Born in the twilight of antibiotics: Implications of antibiotic use to the preterm infant respiratory microbiome and resistome development

The antibiotic resistance crisis threatens human health and calls for urgent actions to secure the future from drug resistant infections. The overuse, misuse and even use of antibiotics stand as the main drivers of the global increase in antimicrobial resistance. The need to gain a better understanding of how microbes develop resistance is therefore of outmost importance. Not only major pathogens are members of the human microbiome in both health and disease, but also the human microbiome represents an important reservoir of antibiotic resistance genes. Despite its relevance, little is known about the landscape of resistance genes in humans, known as the human resistome, and the impact of antibiotics. In this project, we address the off-target impact of antibiotics on the human microbiome and resistome. Our aims are to (1) develop tools for the study of resistomes, (2) investigate the impact of antibiotics on the respiratory and gut microbiomes of infants in countries with different challenges regarding antimicrobial resistance, (3) examine the impact of early-life antibiotic exposure on immune protection against infections. The first aim has been addressed by creating ResistoXplorer, a web-tool that enables visual, statistical and analytical exploration of resistomes using comprehensive databases and analytical tools. We have also established a methodology for functional metagenomics analysis, and applied the technology for the identification of novel antibiotic resistance genes in the microbiome. The second aim is currently being addressed, and is based on serial samples and metadata from preterm infants born in India and in Norway, and that investigates the impact of antibiotics on the microbiome and resistome development of infants until 6-months of age. The third aim is based on an animal model, which so far has provided results showing that early-life exposure to antibiotics impact immune responses protective against pneumococcal respiratory infection. The project is a collaboration between UiO, LHMC & KSCH Hospitals and Tata Consultancy Services Ltd in New Delhi, the Norwegian Institute of Public Health, and the Oslo University Hospital in Norway.

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This project addresses the urgent need for improved evidence-based guidance for antibiotic use in preterm infants. Infants in this vulnerable group are highly exposed to antibiotic interventions during early life, and often for extended periods. While antibiotics have saved millions of lives, the worldwide rise in resistance leaves sad imprints in this group, with thousands dying during the first days of life due to resistance to antibiotics. In addition to resistance during this critical period of development, antibiotics promote microbiome disruptions that can have life-long consequences, including among other conditions, increased risk to respiratory infections. In this project we aim to gain insights into how the respiratory microbiome and the collection of resistance genes carried by the microbiome, the resistome, develop in preterm infants. Particular focus will be on the possible effect of antibiotic interventions on the development of microbiomes with enhanced pathogenic potential and antibiotic resistance. Moreover, using a mouse model of respiratory infection, we will investigate how different antibiotic treatment modalities may increase the risk of preterm infants to infections. The project is based on current collaborations between LHMC & KSCH hospitals in New Delhi and the OUS in Norway, and on ongoing collaborations between OUS, UoO and NIPH. The research team leading the project is represented by a distinctive combination of expertise in neonatology, paediatrics, infectious diseases, public health, and microbiology. The results are expected to provide information to better guide the rationale for antibiotic use in preterm infants.