Effects of 2ʹ-fucosyllactose on brain and cognitive development of intrauterine growth restricted piglets

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