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.
Highlights
Preterm infants, those born at less than 32-week of gestational and/or with a birth weight less than 1500 g, are at risk for adverse neurological outcomes including later cognitive and behavioral deficits[12,13]
Western blot analysis of cerebral cortex homogenates with anti-Neuronal nuclei (NeuN) antibody showed significantly increased levels of NeuN expression in MPRETERM INFANT-High (MPI-H) mice colonized with microbiota from a preterm infant with good growth compared with germ free (GF) pups at two weeks of age (Fig. 1A,B)
MPRETERM INFANT-Low (MPI-L) pups colonized with microbiota from a preterm donor with poor growth demonstrated significantly lower NeuN expression compared to MPI-H mice colonized with a preterm donor with a good growth at four weeks of age (Fig. 1C,D)
Summary
Those born at less than 32-week of gestational and/or with a birth weight less than 1500 g, are at risk for adverse neurological outcomes including later cognitive and behavioral deficits[12,13] These deficits are considered to be the consequence of complications associated with prematurity which impairs brain development[14]. We demonstrated that MPI-L mice had increased intestinal inflammation using nuclear factor-kappa beta (NF-κB) activation as a marker and by investigating production of NF-κB-mediated inflammatory cytokines at both the intestinal and serum level when compared to MPI-H mice These differences were seen at baseline, even without a secondary insult and demonstrated that the gut microbiota has local intestinal effects, and has systemic effects including inducing a systemic inflammatory response and influencing overall growth. Since IGF-1 regulates brain development and microbiota-mediated IGF-1 has been shown to regulate growth, we hypothesized that the two growth phenotype associated-microbiomes could regulate both somatic growth and brain development through IGF-1
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