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

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.