Upon birth, the sterile gut of a newborn is colonized by microbiota, which are required for normal adolescent brain and immune system development [6]. These early colonizers are instrumental during development in educating the immune system, metabolizing nutrients, and influencing complex behaviors. One example of the impact of early colonization is illustrated by differences in cognitive scores between infants born via cesarean section and vaginally born children [6]. The lower scores of children born via cesarean section may result from differences in early gut colonization by microbes from the mother’s skin (caesarean) or vagina (natural birth), respectively [6]. Infants who have increased exposure to antibiotics have a greater risk of developing behavioral symptoms such as depression [1]. Further evidence of early-life influences comes from observations that formula feeding, which alters the microbiome, may be a risk factor for ASD [7], although considerable additional work in humans is needed to establish causality.

Prenatal stress can also affect microbiome composition after birth and is linked to increased risk of developmental disorders of the brain [2]. Stress induces distinct changes in the vaginal microbiome composition, so mothers who are under stress may transmit an imbalanced bacterial community to their offspring [2]. Stress responses can be measured by activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is one of the major routes of communication between the periphery and the brain. Male mouse pups born to stress-exposed dams exhibit increased stress, indicated by elevated levels of corticosterone in the serum and altered gene expression in the hypothalamus [2]. It is difficult to determine whether this phenotype results from prenatal effects or microbial colonization at birth. Jašarević et al. [2] showed that colonization of mice with untreated, control vaginal microbiota normalized, albeit partially, features such as body weight and corticosterone levels following acute stress in male offspring. The fact that these negative effects could not be reversed fully suggests that stress also affects the mouse pups before birth (i.e., prior to microbiome exposure). This idea is supported by transcriptomic data from the murine fetal intestine that reveals differential expression of genes implicated in innate immunity and inflammation based on prenatal stress-exposure in males [2]. Therefore, it is likely that environmental risk factors, such as prenatal stress, alter the intestinal niche of the fetus before microbes even colonize the gut and could select against beneficial microbes.

In theory, reduced prenatal stress should promote microbiome health and normal immune system development. When early-life perturbations such as cesarean section or treatment with antibiotics contribute to symptoms, colonizing newborns with missing or depleted microbes or with a complex microbiome from a verified healthy donor may provide benefits [8].