The maternal microbiome modulates fetal neurodevelopment in mice

Abstract

Summary “Dysbiosis” of the maternal gut microbiome, in response to challenges such as infection 1 , altered diet 2 and stress 3 during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior 4 . However, whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenge is poorly understood. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit reduced expression of genes related to axonogenesis, deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic factors. Gnotobiotic colonization of microbiota-depleted dams with a limited consortium of bacteria prevents abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling reveals that the maternal microbiota regulates numerous small molecules in the maternal serum and brains of fetal offspring. Select microbiota-dependent metabolites promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites abrogates deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yields adult offspring with altered tactile sensitivity in two aversive somatosensory behavioral tasks, with no overt differences in many other sensorimotor behaviors. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology

“…Within the first three months of life in humans, its size increases more than 50% from the time of birth, reaching 90% of the size of the adult organ within the first five years of life (72). In this period, neuronal development takes place (73) and it is supported and shaped by maternal microbiota (74)(75)(76)(77)(78)(79).…”

Metabolomic signature of the maternal microbiota in the fetus

“…A recent study indicates that TMAO, and possibly also 5-AVAB, have a role in development of the fetal brain (Vuong et al, 2020). More than twofold reduction of TMAO and 5-AVAB was detected in the maternal blood and fetal brain of both GF and antibiotic-treated pregnant mice relative to SPF controls.…”

“…The cord plasma of pre-eclamptic infants has been shown to contain increased levels of 5-AVAB (Jääskeläinen et al, 2018;Jääskeläinen et al, 2020). 5-AVAB has also been detected in the fetal mouse brain, with levels strongly dependent on the presence of maternal gut microbiota (Vuong et al, 2020).…”

“…Colonization of GF dams with ingenious spore-forming bacteria increased the levels of these compounds in the fetal brain. The maternal microbiota was shown to promote fetal thalamocortical axonogenesis, and the effect could be reproduced by supplementing microbiota-depleted dams with TMAO (Vuong et al, 2020).…”

Priming for Life: Early Life Nutrition and the Microbiota-Gut-Brain Axis

“…Researchers who analysed meconium (the first faecal sample of the new-born) found low amounts of viable bacteria present but confirmed that the main bacterial colonization of the gut happens at the time of birth [ 105 ]. Even though it is difficult to assess the ‘in utero sterility hypothesis’ due to possibility of external contamination of samples, it is believed that microbes and their metabolites in the maternal intestines influence in utero CNS development and function [ 106 ].…”