Summary “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 offspring brain function and behavior 4 . However, whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenge 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 reduced expression of genes related to axonogenesis, deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic factors. Gnotobiotic colonization of microbiota-depleted dams with a limited consortium of bacteria prevents abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling reveals that the maternal microbiota regulates numerous small molecules in the maternal serum and brains of fetal offspring. Select microbiota-dependent metabolites promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites abrogates deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yields adult offspring with altered tactile sensitivity in two aversive somatosensory behavioral tasks, with no overt differences in many other sensorimotor behaviors. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

The gut microbiota regulates levels of serotonin (5-hydroxytryptamine, 5-HT) in the intestinal epithelium and lumen 1-5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or by genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter (NSS)-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor, fluoxetine. 5-HT reduces expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally-colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Altogether, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The microbiome modulates host immune function across the gastrointestinal tract, peripheral lymphoid organs, and central nervous system. In this review, we highlight emerging evidence that microbial effects on select immune phenotypes arise developmentally, where the maternal and neonatal microbiome influence immune cell ontogeny in the offspring during gestation and early postnatal life. We further discuss roles for the perinatal microbiome and early-life immunity in regulating normal neurodevelopmental processes. In addition, we examine evidence that abnormalities in microbiota-neuroimmune interactions during early life are associated with altered risk of neurological disorders in humans. Finally, we conclude by evaluating the potential implications of microbiota-immune interventions for neurological conditions. Continued progress toward dissecting mechanistic interactions between the perinatal microbiota, immune system, and nervous system might uncover fundamental insights into how developmental interactions across physiological systems inform later-life health and disease.

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There is increasing evidence that the microbiome regulates host metabolism, but specific mechanisms underlying these interactions remain poorly understood. In a recent paper in Science, Wang et al. (2017) reveal that the gut microbiota regulates the expression of circadian-clock genes to impact host lipid metabolism and body composition.