Synbiotic supplementation leads to gut microbiome communities with functional capacity linked to better brain white matter development in preterm infants.

Preterm birth, a major cause of brain injury, is often linked to dysregulated gut microbiome development. This association underscores microbial metabolic function as a modifiable target to support neurodevelopment. In this secondary analysis of data derived from a randomized controlled trial (Trial Registration: ISRCTN96620855), we tested whether daily nutritional supplementation with Bifidobacterium breve M-16V, short- and long-chain oligosaccharides, and L-glutamine could steer the gut microbiome of very and extremely preterm infants toward communities that support brain maturation. The gut microbiome was profiled with longitudinal shotgun metagenomics at nine time points during the intervention, which started at 48-72 h after birth and continued until 36 weeks postmenstrual age. Additionally, MRI scans were conducted when infants reached term-equivalent age to evaluate brain maturation. Supplementation promoted the early establishment of Bifidobacterium-rich communities in the test group, with enhanced capacity for amino acid biosynthesis and pyruvate fermentation towards acetate and lactate production. Integration of microbiome data with brain developmental markers post hoc showed that the same functions were markedly reduced in infants with delayed white-matter myelination. By integrating microbiome functional capacity profiling and evaluation of brain maturation via MRI, this study demonstrated that early microbial modulation could influence brain development, positioning the preterm gut microbiome as a clinically actionable target.