Effects of Intestinal Microbiota on Brain Development in Humanized Gnotobiotic Mice

Abstract

Poor growth in the Neonatal Intensive Care Unit is associated with an increased risk for poor neurodevelopmental outcomes for preterm infants, however the mechanism is unclear. The microbiome has increasingly been recognized as a modifiable environmental factor to influence host development. Here we explore the hypothesis that the microbiome influences both growth phenotype and brain development. A germ free mouse transfaunation model was used to examine the effects of preterm infant microbiotas known to induce either high growth or low growth phenotypes on postnatal brain development. The microbiome which induced the low growth phenotype was associated with decreases in the neuronal markers NeuN and neurofilament-L as well as the myelination marker MBP when compared to the microbiome associated with the high growth phenotype. Additionally, poor growth phenotype-associated microbiota was associated with increased neuroinflammation marked by increased Nos1, as well as alteration in IGF-1 pathway including decreased circulating and brain IGF-1, decreased circulating IGFBP3, and increased Igfbp3 brain mRNA expression. This study suggests that growth-associated microbiota can influence early neuron and oligodendrocyte development and that this effect may be mediated by effects on neuroinflammation and circulating IGF-1.