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Title:Effects of 2ʹ-fucosyllactose on brain and cognitive development of intrauterine growth restricted piglets
Author(s):Williams, Jennifer Nicole
Advisor(s):Johnson, Rodney W
Contributor(s):Johnson, Rodney W; Holscher, Hannah D
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Intrauterine growth restriction (IUGR)
Small for gestational age (SGA)
Magnetic resonance imaging (MRI)
Ribonucleic acid (RNA)-sequencing
Abstract:Intrauterine growth restriction (IUGR) leads to small for gestational age (SGA) neonates, increasing risk of brain and cognitive impairments that persist into adulthood. Human milk oligosaccharides (HMO) have been postulated to exert positive effects on brain development. HMOs are the third most abundant solid component of breast milk with 2′-fucosyllactose (2′FL) being the most abundant HMO. We aimed to determine whether orally administered 2′FL enhances brain and cognitive development in small for gestational aged neonates. Sex-matched, littermate pairs of SGA (0.5-0.9kg) and appropriate for gestational age (AGA, 1.3-1.8kg) piglets were acquired on postnatal day (PD) 2, placed in individual cages, and divided into two diet groups. One group was provided a sow milk replacer diet (300ml/kg/d) while the other received the same diet supplemented with 2′FL (1.17g/L). On PD 14, spatial learning was assessed using a T-maze task, and on PD 28, brain macrostructure, microstructure, and hippocampal metabolites were assessed by magnetic resonance imaging. A sub-set of pigs was euthanized at PD14 and hippocampal tissue was dissected and used for RNA-sequencing. Body weight was different between SGA and AGA throughout the course of the study (p<0.05), with 2′FL having no effect. At PD 28, the brain-to-body-weight ratio of SGA piglets was greater than that of AGA piglets (p<0.0001), suggesting a “brain-sparing” effect during IUGR. The brain-to-body-weight ratio was not affected by 2′FL. Performance of all piglets during acquisition and reversal phases of the spatial T-maze task improved over time (p<0.0001), but SGA piglets reached criterion faster than AGA piglets (p<0.05), with no effect of diet. MRI revealed 12 brain regions (p<0.01) that were larger in AGA than SGA piglets. Furthermore, SGA piglets had less grey matter than AGA (p<0.001) in 4 subcortical regions and reduced whole brain fractional anisotropy (p<0.01) suggesting lower white matter integrity. No effects of 2′FL on brain structure were found. RNA-sequencing revealed 529 differentially expressed genes (DEGs) in hippocampal tissue (p<0.006). A total of 115 DEGs were identified in response to size, of which 62 were up-regulated and 53 were down-regulated in SGA piglets compared to AGA piglets. Up-regulated genes in SGA piglets were associated with chromatin silencing, DNA binding, nuclear chromatin, and the nucleosome; and down-regulated genes in SGA piglets were associated with KEGG pathways for measles, influenza A, hepatitis C, and herpes simplex infection. A main effect of diet revealed 252 DEGs, of which 144 up-regulated and 108 down-regulated genes in 2′FL piglets compared to CON. Genes that were up-regulated in response to 2′FL were connected to integral components of membranes and transmembrane helix, while down-regulated genes were clustered based on ion channel and transport, zinc ion binding, zinc-finger, and metal-binding. Finally, in the size by diet interaction, there were no clusters discovered as a result of up-regulated gene expression, however, down-regulated genes were associated with transmembrane helix, membranes, and integral components of membrane. Collectively, the results show that neonates born SGA have altered brain structure and hippocampal gene expression. While 2′FL did not have measurable effects on brain structure or spatial learning in either SGA or AGA piglets, it elicited a distinct gene expression profile in the hippocampus suggesting epigenetic modifications that may contribute to development and function.
Issue Date:2017-07-21
Rights Information:Copyright 2017 Jennifer Williams
Date Available in IDEALS:2018-03-02
Date Deposited:2017-08

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