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

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.