Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection.

Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs. [Display omitted] • The milk microbiota of high-fiber diet-fed dams increases infant gut propionate levels • Propionate induces intestinal epithelial cell expression of Flt3L, a DC growth factor • Gut-derived Flt3L promotes DC hematopoiesis in the bone marrow in early life • pDCs confer protection against severe respiratory infection via Treg cell expansion Maternal diet influences infant susceptibility to severe lower respiratory infection, the leading cause of childhood mortality. Sikder et al. demonstrate that a high-fiber diet promotes microbiota that transiently induce Flt3L in the infant gut. Intestinal Flt3L drives neonatal dendritic cell hematopoiesis, subsequent Treg expansion, and disease resistance in early life. [ABSTRACT FROM AUTHOR]