Understanding how infant factors shape the gut microbiome in preterm infants at risk of necrotising enterocolitis

Abstract

Very preterm infants born <32 weeks of gestation are at increased risk of various diseases such as necrotising enterocolitis (NEC), a devastating gastrointestinal disorder affecting up to 10% of preterm infants. Origins of NEC are multifactorial, associated with both a naïve immune system and disturbances to the gut microbiome. This thesis aimed to characterise the gut microbiome of preterm infants at risk of NEC and identify factors that may impact this development. Analysing longitudinal stool samples (n = 1431) from infants who did not develop NEC, revealed probiotics to be the main driver of the gut microbiota in this ‘healthy’ population, driving transition into different preterm gut community types (PGCTs) dependent on probiotic type. Functional analyses identified PGCT-associated stool metabolites and in pretermderived organoids, sterile faecal supernatants impacted intestinal organoid monolayer gene expression in a PGCT-specific manner. Comparing healthy infants to those who developed NEC (n = 75 infants, n = 547 samples) revealed that preceding diagnosis, the relative abundance of Proteobacteria such as Klebsiella variicola was higher whilst the relative abundance of Actinobacteria, mainly Bifidobacteria was lower, concordant with other studies. Exploring the microbial origins of NEC in the context of probiotics, both the type and administration of probiotics influenced microbial associations with NEC, in particular the colonisation patterns of different probiotic-associated strains. Finally, the complex relationship between temporal development of the gut microbiome, metabolome and circulating T-lymphocytes in the preterm population was characterised. Greatest concordance was found between the gut microbiome and metabolome, with little relationship observed between the gut environment and circulating T-lymphocytes. Together, the results described provide important insights into gut microbiome development in preterm infants during early life, the modifiable factors associated with modulation of the gut microbiome, and how this might be tailored to improve gut health.