Investigating diet-microbe-host interaction in preterm infants at risk of necrotising enterocolitis

Abstract

Necrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants born <32 weeks gestation. The underlying mechanisms are poorly understood, but mothers own breast milk (MOM) and infant gut microbiome play a role. In MOM, human milk oligosaccharides (HMOs) influence the infant health in multiple ways, including shaping infant gut colonisation by potentially beneficial bacteria (mainly bifidobacteria). In the infant gut, a lack of colonisation with bifidobacteria, coupled with a community rich in Pseudomonadota, have been associated with NEC development. In this thesis, the interaction between HMO profiles and infant gut microbiome in NEC was investigated. To further understand the potential mechanism of HMOs in promoting infant health, basic microbiology and an experimental preterm intestinal-derived organoid model were employed. It was hypothesised that the HMO and bacterial profiles in MOM given to NEC infants would differ from healthy infants, and that these differences would be associated with the infant gut microbiome. The results confirmed and expanded upon previous work, finding that the concentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by NEC infants compared to controls. No difference in the microbiome of MOM was observed between mothers whose infants developed NEC or not, while infants receiving low MOM DSLNT were associated with reduced transition into preterm gut community types dominated by Bifidobacterium spp. Numerous bifidobacteria isolated from preterm infants showed growth in vitro on selected HMOs, however, only a B. bifidum isolate could metabolise DSLNT. Finally, the interaction between selected HMOs and preterm intestinal-derived organoids from NEC and non-NEC tissue was investigated, finding differences in specific genes involved in cell differentiation and proliferation. This work provides new insights into the interaction between MOM, infant gut microbiome and the intestine in preterm infants with association to NEC development.