ABSTRACT “Leaky gut”, or high intestinal barrier permeability, is common in preterm newborns. The role of microbiota in this process remains largely uncharacterized. We employed both short- and long-read sequencing of the 16S rRNA gene and metagenomes to characterize the intestinal microbiome of a longitudinal cohort of 113 preterm infants born between 24 0/7 -32 6/7 weeks of gestation. Enabled by enhanced taxonomic resolution, we found significantly increased abundance of Bifidobacterium breve and a diet rich in mother’s breastmilk to be associated with intestinal barrier maturation during the first week of life. We combined these factors using genome- resolved metagenomics and identified a highly specialized genetic capability of the Bifidobacterium strains to assimilate human milk oligosaccharides and host-derived glycoproteins. Our study proposed mechanistic roles of breastmilk feeding and intestinal microbial colonization in postnatal intestinal barrier maturation; these observations are critical towards advancing therapeutics to prevent and treat hyperpermeable gut- associated conditions, including necrotizing enterocolitis. IMPORTANCE Despite improvements in neonatal intensive care, necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality. “Leaky gut”, or intestinal barrier immaturity with elevated intestinal permeability, is the proximate cause of susceptibility to NEC. Early detection and intervention to prevent leaky gut in “at-risk” preterm neonates is critical to lower the risk for potentially life-threatening complications like NEC. However, the complex interactions between the developing gut microbial community, nutrition, and intestinal barrier function, remain largely uncharacterized. In this study, we revealed the critical role of sufficient breastmilk feeding volume and specialized carbohydrate metabolism capability of Bifidobacterium in coordinated postnatal improvement of intestinal barrier. Determining the clinical and microbial biomarkers that drive the intestinal developmental disparity will inform early detection and novel therapeutic strategies to promote appropriate intestinal barrier maturation, prevent NEC and other adverse health conditions in preterm infants.

Highly specialized carbohydrate metabolism capability in <i>Bifidobacterium</i> strain associated with intestinal barrier maturation in early preterm infants

Highly specialized carbohydrate metabolism capability in Bifidobacterium strain associated with intestinal barrier maturation in early preterm infants