Development of the preterm gut microbiota in infants at risk of necrotising enterocolitis and sepsis

Stewart, Christopher (2014) Development of the preterm gut microbiota in infants at risk of necrotising enterocolitis and sepsis. Doctoral thesis, Northumbria University.

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Abstract

The gut microbiota comprises all the microorganisms colonising the gastrointestinal tract. It is a complex and dynamic community influenced by genetic and environmental factors. While the gut microbiota has crucial roles in micronutrient production and immunomodulation, it has also been associated with necrotising enterocolitis (NEC) and sepsis in preterm infants, which can exist exclusively or concurrently. As the number of babies born preterm continues to rise, so too will the incidence of these disease states. Exploring the development of the preterm gut microbiota longitudinally may offer important insights into the role of modern clinical practises in shaping the community and its subsequent role in disease pathogenesis.

To explore the development of the preterm gut microbiota we compared routine culture data with denaturing gradient gel electrophoresis (DGGE). Both techniques revealed differential profiles between patients with NEC and sepsis, compared to healthy controls. This was due, in part, to an increased abundance of Staphylococcus spp. identified in patients with NEC and sepsis. Based on these findings we explored the differential community development utilising a more extensive molecular approach, advancing on previous studies by exploring both the bacterial and fungal communities and also exploring the viability of each organism. For the fungal community, only non-viable fungal species were detected but showed no significant association with NEC or sepsis. Conversely, the viable bacterial community largely corresponded to that of the total community and showed Sphingomonas sp. was significantly associated with NEC. Interestingly, antifungal treatment had a significantly effect on the bacterial community and antibiotics limited the bacterial diversity which may have important consequences in the pathogenesis of disease.

We further analysed a twin cohort to investigate the role of host genetics in influencing the development of the gut microbiota and the subsequent risk of disease. Twins showed comparable gut microbiota development with antibiotics attributable for major shifts in the community. A twin discordant for NEC showed a reduction in diversity and prevalence of an Escherichia sp. prior to the diagnosis which was not observed in the control twin. To further explore the discrepancies in the organisms associated with NEC and sepsis, overcoming the limitations of previous studies, we utilised next generation sequencing (NGS) in a large cohort with regular sampling pre and post disease diagnosis, matched to controls. Gestational age was shown to have important influences on the community development. No consistent associations between reduced diversity or increased dominance prior to disease diagnosis were observed, although Escherichia coli was prevalent prior to diagnosis of NEC. The organism identified in sepsis cases was present in the gut microbiota and was usually a dominant member. A diverse community seems to be important to the health of a neonate supporting the notion that a stable and diverse gut microbiota is important for preterm neonatal health.

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