Project Summary/Abstract This proposal details a 5-year training plan to prepare the physician candidate, Thao (Tina) Ho, for a career as an independent, translational investigator who will become a leader in the field of iron deficiency and anemia of prematurity. The project will identify the effects of enteral iron supplementation, as prevention for anemia, on intestinal health of preterm infants through complementary clinical and basic science studies. All preterm infants are at risk for iron deficiency. Enteral iron supplementation is recommended to all preterm infants at 2-4 mg/kg/day; however, they are often given at higher doses, 6-10 mg/kg/day. Emerging evidence suggest that enteral iron can exacerbate the overgrowth of enteric pathogens and suppress beneficial bacteria. This imbalance, or intestinal dysbiosis, intestinal inflammation, and disrupted barrier are observed in necrotizing enterocolitis, a devastating intestinal disease of prematurity. Preterm infants are colonized with higher percentage of enteric pathogens at baseline compared to term infants. Dr. Ho’s preliminary data has led to the hypothesis that high enteral iron supplementation exacerbates intestinal dysbiosis, mucosal inflammation and permeability in preterm infants. Dr. Ho will test this hypothesis by conducting a randomized study to compare the fecal bacterial composition, mucosal inflammation and barrier function between premature infants given high vs. low iron regimens and investigating the cellular mechanisms with cytokine production and gene expression using human 3D enteroid models. At the completion of this project, Dr. Ho will be experienced in 1) designing and conducting clinical studies, 2) advanced biostatistical analyses and interpreting the results of large clinical datasets, and 3) performing experiments on 3D cell models. The candidate’s independent analytical thinking will grow with regular discussions among NIH-funded researchers and didactics provided by the University of South Florida. This award will allow her more protected time to develop necessary skills and collaboration to establish independence by the 4-5th year. Dr. Ho will work under the primary mentorship of Dr. Groer, an expert in translational microbiome and infant health research with many successful mentees. To complement her primary mentor, Dr. Ho’s mentoring team, Drs. Adams and Kim, will support her in cell culture techniques, microbiology, and genomics. Dr. Ho also has established a superb team of scientific advisors with the following expertise: Dr. Michael Georgieff (iron and neurodevelopment), Dr. Josef Neu (intestinal immunology), Dr. Sharon Donovan (childhood nutrition and intestinal microbiome), and Dr. Jason Spence (3D intestinal models). They have committed their time to her career development and research goals long before this application. Their mentorships, the fast-growing and supportive research environment at USF, the innovative research strategy, and a focused career development plan will provide a strong platform for Dr. Ho to secure an R01 to investigate the long-term health effects from different iron doses to optimize the prevention of iron deficiency and anemia of prematurity.

Iron deficiency is the most common single nutrient deficiency in the world and all preterm infants need enteral iron supplementation to prevent iron deficiency and iron deficiency anemia. Iron-rich environment can stimulate the growth of enteric pathogens and suppress the growth of beneficial bacteria. This project will clarify the effects of enteral iron supplementation on the developing microbiome and intestines in preterm infants and this knowledge will potentially impact not just the care of preterm infants but also the care of children, and adults with anemia.