Mapping intestinal host-microbiota communications at birth, and their potential immunological impact

The interactions between the gut microbiota and the immune system at birth influence long-term immunological development and the long-term risk of asthma, allergies, and other inflammatory diseases. One of the major factors that determine neonatal gut microbiota composition is delivery mode, and numerous studies have demonstrated dysbiotic microbiome composition in cesarean-section (CS)-born infants. Here, we aim to understand how intestinal colonization by microbiota at birth shapes the immune system and impacts health and disease throughout life. Moreover, we aim to determine whether delivery mode-related alterations to neonatal microbiota composition in humans disrupt early-life intestinal responses, and to identify the molecular mechanisms that control disease susceptibility throughout life. To address these aims, we developed an intestinal gut organ culture system for the murine embryonic gut. Intestinal tissues were dissected from E19 mice embryos (fully developed, yet still germ-free) and were colonized on-a-chip with microbiota collected from human babies, born by vaginal or CS delivery. We found that ex-vivo colonization of the embryonic gut elicits rapid and distinct transcriptional responses to the microbiota, that display birth mode-specific features. i.e., CS-derived microbiota, but not vaginal birth-derived microbiota, induced colonic proinflammatory gene expression. We further identified specific bacterial strains that mediate the effects induced by whole-microbiota colonization. Collectively, we suggest that birth-mode related differences in microbiota composition trigger distinct intestinal responses at birth, which potentially mediate long-term immunological development and diseases susceptibility.