Milk osteopontin protects against infant bronchiolitis by enhancing microbiome-mediated extramedullary DC hematopoiesis

Breastfeeding reduces the risk of severe lower respiratory infections (sLRI), a leading cause of infant mortality however, the protective mechanisms remain elusive. Here we demonstrated that the absence of milk-derived osteopontin (OPN), highly expressed in colostrum, predisposes neonate mice to viral and bacterial sLRI, consequent to disrupted dendritic cell (DC) hematopoiesis in the liver and lung. Oral supplementation with bovine milk-derived OPN to neonates reared by OPN-deficient dams ameliorated disease susceptibility. This protection was associated with increased enteric Lactobacillales abundance and an altered metabolome, most notably elevated levels of 3-phenyllactic acid (PLA). OPN or PLA supplementation restored DC hematopoiesis and disease tolerance via the induction of hepatic stem cell factor (SCF) and airway Flt3L. These beneficial effects were attenuated by plasmacytoid DC depletion, immunoneutralization of SCF, or genetic deletion of airway epithelial Flt3L. Our findings identify a novel microbiome-host interaction by which milk OPN confers protection against sLRI.