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.

Alterations in the brain-gut system have been implicated in various disease states, but little is known about how early-life adversity (ELA) impacts development and adult health as mediated by brain-gut interactions. We hypothesize that ELA disrupts components of the brain-gut system, thereby increasing susceptibility to disordered mood. In a sample of 128 healthy adult participants, a history of ELA and current stress, depression, and anxiety were assessed using validated questionnaires. Fecal metabolites were measured using liquid chromatography tandem mass spectrometry-based untargeted metabolomic profiling. Functional brain connectivity was evaluated by magnetic resonance imaging. Sparse partial least squares-discriminant analysis, controlling for sex, body mass index, age, and diet was used to predict brain-gut alterations as a function of ELA. ELA was correlated with four gut-regulated metabolites within the glutamate pathway (5-oxoproline, malate, urate, and glutamate gamma methyl ester) and alterations in functional brain connectivity within primarily sensorimotor, salience, and central executive networks. Integrated analyses revealed significant associations between these metabolites, functional brain connectivity, and scores for perceived stress, anxiety, and depression. This study reveals a novel association between a history of ELA, alterations in the brain-gut axis, and increased vulnerability to negative mood and stress. Results from the study raise the hypothesis that select gut-regulated metabolites may contribute to the adverse effects of critical period stress on neural development via pathways related to glutamatergic excitotoxicity and oxidative stress.

Early life stress (ELS) is a potent developmental disruptor and increases the risk for psychopathology. Various forms of ELS have been studied in both humans and rodents, and have been implicated in altered DNA methylation, gene transcription, stress hormone levels, and behavior. Although recent studies have focused on stress-induced epigenetic changes, the extent to which ELS alters HPA axis function and stress responsivity across generations, whether these effects are sex-specific, and how lineage interacts with upbringing to impact these effects, remain unclear. To address these points, two generations of rodents were utilized, with the first generation subjected to ELS via maternal separation, and the second to a balanced cross-fostering paradigm. We hypothesized that ELS would disrupt normative development in both generations, manifesting as altered methylation and expression of genes associated with stress signaling pathways (Nr3c1, Nr3c2, and Bdnf), blunted corticosterone (CORT), and anxiety-like behaviors. Additionally, we expected deficits in the second generation to be modulated by caretaking environment and for the pattern of results to differ between the sexes. Results suggest that direct exposure to ELS leads to sex-specific effects on gene regulation and HPA functioning in adulthood, with maternal separation leading to increases in Bdnf methylation in both sexes, decreases in Bdnf expression in females, and decreases in Nr3c1 methylation in males, as well as blunted CORT and less anxiety-like behavior in females. These alterations converged with caretaking to impart perturbations upon the subsequent generation. Across sex, ELS lineage led to decreased methylation of Nr3c1, and increased methylation of Bdnf. In fostered animals, upbringing by a previously stressed mother interacted with offspring lineage to impact methylation of Nr3c1 and Bdnf. Upbringing was also implicated in altered anxiety-like behavior in males, and baseline CORT levels in females. Such effects may correspond with observed alterations in maternal behavior across groups. In conclusion, ELS conferred enduring sex-specific alterations, both first-hand and trans -generationally via lineage and upbringing. Importantly, lineage of cross-fostered pups was sufficient to normalize or disturb maternal behavior of foster-dams, an observation requiring further elucidation. These results have implications for multi-generational effects of ELS in humans and may motivate early interventions.

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