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CORDIS

Gut epithelial dynamics and function at the nexus of early life infection and long-term health

Project description

Investigating the role of postnatal epithelial cells in human health after early pathogen exposure

The enteric microbiota, the mucosal immune system and the epithelial barrier are the factors that establish intestinal host–microbe homeostasis after birth. The mucosal immune system and the establishment of the enteric microbiota have been extensively studied in contrast to the postnatal evolvement of epithelial cells. The EU-funded EarlyLife project aims to generate a comprehensive map of postnatal epithelial cell type differentiation and investigate the impact of early life infection by important human bacterial, viral and parasitic pathogens on long-term immune-mediated, inflammatory and metabolic diseases. These long-term effects will be functionally studied using epigenetic and transcriptomic profiling, microbiota-transfer experiments and human stem cell organoid cultures in combination with in vivo genetic models.

Objective

Infections of the gastrointestinal tract and their long-term consequences remain a major cause of childhood mortality and morbidity worldwide. In addition, early life is recognized as a critical and non-redundant time period to prime the mucosal tissue and establish the enteric microbiota that determine the risk to develop prevalent inflammatory, immune-mediated, and metabolic diseases. Three factors: the enteric microbiota, the mucosal immune system and the epithelial barrier cooperate to establish intestinal host-microbial homeostasis after birth. Maturation of the mucosal immune system and establishment of the enteric microbiota have been extensively studied. In contrast, postnatal evolvement of epithelial cell type heterogeneity and functional specialization and the influence of enteric infection on this process have not been explored. With EarlyLife, I propose to further advance innovative, multiscale technical approaches and analytical protocols in combination with novel in vivo models to generate the first comprehensive map of postnatal epithelial cell type and subtype differentiation and analyze the impact of early life infection by important human bacterial, viral and parasitic pathogens. Long-term inflammatory, immune-mediated and metabolic effects will be functionally studied using epigenetic profiling, microbiota-transfer experiments, stem cell organoid culture and co-culture, as well as genetic models. Identified mechanisms will be confirmed using single-cell analysis of human mucosal biopsies, human stem cell organoids and transcriptomic profiling of human fecal samples. As a result, I expect to identify mechanisms of enhanced infection susceptibility of the neonate, decipher the critical and non-redundant influence of the postnatal period for mucosal homeostasis and explain the role of early life imprinting for long-term immune-mediated, inflammatory and metabolic diseases.

Host institution

UNIVERSITAETSKLINIKUM AACHEN
Net EU contribution
€ 2 450 000,00
Address
Pauwelsstrasse 30
52074 Aachen
Germany

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Region
Nordrhein-Westfalen Köln Städteregion Aachen
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 2 450 000,00

Beneficiaries (1)