Liver-Gut-Microbiome Axis and Fatty acid absorption in Preterm Infants

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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.