| Autor: |
Vuong HE; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA. hvuong2323@gmail.com., Pronovost GN; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Williams DW; Oral Immunity and Inflammation Section, NIDCR, NIH, Bethesda, MD, USA., Coley EJL; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Siegler EL; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Qiu A; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Kazantsev M; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Wilson CJ; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Rendon T; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Hsiao EY; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA. |
| Abstrakt: |
'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 brain function and behaviour of the offspring 4 . However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. 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 exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain. |
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