Determining the influence of diet and the gut microbiome in preterm infant health and disease

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Preterm infants born <32 weeks gestation are 'immature' physiologically, anatomically and immunologically. Around 10% will develop necrotising enterocolitis (NEC), an inflammatory mediated bowel disease and 20% will develop late onset sepsis. Abnormal gut microbiome development and diet are integral to pathogenesis of both diseases. Breast milk contains a range of components that can modulate microbiome development, including an abundance of human milk oligosaccharides (HMOs), which can act as growth substrates for probiotic bacteria. The project will be based on preterm infant health and disease, but within this area there is flexibility in what the student can focus on, which can be modified as the project progresses. Some key objectives are likely to include: 1) Investigate the influence of maternal milk or donor milk on the preterm gut microbiome and risk of developing NEC and/or late onset sepsis 2) Experimentally test how mothers own milk, donor human breast milk, and preterm formula impact host function using a tissue-derived organoid model that recapitulates the preterm gut epithelium 3) Determine if novel therapeutics can modulate the preterm gut microbiome and host function toward a state associated with health The student will work closely with academic and clinical supervisors and will have access to the Great North Neonatal Biobank, containing >10,000 breast milk and >30,000 preterm stool samples. They will perform metagenomic sequencing to longitudinally profile the microbiome in these important samples, alongside directly microbiological culture of bacterial isolates. The student will also establish preterm tissue-derived organoids (i.e., enteroids) from resected tissue, and use these to test how the different dietary components impact host function at the epithelial surface under a physiologically relevant oxygen gradient. This will include co-culture of donor milk, formula, and breast milk, as well as specific components including HMOs and bacterial species previously isolated. The clinically focused work incorporates both discovery and translational aspects. During the course of this interdisciplinary project, the student will gain a wide range of relevant experience in wet-lab techniques such as microbiology, molecular biology, tissue culture, transcriptomics (host), metatranscriptomics (bacteria), alongside computational skills including the bioinformatic and statistical analysis of large multi-omic datasets.