Intestinal Commensal Bacteria Promote At2 Self-Renewal And At1 Differentiation In An Il-22 Dependent Fashion And Prepare The Newborn To Fight Potentially Fatal Respiratory Pathogens

Abstract We demonstrated that disruption of intestinal commensal bacteria with antibiotics (ABX) severely diminished the levels of cytokine interleukin (IL)-22 in the newborn lung and rendered the ABX-exposed newborn mice susceptible post challenge with Streptococcus pneumoniae (S. pneumoniae). These experimental data suggest that colonization by intestinal commensal bacteria is vital for newborn’s lung defense against respiratory pathogens. Pregnant mouse dams were treated with ABX, and newborn mice were challenged with intratracheal S. pneumoniae (on postnatal day 5). Lungs were harvested and stained. AT2 cells and fibroblast harvested from ABX-treated or ABX-free newborn mice were cultured in matrigel to generate alveolar organoids. After harvest, the organoids were stained. To test the role of IL-22 signaling, Il22rafl/fl mice were bred with SftpcCreERT2 mice. The progeny was treated with tamoxifen and then challenged with S. pneumoniae. We found increased alveolar injury, loss of AT1 cells and reduced the frequency of proliferating AT2 cells in ABX-treated newborn mice compared to ABX-free newborn mice post-challenge with S. pneumoniae. Reconstitution of intestinal commensal bacteria or treatment with recombinant IL-22 restored the numbers of proliferating AT2 cells, reduced the injury score, and improved survival in ABX-treated newborn mice. Organoids derived ABX-exposed newborns demonstrated reduced growth and diminished AT1 differentiation. Using a developmentally appropriate and clinically relevant model, we report that intestinal commensal bacteria promote AT2 self-renewal and AT1 differentiation in an IL-22 dependent fashion, thus preparing the newborn to fight potentially fatal respiratory pathogens.