Gut-derived metabolites influence neurodevelopmental gene expression and Wnt signaling events in a germ-free zebrafish model

Abstract Background Small molecule metabolites produced by the microbiome are known to be neuroactive and are capable of directly impacting the brain and central nervous system, yet there is little data on the contribution of these metabolites to the earliest stages of neural development and neural gene expression. Here, we explore the impact of deriving zebrafish embryos in the absence of microbes on early neural development as well as investigate whether any potential changes can be rescued with treatment of metabolites derived from the zebrafish gut microbiota. Results Overall, we did not observe any gross morphological changes between treatments but did observe a significant decrease in neural gene expression in embryos raised germ-free, which was rescued with the addition of zebrafish metabolites. Specifically, we identified 354 genes significantly downregulated in germ-free embryos compared to conventionally raised embryos via RNA-Seq analysis. Of these, 42 were rescued with a single treatment of zebrafish gut-derived metabolites to germ-free embryos. Gene ontology analysis revealed that these genes are involved in prominent neurodevelopmental pathways including transcriptional regulation and Wnt signaling. Consistent with the ontology analysis, we found alterations in the development of Wnt dependent events which was rescued in the germ-free embryos treated with metabolites. Conclusions These findings demonstrate that gut-derived metabolites are in part responsible for regulating critical signaling pathways in the brain, especially during neural development.