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.

Rethinking the Role of the Nervous System: Lessons From the Hydra Holobiont

“…[70,71] On the other hand, the microbiota of Hydra shows a remarkable dynamics during ontogenesis. [73,74] Finally, our recent data suggest that the transcriptional factor FoxO serves as an intracellular hubprotein, and controls both bacterial colonization and stem cell activity in Hydra. Strikingly, these shifts correlate with changes in the nerve cell density during the ontogeny of Hydra.…”

Necrotizing Enterocolitis, Gut Microbiota, and Brain Development: Role of the Brain-Gut Axis

“…Gut microbiota can elicit signals to the brain and vice versa via the vagal nerve system. SFCAs may have a direct effect on brain function and development [3, 58, 59]. …”

Connection between gut microbiome and brain development in preterm infants

“…To specifically study the impact of preterm infant dysbiosis on neuroinflammation, we used a fecal transfaunation model. We demonstrated that the microbiota of a preterm infant associated with a poor growth phenotype when transfaunated to germ‐free (GF) pregnant mice was associated with both systemic inflammation and neuroinflammation in the pups as evidenced by elevated pro‐inflammatory mediators including IL‐1β, TNF, and IFNγ in the circulation and increased NOS1 in the brain (Lu et al, ). Emerging studies using whole microbial communities associated with a phenotype instead of a single bacterial product, that is, a cytokine or a bacterial component, shed new light on how dysbiosis of the gut microbiota impacts neurological development, raising the possibility of whole microbiota manipulation as a therapeutic target.…”

“…One approach to model the early effects on newborn development is to colonize GF pregnant dams with specific microbial communities and evaluate the offspring neurodevelopment. Using this model, we have demonstrated that maternal colonization with microbiota from a poor growth human infant resulted in altered neuronal development evidenced by decreased expression of the neuronal development marker NeuN and an altered myelination process evidenced by reduced expression of the myelination marker myelin basic protein at both preweaned and immediate postweaned ages of the offspring (Lu et al, ). The preterm infant microbiota effects on brain development were mediated by local and systemic IGF‐1 levels and neuroinflammation.…”

“…To specifically study the impact of preterm infant dysbiosis on neuroinflammation, we used a fecal transfaunation model. We demonstrated that the microbiota of a preterm infant associated with a poor growth phenotype when transfaunated to germ-free (GF) pregnant mice was associated with both systemic inflammation and neuroinflammation in the pups as evidenced by elevated pro-inflammatory mediators including IL-1β, TNF, and IFNγ in the circulation and increased NOS1 in the brain (Lu et al, 2018(Lu et al, , 2015.…”