Establishment of the microbiome in the context of neonatal sepsis – effects on long-term vulnerability of preterm infants with a birth weight < 1500g

• Applicant: Professor Dr. Christoph Härtel
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428687216

Preterm infants with a birth weight < 1500g are highly susceptible to infection and the subsequent development of diseases related to sustained inflammation. The scientific hypothesis underlying this application is that early microbiome establishment is critical for the long-term vulnerability of VLBWI. In a large VLBWI cohort, we propose that microbiome distortions (dysbiosis) precede the development of sepsis during the first 28 days of life, and that sepsis is a major risk factor for persistent dysbiosis. The primary objective of our proposal is to characterize the microbiome differences between preterm infants who develop sepsis and unaffected infants. We will evaluate whether microbiome “sepsis patterns” have an impact on multifactorial clinical outcomes in infancy (e.g. chronic pulmonary insufficiency of prematurity, CPIP) and on long-term health. Specific aims are: (1) To characterize the pre-event microbiome of infants developing sepsis as compared to unaffected infants with similar risk profile during the neonatal period (prediction of sepsis)(2) To determine the metabolome of preterm infants and to predict the metabolic capabilities of coexisting bacteria in the microbiome of sepsis patients as compared to unaffected infants in silico (3) To develop prognostic regression models for long-term clinical outcome (e.g. CPIP) including early life microbiome/metabolome patterns We will synergistically use the infrastructure of population-based studies initiated by the University of Lübeck Children´s Hospital, i.e. the Immunoregulation of the Newborn (IRoN) study which investigates the immunological aspects of the delicate immune-microbiome interaction in preterm infants. To address aim 1, we will prospectively evaluate the gut microbiome of exposed infants [day 1-28 of life]. Comparative microbiome analysis between sepsis patients and unaffected infants will be performed by 16S rRNA, whiole genome and deep metagenomic sequencing. To address aim 2, we will determine stool and urine metabolites by NMR spectroscopy for preterm infants with sepsis as compared to unaffected controls. Using a systems biology approach we will complement the microbiome/metabolome results by the in silico construction of functional metabolic models that allow the prediction of complex community traits (metabolite exchange of coexisting bacteria). All data will be integrated in a computational framework to specify “sepsis” and “resilience” patterns. These patterns will be evaluated for their sustainability throughout infancy and incorporated in multivariate prognostic regression models to predict their impact on long-term health (aim 3). We perform detailed phenotyping of preterm infants during childhood and specifically focus on parameters of growth and respiratory function, since the prevalence of CPIP is high in VLBWI (~30%). Thereby we will build on an existing infrastructure which has the potential to follow these vulnerable infants lifelong.

• DFG Programme: Research Grants