Dataset Information

The Maternal Microbiome Programs the m⁶A Epitranscriptome of the Mouse Fetal Brain and Intestine.

ABSTRACT: The microbiome exerts profound effects on fetal development and health, yet the mechanisms underlying remain elusive. N6-methyladenosine (m⁶A) plays important roles in developmental regulation. Although it has been shown that the microbiome affects the mRNA m⁶A modification of the host, it remains unclear whether the maternal microbiome affects m⁶A epitranscriptome of the fetus so as to impact fetal development. Here, we found that loss of the maternal microbiome altered the expression of m⁶A writers and erasers, as well as the m⁶A methylome of the mouse fetal brain and intestine on embryonic day 18. From the m⁶A profiles, we identified 2,655 and 2,252 m⁶A modifications regulated by the maternal microbiome in the fetal brain and intestine, respectively, and we demonstrated that these m⁶A-modified genes were enriched in the neuro/intestinal developmental pathways, such as the Wnt signaling pathway. Finally, we verified that antibiotic treatment mostly recapitulated changes in m⁶A, and we further showed that the loss of heterozygosity of Mettl3 rescued m⁶A levels and the expression changes of some developmental genes in the fetal intestine that resulted from antibiotic treatment. Collectively, our data revealed that the maternal microbiome programs the m⁶A epitranscriptome of the mouse fetal brain and intestine.

SUBMITTER: Xiao Z

PROVIDER: S-EPMC9301011 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Maternal Microbiome Programs the m6A Epitranscriptome of the Mouse Fetal Brain and Intestine.

Xiao Zhuoyu Z Liu Sun S Li Zengguang Z Cui Jinru J Wang Hailan H Wang Zihan Z Ren Qihuan Q Xia Laixin L Wang Zhijian Z Li Yuan Y

Frontiers in cell and developmental biology 20220707

The microbiome exerts profound effects on fetal development and health, yet the mechanisms underlying remain elusive. N6-methyladenosine (m6A) plays important roles in developmental regulation. Although it has been shown that the microbiome affects the mRNA m6A modification of the host, it remains unclear whether the maternal microbiome affects m6A epitranscriptome of the fetus so as to impact fetal development. Here, we found that loss of the maternal microbiome ...[more]

PMID: 35874829

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Project description:BackgroundThe 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.ResultsIn 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.ConclusionsThe 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 which have not been previously observed in this context. Many of the potentially important metabolites remain to be identified.

Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development 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 widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

Dataset Information

The Maternal Microbiome Programs the m⁶A Epitranscriptome of the Mouse Fetal Brain and Intestine.

Publications

The Maternal Microbiome Programs the m<sup>6</sup>A Epitranscriptome of the Mouse Fetal Brain and Intestine.

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