Maternal regulation of biliary disease in neonates via gut microbial metabolites. Biliary atresia and gut environment

Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life is unknown. Based on the enrichment of butyrate-producing bacteria in newborn mice with biliary injury that phenocopies human biliary atresia, we hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to the disease. Butyrate administration to mothers rendered newborn offspring resistant to rotavirus-induced biliary injury and improved survival. The survival trait was linked to shared fecal microbial signatures in mice and in human infants with biliary atresia, and with fecal metabolomic enrichment by butyrate and glutamine. When administered to rotavirus-infected newborn mice or added to lymphocyte and epithelial cell culture, butyrate and glutamine suppressed activated lymphocytes independently, with glutamine also programming resistance of epithelial cells to natural killer cell-induced lysis. Thus, maternal influence on fecal metabolite composition in offspring modulates tissue injury and disease expression in newborns.