Gut-immune-brain axis dysfunction in premature neonates

Extremely premature infants, which are born before the 28th week of gestation and weighing <1,000 grams, are a highly vulnerable patient group. They frequently experience early-life brain injury that can lead to life-long neurological impairments. Recent research suggests that the gut microbiome can affect the immune system and brain development. As the neonatal gut microbiota-immune-brain axis is important in both short- and long-term neurological diseases, it is a promising target for early-life therapeutic intervention. In order to achieve this, a deeper understanding of the interplay between the microbiome, the immune system, and the brain in early-life is urgently needed. This project aims to determine how dysfunction in the gut microbiota- immune-brain axis in extremely premature infants contributes to brain damage and long-term cognitive impairment. The molecular mechanisms underlying the etiology of these neurodevelopmental issues will be addressed in three project areas focused on the components of the axis: the gut microbiome, immune system, and brain. We will take a stepwise, bottom-up approach to test how the gut communicates with the brain using cutting-edge model systems. Promising leads will be integrated in pre-clinical models to test novel intervention strategies. Specifically, we will determine interactions in the microbiome and how the microbiome communicates with the immune system. We will also dissect how cell-cell interactions propagate gut-derived signals to drive neuronal inflammation, focusing on immune cells as central mediators of the axis. We will characterize intestinal events preceding systemic inflammation and will test the impact of microbial components and inflammatory cues on microglial activation and neuronal cell development and physiology. We will then examine how a dysfunctional axis impacts cognition in pre-clinical models and an established patient cohort. This project aims to make a major advance in the field by comprehensively investigating how the neonatal gut microbiome and its metabolites interact with the immune system and neurodevelopment. The project will provide fundamental insights into gut microbial ecology and immune- and neurodevelopment. It will contribute to novel translation-oriented strategies for early- life therapeutic interventions to improve the health of premature infants. Investigation of the neonatal gut microbiota-immune-brain axis requires a multidisciplinary team including pediatricians, microbiologists, immunologists, systems biologists, and cognitive neuroscientists. Our research team unifies these expertises, and includes: D. Berry (microbiology, University of Vienna), C. Campbell (host-microbe interactions and immunology, Centre for Molecular Medicine), I. Wagner (cognitive neuroscience, University of Vienna), B. Warth (systems biology and metabolomics, University of Vienna), and L. Wisgrill (immunology and neonatology, Medical University of Vienna).