictive functional profiles. Preterm infants fed MOM showed a significant greater presence of Bifidobacteriaceae and lower of Staphylococcaceae, Clostridiaceae, and Pasteurellaceae compared to preterm fed DHM. Formula fed microbial profile was different to those observed in preterm fed MOM. Remarkably, preterm infants fed DHM showed closer microbial profiles to preterm fed their MOM. Inferred metagenomic analyses showed higher presence of Bifidobacterium genus in mother's milk group was related to enrichment in the Glycan biosynthesis and metabolism pathway that was not identified in the DHM or in the formula fed groups. In conclusion, DHM favors an intestinal microbiome more similar to MOM than formula despite the differences between MOM and DHM. This may have potential beneficial long-term effects on intestinal functionality, immune system, and metabolic activities.
| S-EPMC6030370 | biostudies-literature
Project description:Background: Infants born preterm or small for gestational age (SGA, due to fetal growth restriction) both show an increased risk of neonatal infection. However, it remains unclear how the co-occurrence of preterm birth and SGA may affect neonatal immunity and infection risk. We hypothesized that fetal growth restricted (FGR) preterm newborns possess impaired immune competence and increased susceptibility to systemic infection and sepsis, relative to corresponding normal birth weight (NBW) newborns. Methods: Using preterm pigs as a model for preterm infants, gene expression in lipopolysaccharide (LPS) stimulated cord blood was compared between NBW and FGR (lowest 25% birth weight percentile) preterm pigs. Next, clinical responses to a systemic Staphylococcus epidermidis (SE) challenge were investigated in newborn FGR and NBW preterm pigs. Finally, occurrence of spontaneous infections were investigated in 9 d-old FGR and NBW preterm pigs, with or without neonatal antibiotics treatment. Results: At birth, preterm FGR piglets showed diminished ex vivo cord blood responses to LPS for genes related to both innate and adaptive immunity, and also more severe septic responses following SE infection (e.g., higher blood lactate, decreased blood pH, neutrophil and platelet counts, relative to NBW pigs). After 9 d, FGR pigs had higher incidence and severity of spontaneous infections (e.g., higher bacterial densities in the bone marrow), increased regulatory T cell numbers, reduced neutrophil phagocytosis capacity, and impaired ex vivo blood gene responses to LPS, especially when receiving neonatal antibiotics. Conclusion: FGR at preterm birth is associated with poor immune competence, impaired infection resistance, and greater sepsis susceptibility in the immediate postnatal period. Our results may explain the increased morbidity and mortality of SGA preterm infants and highlight the need for clinical vigilance for this highly sensitive subgroup of preterm neonates.
| S-EPMC7438575 | biostudies-literature
Project description:BACKGROUND:Necrotizing enterocolitis (NEC) is an acute gut inflammatory disorder that occurs in preterm infants in the first weeks after birth. Infants surviving NEC often show impaired neurodevelopment. The mechanisms linking NEC lesions with later neurodevelopment are poorly understood but may include proinflammatory signaling in the immature brain. Using preterm pigs as a model for preterm infants, we hypothesized that severe intestinal NEC lesions are associated with acute effects on the developing hippocampus. METHODS:Cesarean-delivered preterm pigs (n?=?117) were reared for 8 days and spontaneously developed variable severity of NEC lesions. Neonatal arousal, physical activity, and in vitro neuritogenic effects of cerebrospinal fluid (CSF) were investigated in pigs showing NEC lesions in the colon (Co-NEC) or in the small intestine (Si-NEC). Hippocampal transcriptome analysis and qPCR were used to assess gene expressions and their relation to biological processes, including neuroinflammation, and neural plasticity. Microglia activation was quantified by stereology. The neuritogenic response to selected proteins was investigated in primary cultures of hippocampal neurons. RESULTS:NEC development rapidly reduced the physical activity of pigs, especially when lesions occurred in the small intestine. Si-NEC and Co-NEC were associated with 27 and 12 hippocampal differentially expressed genes (DEGs), respectively. These included genes related to neuroinflammation (i.e., S100A8, S100A9, IL8, IL6, MMP8, SAA, TAGLN2) and hypoxia (i.e., PDK4, IER3, TXNIP, AGER), and they were all upregulated in Si-NEC pigs. Genes related to protection against oxidative stress (HBB, ALAS2) and oligodendrocytes (OPALIN) were downregulated in Si-NEC pigs. CSF collected from NEC pigs promoted neurite outgrowth in vitro, and the S100A9 and S100A8/S100A9 proteins may mediate the neuritogenic effects of NEC-related CSF on hippocampal neurons. NEC lesions did not affect total microglial cell number but markedly increased the proportion of Iba1-positive amoeboid microglial cells. CONCLUSIONS:NEC lesions, especially when present in the small intestine, are associated with changes to hippocampal gene expression that potentially mediate neuroinflammation and disturbed neural circuit formation via enhanced neuronal differentiation. Early brain-protective interventions may be critical for preterm infants affected by intestinal NEC lesions to reduce their later neurological dysfunctions.
| S-EPMC5994241 | biostudies-literature
Project description:The aim of current study was to determine variations in sow's gut microbiota, serum immunity, and milk metabolite profile mediated by lysozyme supplementation. Twenty-four pregnant sows were assigned to a control group without supplementation and two treatments with 0.5 kg/t and 1.0 kg/t lysozyme provided in formula feed for 21 days (n = 8 per treatment). Microbiota analysis and metagenomic predictions were based on 16s RNA high-throughput sequencing. Milk metabolome was assessed by untargeted liquid chromatography tandem mass spectrometry. Serum biochemical indicators and immunoglobulins were also determined. Gut microbial diversity of sows receiving 1.0 kg/t lysozyme treatment was significantly reduced after the trial. Spirochaetes, Euryarchaeota, and Actinobacteria significantly increased while Firmicutes showed a remarkable reduction in 1.0 kg/t group compared with control. Lysozyme addition rebuilt sow's gut microbiota to beneficial composition identified by reduced richness of Escherichia coli and increased abundance of Lactobacillus amylovorus. Accordingly, microbial metabolic functions including pyrimidine metabolism, purine metabolism, and amino acid related enzymes were significantly up-regulated in 1.0 kg/t group. Microbial metabolic phenotypes like the richness of Gram-positive bacteria and oxidative stress tolerance were also significantly reduced by lysozyme treatment. Serum alanine transaminase (ALT) activity and IgA levels were significantly down-regulated in the 1.0 kg/t group compared with control, but IgM levels showed a significantly increase in 1.0 kg/t group. Milk metabolites such as L-glutamine, creatine, and L-arginine showed significantly dose-dependent changes after treatment. Overall, lysozyme supplementation could effectively improve the composition, metabolic functions, and phenotypes of sow's gut microbiota and it also benefit sows with better serum immunity and milk composition. This research could provide theoretical support for further application of lysozyme in promoting animal gut health and prevent pathogenic infections in livestock production.
| S-EPMC6373202 | biostudies-literature