Branched Chain FA and Gut Development

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DESCRIPTION (provided by applicant): Branched chain fatty acids (BCFA) containing lipids are unusual in most human tissue, but they con- stitute 25-30% of the dry weight of vernix caseosa. The fetus swallows amniotic fluid, and in the late term it contains sloughed vernix particles. The biological significance of the GI tract's exposure to BCFA has not been investigated. We have recently demonstrated, for the first time, that meconium contains BCFA that differ in chain length and branching from the same infant's vernix. Importantly, this shows that BCFA are native to the newborn GI tract throughout its length, and that BCFA are actively and specifically metabolized by the late term fetus; thus, BCFA are metabolically ac- tive. There is virtually nothing known about this metabolism. BCFA are also known to be compo- nents of breast milk, thus exposing the breastfed infant GI tract to BCFA as bacteria colonize and microflora develops. Importantly, BCFA are not normal components of infant formulas since, for most, their lipids are derived from vegetable oils. The GI tract of premature infants born at 24-30 weeks of gestation is not exposed to BCFA because vernix concentrations in the amniotic fluid are low, and premature infant formulas contain no BCFA. These infants are at highest risk of developing necrotizing enterocolitis (NEC), a life-threatening condition affecting 10% of premature infants. Among other factors, NEC is associated with pathogenic bacterial infection rather than colonization by normal flora. BCFA are major components (>95%) of the membranes of many bacteria. We pro- pose here to explore the role of BCFA in the GI tract with consideration to the development of NEC with in vitro and in vivo models: 1) Establish how enterocytes interact with BCFA in vitro, using the Caco-2 model. BCFA uptake and excretion, incorporation into cell membrane lipids, trans- formation (elongation/chain shortening), and effects on cell proliferation and health will be studied. Exon arrays will evaluate differential gene expression to scan the entire genome. 2) Study the influ- ence of BCFA on development of NEC in the ischemic rat pup in vivo. Cecal contents will be studied by meta-genomic methods to evaluate shifts in GI tract microbial ecology due to BCFA. Relevance to human health: Normal development of the gut and its postnatal colonization with nor- mal flora are crucial to general gut health and to avoiding NEC. BCFA, a major component of the normal GI tract of human infants, may be a low risk treatment to avoid NEC, and may also have therapeutic value at other stages of the life cycle. For instance, BCFA may prove useful for those in- dividuals requiring repeated antibiotic treatments such as the elderly or those with chronic conditions, whose GI tracts are repeatedly recolonized. PUBLIC HEALTH RELEVANCE: We recently showed that the profile of branched chain fatty acids (BCFA) in vernix and meconium in term newborn differ in systematic ways, indicating that BCFA are actively metabolized by enterocytes in the late term fetus. The proposed research seeks to experimentally explore BCFA metabolism and its role in the developing GI tract using an in vitro Caco-2 cell model, and an in vivo rat pup NEC model.