Unlike the full term vaginally delivered infant, the premature infant is unprepared to deal with initial colonization of the gut because of an underdeveloped mucosal immune system and thus is more susceptible to age-related gastrointestinal inflammatory diseases (e.g., necrotizing enterocolitis [NEC]). Accordingly a major research need is defining how these immaturities affect colonizing bacterial-intestinal "crosstalk". We have studied immaturities in intestinal host defense using established in vitro and ex vivo human models of intestinal development and have published that human fetal enterocytes respond with excessive (IL-8/IL-6) inflammation to stimuli (LPS, IL-1[3) and to both commensal and pathogenic bacteria. Recently we suggest that excessive inflammation may be due to a developmentally inappropriate expression of the enterocyte NFKB/MyD88 innate immune response genes and that intrauterine cortisone and postpartum probiotics may lessen the excessive IL-8 response by stimulating maturation of these genes. Accordingly, our overall hypothesis is that inappropriate/immature enterocyte inflammation in prematures after initial bacterial colonization may be caused by a developmentally disrupted expression of innate immune response genes and may be prevented by the trophic factor corticosteroids (HC) and/or anti-inflammatory secreted factor(s) in probiotics. To address this hypothesis, we will confirm that fetal primary enterocyte inflammation is due to a developmental expression of NFKB/MyD88 genes, determine if other inflammatory stimuli (TNF-a, IL-1p) and inflammatory pathways (e.g., NFKB/TRIF, etc.) are affected and if other known negative regulators of inflammation, simulated by commensal bacteria, are underexpressed. We will then determine if HC affects these developmentally under expressed genes specifically or has a generalized effect on enterocyte development and if clinically-proven probiotic secretions have an effect. This proposal in human models should provide the mechanistic basis for excessive inflammation in prematures and in vitro evidence for prevention leading eventually to an acceptable regime for preventing NEC.

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Massachusetts General Hospital
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