PROJECT SUMMARY/ABSTRACT
Current nutritional strategies fail to meet the needs of very low birth weight infants, with more than half developing
malnutrition, growth failure, and other poor outcomes. Long Chain Polyunsaturated Fatty Acids (LCPUFAs) are
vital for brain and retinal development, immune function, inflammatory regulation, and health. Placental transfer
of LCPUFAs is highest in the third trimester, but this transfer abruptly stops upon premature birth. Current
nutritional strategies do not correct postnatal LCPUFA deficits. The Liver-Gut-Microbiome Axis regulates enteral
fat and fatty acid digestion, assimilation, and absorption. Gut bacteria metabolize intestinal lipids and secrete
molecules that alter lipid uptake and shape bile acid homeostasis via bile salt hydrolases and other microbial
enzymes. In turn, dietary fatty acids including LCPUFAs impact physiology both directly and by shaping gut
microbial community composition and function. It is unclear how immature gut microbiota and bile acids in VLBW
infants contribute to impaired fatty acid and LCPUFA absorption. We have shown that VLBW infants fed donor
milk have impaired growth and less alpha-diversity of gut microbiota than those fed maternal milk. We
hypothesize that impaired growth and decreased alpha-diversity is caused by the lack of intact lipase due to
pasteurization of donor milk and by impaired fatty acid absorption. We have shown that stool from cholestatic
VLBW infants with impaired growth contains less microbial bile salt hydrolase enzymatic activity, fewer
unconjugated fecal bile acids, and impaired secondary bile acid synthesis compared to VLBW infants without
cholestasis. Together, these results suggest an association between impaired fatty acid absorption, an immature
Liver-Gut-Microbiome Axis, and altered bile acid metabolism. We hypothesize that an immature Liver-Gut-
Microbiome Axis lacks key microbial bile acid modifying genes, resulting in altered bile acid composition
and impaired fatty acid and LCPUFAs absorption. Aim 1: Establish the longitudinal coefficient of fatty acid
absorption of key fatty acids in a prospective VLBW infant cohort. Coefficients of fat absorption (CFA) will be
calculated using GC-MS to measure different individual fatty acids from 72-hour dietary intakes and fecal losses.
We will use linear modeling to identify clinical determinants of CFA over time. Aim 2: Quantify relative
abundances of microbial bile acid modifying genes and activity and determine their impact on bile acid
composition and fatty acid absorption coefficients in preterm infants. Total and individual bile acid concentrations
in serum and stool from VLBW infants using MS. Microbial bile acid modifying genes will be identified in stool
using whole metagenome shotgun sequencing and gene copy numbers will be confirmed by qPCR. Bile salt
hydrolase enzyme activity will be quantified in vitro. Using state-of-the-art technologies and analytic tools, our
expert team will advance our understanding of gut microbial alterations, bile acid homeostasis, and fatty acid
absorption in VLBW infants to define novel mechanisms and future therapeutic targets to enhance nutrient
uptake and to improve fat absorption, growth, and health outcomes in VLBW infants.