A Neonatal anaerobic Gut-microbiome-on-a-Chip to decode bacterial colonization and infant gut T cell maturation

Descrizione del progetto

Modello su chip dell’intestino, del microbioma e delle cellule immunitarie dei neonati

Il microbioma intestinale influisce su diversi sistemi organici e svolge un ruolo importante in malattie e disturbi che vanno dai disturbi metabolici alle malattie cardiovascolari e all’Alzheimer. I meccanismi della simbiosi tra ospite e microbioma durante i primi 1000 giorni di vita, essenziali per la salute nel corso dell’intera esistenza, sono ancora poco conosciuti. Il progetto NeoGutChip, finanziato dal CER, mira a cambiare questa situazione sviluppando il primo modello in vitro di microbioma intestinale umano infantile su chip (iGuMI) che riproduce l’ambiente intestinale del neonato. L’iGuMI consentirà uno studio approfondito del microbioma intestinale, della barriera mucosa e delle interazioni delle cellule immunitarie. Insieme all’identificazione dei geni sottostanti, NeoGutChip fornirà informazioni sulla modulazione immunitaria specifica dei batteri nella prima infanzia e indicherà gli interventi necessari per promuovere la funzione immunitaria nei neonati.

Obiettivo

Developing a healthy host-microbiome symbiosis during the first 1000 days of human life is critical for lifelong health. Despite its importance, our understanding is limited and derives from animal studies or associative human trials. Therefore, there is a pressing need for an infant gut model to capture dynamic microbiome-epithelium-immune interactions in early life. In NeoGutChip I will develop and validate a first-of-its-kind in vitro human Infant Gut-Microbiome-Immune-on-a-chip model (iGuMI) that will faithfully simulate the complex anaerobic environment of the infant gut, which current models cannot achieve. I will capitalize on my cutting-edge GuMI and microbiome engineering experience, to ensure that iGuMI is microbiota- and immune-competent. I will use iGuMI to determine the impact of dietary and microbial factors (especially early bacterial colonizers) on the development and maturation of infant gut microbiota, the mucosal barrier, and immune cells, and unravel the keystone bacterial species and key genes driving these effects. I will realize these objectives through autologous coculture of infant colonic organoids derived epithelium and naïve immune cells in iGuMI. Using bacterial colonization and long-term coculture in iGuMI, I will identify a set of infant gut species driving the immune maturation, and key bacterial genes through RNA sequencing, metabolomics, and loss-of-function assays. Finally, I will investigate mechanism-guided intervention of the microbiota-immune axis in iGuMI to promote anti-inflammatory T cells and mucosal barrier function in infant gut. The successful completion of NeoGutChip will decode the strain-by-strain view of immune modulation by infant gut microbiota in early life and offer a molecular basis to rationally “design” new interventions that directionally promote immune health in babies. Finally, iGuMI can be further developed into a preclinical tool, representing a breakthrough for pediatric biology and medicine.