Mechanistic investigation of human milk feeding on neurodevelopment: a comparative study using neonatal piglets and translatable biomarkers

SUMMARY/ABSTRACT Approximately 10% of all infants are born prematurely, and up to 50% of preterm infants experience neurodevelopmental delays/disorders. Prematurity is associated with smaller brain regions that are correlated with lower developmental scores. Moreover, up to 75% preterm infants experience systemic inflammation that

is also associated with lower developmental scores and brain white matter injury. In contrast, human milk (HM) feeding is associated with better neurodevelopment in both term and preterm infants. Current literature suggests both prematurity and neonatal inflammation may contribute to neurodevelopmental hindrance. This study will be

the first to examine the molecular mechanisms of how HM affects the gut-brain axis (intestinal, systemic, and brain inflammation) and to validate relevant human biomarkers for clinical use. There is a critical need to determine how HM improves neurocognitive outcomes to inform clinical practice guidelines.

The long-term goal is to elucidate the molecular mechanisms behind how HM improves neurodevelopment in

preterm infants. The overall objective is to determine the effects of different early-life feedings on intestinal barrier function; intestinal, systemic, and brain inflammation; and neurocognitive development using the high homology neonatal piglet model and validate relevant non-invasive human biomarkers. The central hypothesis is that

early HM feeding preserves intestinal barrier function and reduces intestinal, systemic, and brain inflammation thus improving neurocognitive development. The approach will use a clinically relevant piglet model to 1) compare intestinal growth, inflammation, and barrier function between HM and infant formula (IF) feedings; 2)

assess systemic inflammatory differences between feeding groups; and 3) determine neurocognitive function, brain growth, and neuroinflammation as a function of the feeding groups. This research is innovative because it will be the first study to combine functional, histological, and molecular methods to directly examine the complex mechanisms of how different feeding regimens affect interrelationships

between the intestinal, systemic, and neurological systems in relation to neurodevelopment without the common confounding factors in human observational studies. Further, this research will validate non-invasive human biomarkers to enhance research translation. The expectation is to determine the direct effects of HM and IF

feedings at the intestinal, systemic, and brain levels, and whether these feedings modify intestinal barrier function, immune tissue development, and neurodevelopment. The critical knowledge gained from this study will positively impact the field by directing subsequent research and shaping clinical practice guidelines with evidence

to optimize early feeding that may significantly impact the infant’s ability to: 1) fight systemic inflammation, and 2) mitigate long-term neurodevelopmental deficits. The results from this proposed research will also provide useful non-invasive biomarkers to help monitor developmental and inflammatory status of the infants while

modifying feeding mixtures to ensure achievement of optimal developmental outcomes.