The quality of a pregnant mother's intestinal gut bacteria (microbiome) may have a major impact on the quality of her child's brain and immune system during development. The study was conducted using a mouse model comparing offspring development in pregnant mice (given antibiotics to generate a germ-free microbiome) to mice with an intact microbiome. Metabolites produced by beneficial bacteria in a healthy mouse microbiome were shown to activate critical genes related to immune system and brain development. Beneficial microbiome metabolites also improved placental growth and blood vessel development. Of interest, other studies have shown that mothers of autistic children have placentas of inferior quality. Genes involved in synaptic development were also downregulated in germ-free mice. Offspring of germ-free mice also had increased blood-brain barrier permeability.
ABSTRACT
Background
The maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. To investigate the developmental impacts of maternal microbial metabolites, we compared full-term fetuses from germ-free and specific pathogen-free mouse dams by gene expression profiling and non-targeted metabolomics.
Results
In the fetal intestine, critical genes mediating host-microbe interactions, innate immunity, and epithelial barrier were differentially expressed. Interferon and inflammatory signaling genes were downregulated in the intestines and brains of the fetuses from germ-free dams. The expression of genes related to neural system development and function, translation and RNA metabolism, and regulation of energy metabolism were significantly affected. The gene coding for the insulin-degrading enzyme (Ide) was most significantly downregulated in all tissues. In the placenta, genes coding for prolactin and other essential regulators of pregnancy were downregulated in germ-free dams. These impacts on gene expression were strongly associated with microbially modulated metabolite concentrations in the fetal tissues. Aryl sulfates and other aryl hydrocarbon receptor ligands, the trimethylated compounds TMAO and 5-AVAB, Glu-Trp and other dipeptides, fatty acid derivatives, and the tRNA nucleobase queuine were among the compounds strongly associated with gene expression differences. A sex difference was observed in the fetal responses to maternal microbial status: more genes were differentially regulated in male fetuses than in females.
Conclusions
The maternal microbiota has a major impact on the developing fetus, with male fetuses potentially more susceptible to microbial modulation. The expression of genes important for the immune system, neurophysiology, translation, and energy metabolism are strongly affected by the maternal microbial status already before birth. These impacts are associated with microbially modulated metabolites. We identified several microbial metabolites that have not been previously observed in this context. Many of the potentially important metabolites remain to be identified.