[K08] Preventing necrotizing enterocolitis by optimization of human milk through prenatal dietary supplements

Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Scadenza: 2030-08-31

Importo max: $166,180

Paese: US

Descrizione

PROJECT SUMMARY Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disease which primarily affects premature infants and causes intestinal inflammation and necrosis. Despite decades of research, NEC remains a leading cause of neonatal morbidity and mortality. Premature infants are at risk of NEC, in part, because of an immature intestinal barrier, dysregulated immune response and microbial dysbiosis. While most NEC research has focused on neonatal factors, the role of antenatal factors, such as the maternal diet during pregnancy, on NEC are less clear. We demonstrated that the maternal diet during pregnancy has an enduring effect on the offspring’s susceptibility to intestinal injury. Our prior studies revealed that supplementing the diet of pregnant mice with the microbial metabolite butyrate, referred to as antenatal butyrate supplementation (ABS), enhances the offspring’s intestinal health. In murine models, ABS changes the adult offspring’s microbiome and attenuates gut inflammation in adult offspring with experimentally induced colitis. Our preliminary data demonstrates that ABS reduces injury in a murine model of neonatal intestinal inflammation, potentially through increased expression of TGF-β1 in the neonatal intestine. Cross-fostering experiments in mice suggest that ABS exerts its protective effects through modifications to the postnatal environment, such as changes to maternal milk or maternal microbiome composition. Notably, ABS also led to significantly higher levels of butyrate in breastmilk. Based on this preliminary data, we hypothesize that ABS attenuates NEC-like injury by increasing butyrate-producing bacteria in the maternal microbiome, thereby enhancing butyrate levels in maternal milk which promotes TGF- β1-mediated anti-inflammatory signaling in the neonatal intestine. This proposal aims to investigate the protective role of ABS in NEC pathogenesis and its underlying mechanisms. Specifically, we will 1) determine whether ABS is protective against murine models of NEC via TGF-β1 signaling and characterize the effects of ABS on butyrate levels and microbiome composition across the maternal-neonatal spectrum; and 2) evaluate the butyrate content in preterm human milk and assess its effect on preterm neonatal intestinal health. This proposal integrates murine NEC models, enteroid NEC models and gnotobiotics with translational analyses of preterm human milk and neonatal stool, providing critical insight into the role of butyrate in neonatal intestinal health. Support for this career development award is essential to my goal of becoming an independent physician-scientist investigating the role of microbial metabolites in NEC through pre-clinical and translational studies. Ultimately, this research will inform strategies for maternal dietary interventions, with the goal of preventing NEC in vulnerable preterm infants. Istituzione: EMORY UNIVERSITY PI: Maria Estefania Barbian Progetto: 1K08HD119290-01A1

Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development

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