Investigating microbiome-host interactions in the preterm gut using metagenomics and stem-cell derived enteroid "mini guts"

Preterm infants born <32 weeks gestation represent a unique population and are extremely vulnerable to sepsis and/or necrotising enterocolitis (NEC; inflammatory condition of the gut), with 30% of preterm infants developing one of these diseases. Leakiness of the intestinal epithelial barrier and immaturity of the intestinal epithelial immune response are implicated as key contributory factors. Furthermore, association-based studies have demonstrated that the gut microbiome (i.e., collection of microorganisms and their function) has important links to preterm health and disease. Specifically, recent evidence from our group suggests certain bacteria, such as Bifidobacterium, may increase maturation of mucosal immunity and provide protection from the onset of these diseases.

This project seeks to extensively characterise the preterm gut microbiome and to subsequently investigate how bacteria and preterm gut epithelial cells interact. This holds exciting possibilities to better predict, diagnose, and treat infants at risk of disease. This will be achieved through the following objectives:

1) Carry out metagenomic sequencing and bacterial isolation of stool from preterm infants and maternal breast milk.
2) Perform ex vivo co-culture of dominant preterm bacteria interact with intestinal epithelial cells, utilizing human enteroids ("mini guts") derived from patient stem cells.
3) Systematically explore how the different bacterial isolates and more holistic samples (e.g., breast milk) influence epithelial integrity and functioning. This will be determined using a wide range of cutting edge approaches including trans-epithelial electrical resistance, RNA-sequencing, quantitative PCR, metabolomics, mass cytometry, and microscopy.

This multi-disciplinary project combines wet-lab and computational elements based on state-of-the-art technologies. The clinically focused work incorporates both discovery and translational aspects.

The student will receive extensive training in metagenomic and transcriptomic sequencing, microbiology, metabolomics, tissue culture, stem cells, ex vivo modeling, cellular imaging, bioinformatics, statistics, and analytical techniques.